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Basic and Clinical Endocrinology 7th International student edition Edition

17

Pancreatic Hormones & Diabetes Mellitus

Umesh Masharani MRCD(UK)

John H. Karam MD

Michael S. German MD

  1. THE ENDOCRINE PANCREAS

The pancreas is made up of two functionally different organs: the exocrine pancreas, the major digestive gland of the body; and theendocrine pancreas, the source of insulin, glucagon, somatostatin, and pancreatic polypeptide. Whereas the major role of the products of the exocrine pancreas (the digestive enzymes) is the processing of ingested foodstuffs so that they become available for absorption, the hormones of the endocrine pancreas modulate every other aspect of cellular nutrition from rate of adsorption of foodstuffs to cellular storage or metabolism of nutrients. Dysfunction of the endocrine pancreas or abnormal responses to its hormones by target tissues result in serious disturbances in nutrient homeostasis, including the important clinical syndromes grouped under the name of diabetes mellitus.

ANATOMY & HISTOLOGY

The endocrine pancreas consists of 0.7–1 million small endocrine glands—the islets of Langerhans—scattered within the glandular substance of the exocrine pancreas. The islet volume comprises 1–1.5% of the total mass of the pancreas and weighs about 1–2 g in adult humans.

At least four cell types—A, B, D, and PP (also called β, β, δ, and F)—have been identified in the islets (Table 17-1). These cell types are not distributed uniformly throughout the pancreas. The PP cell, which secretes pancreatic polypeptide (PP), has been found primarily in islets in the posterior portion (posterior lobe) of the head, a discrete lobe of the pancreas separated from the anterior portion by a fascial partition. This lobe originates in the primordial ventral bud as opposed to the dorsal bud. The posterior lobe receives its blood supply from the superior mesenteric artery; the remainder of the pancreas derives most of its blood flow from the celiac artery.

Table 17-1. Cell types in pancreatic islets of Langerhans.

Cell types

Approximate Percentage of Islet Volume

Secretory Products

Dorsally Derived (Anterior Head, Body, Tail)

Ventrally Derived (Posterior Portion of Head)

A cell (α)

10%

< 0.5%

Glucagon, proglucagon, glucagon-like peptides (GLP-1 and GLP-2)

B cell (β)

70–80%

15–20%

Insulin, C peptide, proinsulin, amylin, γ-aminobutyric acid (GABA)

D cell (δ)

3–5%

< 1%

Somatostatin

PP cell (F cell)

< 2%

80–85%

Pancreatic polypeptide

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Islets in the posterior lobe area consist of 80–85% F cells, 15–20% B cells, and less than 0.5% glucagon-producing A cells. The PP cell volume varies with age and sex—the volume tends to be larger in men and in older persons. In contrast to the posterior lobe, the PP-poor islets located in the tail, body, and anterior portion of the head of the pancreas, arising from the embryonic dorsal bud, contain predominantly insulin-secreting B cells (70–80% of the islet cells), with approximately 20% of the cells being glucagon-secreting A cells and about 3–5% D cells that produce somatostatin. A typical islet from this part of the pancreas is depicted in Figure 17-1.

 

Figure 17-1. Photomicrograph of a section of the pancreas. In the islet of Langerhans, A cells appear mainly in the periphery as large cells with dark cytoplasm. Some D cells are also present in the periphery, while the central core is composed chiefly of B cells. (Reproduced, with permission, from Junqueira LC, Carneiro J, Long JA: Basic Histology, 7th ed. McGraw-Hill, 1992.)

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Islet Vascularization

The islets are richly vascularized, receiving five to ten times the blood flow of a comparable portion of exocrine pancreatic tissues. The direction of the blood flow within the islet has been postulated to play a role in carrying insulin secreted from the central region of an islet to its peripheral zone—where the insulin modulates and decreases glucagon release from A cells, which are mainly located in the periphery of islets.

HORMONES OF THE ENDOCRINE PANCREAS

  1. Insulin

Biosynthesis

The human insulin gene is located on the short arm of chromosome 11. A precursor molecule, preproinsulin, a peptide of MW 11,500, is translated from the preproinsulin messenger RNA in the rough endoplasmic reticulum of pancreatic B cells (Figure 17-2). Microsomal enzymes cleave preproinsulin to proinsulin (MW about 9000) almost immediately after synthesis. Proinsulin (Figure 17-3) is transported to the Golgi apparatus, where packaging into clathrin-coated secretory granules takes place. Maturation of the secretory granule is associated with loss of the clathrin coating and conversion of proinsulin into insulin and a smaller connecting peptide, or C peptide, by proteolytic cleavage at two sites along the peptide chain. Normal mature (uncoated) secretory granules contain insulin and C peptide in equimolar amounts and only small quantities of proinsulin, a small portion of which consists of partially cleaved intermediates.

Biochemistry

Proinsulin (Figure 17-3) consists of a single chain of 86 amino acids, which includes the A and B chains of the insulin molecule plus a connecting segment of 35 amino acids. Two proteins—the prohormone-converting enzymes PC1/3 and PC2—are packaged with proinsulin in the immature secretory granules. These enzymes recognize

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and cut at pairs of basic amino acids, thereby removing the intervening sequence. After the two pairs of basic amino acids are removed by carboxypeptidase E, the result is a 51-amino-acid insulin molecule and a 31-amino-acid residue, the C peptide, as shown in Figure 17-3.

 

Figure 17-2. Structural components of the pancreatic B cell involved in glucose-induced biosynthesis and release. Schematic representation of secretory granular alignment on microfilament “tracks” that contract in response to calcium. (Based on data presented by Orci L: A portrait of the pancreatic B cell. Diabetologia 1974;10:163.) (Modified and reproduced, with permission, from Junqueira LC, Carneiro J, Long JA: Basic Histology, 5th ed. McGraw-Hill, 1986.)

A small amount of proinsulin produced by the pancreas escapes cleavage and is secreted intact into the bloodstream, along with insulin and C peptide. Most anti-insulin sera used in the standard immunoassay for insulin cross-react with proinsulin; about 3–5% of immunoreactive insulin extracted from human pancreas is actually proinsulin. Because proinsulin is not removed by the liver, it has a half-life three to four times that of insulin. This allows proinsulin to accumulate in the blood, where it accounts for 12–20% of the circulating immunoreactive “insulin” in the basal state in humans. Human proinsulin has about 7–8% of the biologic activity of insulin. The kidney is the principal site of proinsulin degradation.

 

Figure 17-3. Structure of human proinsulin C peptides and insulin molecules connected at two sites by dipeptide links.

Of the two major split proinsulin products present in plasma, the one split at arginine 32–33 far exceeds in amount the barely detectable 65–66 split product. In control subjects, concentrations of proinsulin and 32–33 split proinsulin after an overnight fast averaged 2.3 and 2.2 pmol/L, respectively, with corresponding postprandial rises to 10 and 20 pmol/L.

C peptide, the 31-amino-acid residue (MW 3000) formed during cleavage of insulin from proinsulin, has no known biologic activity. It is released from the B cells in equimolar amounts with insulin. It is not removed by the liver but is degraded or excreted chiefly by the kidney. It has a half-life three to four times that of insulin. In the basal state after an overnight fast, the average concentration of C peptide may be as high as 1000 pmol/L.

Insulin is a protein consisting of 51 amino acids contained within two peptide chains: an A chain, with 21 amino acids; and a B chain, with 30 amino acids. The chains are connected by two disulfide bridges as shown in Figure 17-3. In addition, there is an intrachain disulfide bridge that links positions 6 and 11 in the A chain. The molecular weight of human insulin is 5808.

Human insulin differs only slightly in amino acid composition from the two mammalian insulins that have been used for therapeutic insulin replacement. Pork insulin differs from human by only one amino

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acid—alanine instead of threonine at the carboxyl terminus of the B chain (position B 30). Beef insulin differs by three amino acids—alanine instead of threonine at A 8 as well as the B 30 position and valine instead of isoleucine at A 10.

Endogenous insulin has a circulatory half-life of 3–5 minutes. It is catabolized chiefly by insulinases in liver, kidney, and placenta. Approximately 50% of insulin is removed in a single pass through the liver.

Secretion

The human pancreas secretes about 40–50 units of insulin per day in normal adults. The basal concentration of insulin in the blood of fasting humans averages 10 ľU/mL (0.4 ng/mL, or 61 pmol/L). In normal control subjects, insulin seldom rises above 100 ľU/mL (610 pmol/L) after standard meals. There is an increase in peripheral insulin concentration beginning 8–10 minutes after ingestion of food and reaching peak concentration in peripheral blood by 30–45 minutes. This is followed by a rapid decline in postprandial plasma glucose concentration, which returns to baseline values by 90–120 minutes.

Basal insulin secretion, which occurs in the absence of exogenous stimuli, is the quantity of insulin secreted in the fasting state. Although it is known that plasma glucose levels below 80–100 mg/dL (4.4–5.6 mmol/L) do not stimulate insulin release, it has also been demonstrated that the presence of glucose is necessary (in in vitro systems) for most other known regulators of insulin secretion to be effective.

Stimulated insulin secretion is that which occurs in response to exogenous stimuli. In vivo, this is the response of the B cell to ingested meals. Glucose is the most potent stimulant of insulin release. The perfused rat pancreas has demonstrated a biphasic release of insulin in response to glucose (Figure 17-4). When the glucose concentration in the system is increased suddenly, an initial short-lived burst of insulin release occurs (the first phase); if the glucose concentration is held at this level, the insulin release gradually falls off and then begins to rise again to a steady level (the second phase). However, sustained levels of high glucose stimulation (≥ 4 hours in vitro or > 24 hours in vivo) results in a reversible desensitization of the B cell response to glucose but not to other stimuli.

Glucose is known to enter the pancreatic B cell by passive diffusion, which is facilitated by a specific membrane protein termed glucose transporters. Because the transporters function in both directions and the B cell has an excess of glucose transporters, the glucose concentration

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inside the B cell is in equilibrium with the extracellular glucose concentration. There is a body of data suggesting that metabolism of glucose is essential in stimulating insulin release. Indeed, agents such as 2-deoxyglucose that inhibit the metabolism of glucose interfere with release of insulin. The rate-limiting step in glucose metabolism by the pancreatic B cell appears to be the phosphorylation of glucose by the low-affinity enzyme glucokinase. The catabolism of glucose in the B cell results in a rise in the intracellular ATP/ADP ratio. This rise causes the ATP-sensitive potassium channels on the surface of the B cell to close, thereby depolarizing the cell and activating the voltage-sensitive calcium channel.

 

Figure 17-4. Multiphasic response of the in vitro perfused pancreas during constant stimulation with glucose. (Modified from Grodsky GM et al: Further studies on the dynamic aspects of insulin release in vitro with evidence for a two-compartmental storage system. Acta Diabetol Lat 1969;6[Suppl 1]:554.)

Insulin release has been shown to require calcium. The following effects of glucose on calcium ion movement have been demonstrated: (1) Calcium uptake is increased by glucose stimulation of the B cell. (2) Calcium efflux from the cell is retarded by some action of glucose. (3) Mobilization of calcium from mitochondrial compartments occurs secondary to cAMP induction by glucose.

cAMP is another important modulator of insulin release. As mentioned above, glucose has been shown to directly induce cAMP formation. Furthermore, many nonglucose stimuli to insulin release are known to increase intracellular cAMP. Elevations of cAMP, however, will not stimulate insulin release in the absence of glucose.

Other factors involved in the regulation of insulin secretion are summarized in Table 17-2. These factors can be divided into three categories: direct stimulants, which are known to stimulate insulin release directly; amplifiers, which appear to potentiate the response of the B cell to glucose; and inhibitors. The action of the amplifier substances, many of which are gastrointestinal hormones stimulated by ingestion of meals, explains the observation that insulin response to an ingested meal is greater than the response to intravenously administered substrates.

Table 17-2. Regulation of insulin release in humans.

Stimulants of insulin release
   Glucose, mannose
   Leucine
   Vagal stimulation
   Sulfonylureas
Amplifiers of glucose-induced insulin release

1. Enteric hormones:
   Glucagon-like peptide I (7–37)
   Gastric inhibitory peptide
   Cholecystokinin
   Secretin, gastrin

2. Neural amplifiers: beta-adrenergic stimulation

3. Amino acids: arginine

Inhibitors of insulin release
   Neural: alpha-adrenergic effect of catecholamines
   Humoral: somatostatin
   Drugs: diazoxide, phenytoin, vinblastine, colchicine

Insulin Receptors & Insulin Action

Insulin action begins with binding of insulin to a receptor on the surface of the target cell membrane. Most cells of the body have specific cell surface insulin receptors. In fat, liver, and muscle cells, binding of insulin to these receptors is associated with the biologic response of these tissues to the hormone. These receptors bind insulin rapidly, with high specificity and with an affinity high enough to bind picomolar amounts.

Insulin receptors, members of the growth factor family (see Chapter 3 and Figures 3-7 and 3-8), are membrane glycoproteins composed of two protein subunits encoded by a single gene. The larger alpha subunit (MW 135,000) resides entirely extracellularly, where it binds the insulin molecule. The alpha subunit is tethered by disulfide linkage to the smaller beta subunit (MW 95,000). The beta subunit crosses the membrane, and its cytoplasmic domain contains a tyrosine kinase activity that initiates the intracellular signaling pathways.

Upon binding of insulin to the alpha subunit, the beta subunit activates itself by autophosphorylation. The activated beta subunit then recruits additional proteins to the complex and phosphorylates a network of intracellular substrates, including insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2), and others (Figure 17-5). These activated substrates each lead to subsequent recruitment and activation of additional kinases, phosphatases, and other signaling molecules in a complex pathway that generally contains two arms: the mitogenic pathway, which mediates the growth effects of insulin; and the metabolic pathway, which regulates nutrient metabolism. In the metabolic signaling pathway, activation of phosphatidylinositol-3-kinase leads to the movement of GLUT 4-containing vesicles to the cell membrane, increased glycogen and lipid synthesis, and stimulation of other metabolic pathways. After insulin is bound to its receptor, a number of insulin-receptor complexes are internalized. However, it remains controversial whether these internalized complexes contribute to further action of insulin or whether they limit continued insulin action by exposing insulin to intracellular scavenger lysosomes.

Abnormalities of insulin receptors—in concentration, affinity, or both—will affect insulin action. Down-regulation is a phenomenon in which the

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number of insulin receptors is decreased in response to chronically elevated circulating insulin levels, probably by increased intracellular degradation. When insulin levels are low, on the other hand, receptor binding is up-regulated. Conditions associated with high insulin levels and lowered insulin binding to the receptor include obesity, high intake of carbohydrates, and (perhaps) chronic exogenous overinsulinization. Conditions associated with low insulin levels and increased insulin binding include exercise and fasting. The presence of excess amounts of cortisol decreases insulin binding to the receptor, although it is not clear if this is a direct effect of the hormone itself or one that is mediated through accompanying increases in the insulin level.

 

Figure 17-5. A simplified outline of insulin signaling. A minimal diagram of the mitogenic and metabolic arms of the insulin signaling pathway is shown. (GLUT 4, glucose transporter 4; Grb-2, growth factor receptor binding protein 2; GS, glycogen synthase [P indicates the inactive phosphorylated form]; GSK-3, glycogen synthase kinase 3; IRS, insulin receptor substrate [four different proteins]; MAP kinase, mitogen-activated protein kinase; PDK, phospholipid-dependent kinase; PI3 kinase, phosphatidylinositol 3 kinase; PKB, protein kinase B; PP-1, glycogen-associated protein phosphatase-1; Ras, rat sarcoma protein; SHC, Src and collagen homology protein; SOS, son-of-sevenless related protein; TK, tyrosine kinase.)

The insulin receptor itself is probably not the major determinant of insulin sensitivity under most circumstances, however. Clinically relevant insulin resistance most commonly results from defects in postreceptor intracellular signaling pathways, though the exact nature of these defects in most patients remains elusive.

Metabolic Effects of Insulin

The major function of insulin is to promote storage of ingested nutrients. Although insulin directly or indirectly affects the function of almost every tissue in the body, the discussion here will be limited to a brief overview of the effects of insulin on the three major tissues specialized for energy storage: liver, muscle, and adipose tissue. In addition, the paracrine effects of insulin will be discussed briefly. The section on hormonal control of nutrient metabolism (see below) presents a

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detailed discussion of the effects of insulin and glucagon on the regulation of intermediary metabolism.

  1. PARACRINE EFFECTS

The effects of the products of endocrine cells on surrounding cells are termed “paracrine” effects, in contrast to actions that take place at sites distant from the secreting cells, which are termed “endocrine” effects (Chapter 1). Paracrine effects of the B and D cells on the close-lying A cells (Figure 17-1) are of considerable importance in the endocrine pancreas. The first target cells reached by insulin are the pancreatic A cells at the periphery of the pancreatic islets. In the presence of insulin, A cell secretion of glucagon is reduced. In addition, somatostatin, which is released from D cells in response to most of the same stimuli that provoke insulin release, also acts to inhibit glucagon secretion.

Because glucose stimulates only B and D cells (whose products then inhibit A cells) whereas amino acids stimulate glucagon as well as insulin, the type and amounts of islet hormones released during a meal depend on the ratio of ingested carbohydrate to protein. The higher the carbohydrate content of a meal, the less glucagon will be released by any amino acids absorbed. In contrast, a predominantly protein meal will result in relatively greater glucagon secretion, because amino acids are less effective at stimulating insulin release in the absence of concurrent hyperglycemia but are potent stimulators of A cells.

  1. ENDOCRINE EFFECTS

(Table 17-3.)

  1. Liver—The first major organ reached by insulin via the bloodstream is the liver. Insulin exerts its action on the liver in two major ways:

o   Insulin promotes anabolism—Insulin promotes glycogen synthesis and storage at the same time it inhibits glycogen breakdown. These effects are mediated by changes in the activity of enzymes in the glycogen synthesis pathway (see below). The liver has a maximum storage capacity of 100–110 g of glycogen, or approximately 440 kcal of energy.

Insulin increases both protein and triglyceride synthesis and VLDL formation by the liver. It also inhibits gluconeogenesis and promotes glycolysis through its effects on enzymes of the glycolytic pathway.

o   Insulin inhibits catabolism—Insulin acts to reverse the catabolic events of the postabsorptive state by inhibiting hepatic glycogenolysis, ketogenesis, and gluconeogenesis.

  1. Muscle—Insulin promotes protein synthesis in muscle by increasing amino acid transport as well as by stimulating ribosomal protein synthesis. In addition, insulin promotes glycogen synthesis to replace glycogen stores expended by muscle activity. This is accomplished by increasing glucose transport into the muscle cell, enhancing the activity of glycogen synthase, and inhibiting the activity of glycogen phosphorylase. Approximately 500–600 g of glycogen is stored in the muscle tissue of a 70-kg man, but because of the lack of glucose 6-phosphatase in this tissue, it cannot be used as a source of blood glucose. except by indirectly supplying the liver with lactate for conversion to glucose.
  2. Adipose tissue—Fat, in the form of triglyceride, is the most efficient means of storing energy. It provides 9 kcal per gram of stored substrate, as opposed to the 4 kcal/g generally provided by protein or carbohydrate. In the typical 70-kg man, the energy content of adipose tissue is about 100,000 kcal.

Insulin acts to promote triglyceride storage in adipocytes by a number of mechanisms: (1) It induces the production of lipoprotein lipase in adipose tissue (this is the lipoprotein lipase that is bound to endothelial cells in adipose tissue and other vascular beds), which leads to hydrolysis of triglycerides from circulating lipoproteins. (2) By increasing glucose transport into fat cells, insulin increases the availability of α-glycerol phosphate, a substance used in the esterification of

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free fatty acids into triglycerides. (3) Insulin inhibits intracellular lipolysis of stored triglyceride by inhibiting intracellular lipase (also called “hormone-sensitive lipase”). This reduction of fatty acid flux to the liver appears to be a key regulatory factor in the action of insulin to lower hepatic gluconeogenesis and ketogenesis.

Table 17-3. Endocrine effects of insulin.

Effect on liver:
   Reversal of catabolic features of insulin deficiency
      Inhibits glycogenolysis
      Inhibits conversion of fatty acids and amino acids to keto acids
      Inhibits conversion of amino acids to glucose
   Anabolic action
      Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase)
      Increases triglyceride synthesis and very low density lipoprotein formation
Effect on muscle:
   Increased protein synthesis
      Increases amino acid transport
      Increases ribosomal protein synthesis
   Increased glycogen synthesis
      Increases glucose transport
      Induces glycogen synthetase and inhibits phosphorylase
Effect on adipose tissue:
   Increased triglyceride storage
      Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins
      Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport
      Intracellular lipase is inhibited by insulin

Table 17-4. Etiologic classification of diabetes mellitus.1

1. Type 1 diabetes2 (B cell destruction, usually leading to absolute insulin deficiency)

1. Immune-mediated

2. Idiopathic

2. Type 2 diabetes2 (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)

3. Other specific types

1. Genetic defects of B cell function

1. Chromosome 12, HNF-1α (formerly MODY 3)

2. Chromosome 7, glucokinase (formerly MODY 2)

3. Chromosome 20, HNF-4α (formerly MODY 1)

4. Mitochrondrial DNA

5. Others

2. Genetic defects in insulin action

1. Type A insulin resistance

2. Leprechaunism

3. Rabson-Mendenhall syndrome

4. Lipoatrophic diabetes

5. Others

3. Diseases of the exocrine pancreas

1. Pancreatitis

2. Trauma, pancreatectomy

3. Neoplasia

4. Cystic fibrosis

5. Hemochromatosis

6. Fibrocalculous pancreatopathy

7. Others

4. Endocrinopathies

1. Acromegaly

2. Cushing's syndrome

3. Glucagonoma

4. Pheochromocytoma

5. Hyperthyroidism

6. Somatostatinoma

7. Aldosteronoma

8. Others

5. Drug- or chemical-induced

1. Vacor

2. Pentamidine

3. Nicotinic acid

4. Glucocorticoids

5. Thyroid hormone

6. Diazoxide

7. Beta-adrenergic agonists

8. Thiazides

9. Phenytoin

10.                                     Alpha-interferon

11.                                     Others

6. Infections

1. Congenital rubella

2. Cytomegalovirus

3. Others

7. Uncommon forms of immune-mediated diabetes

1. Stiff-man syndrome

2. Anti-insulin receptor antibodies

3. Others

8. Other genetic syndromes sometimes associated with diabetes

1. Down's syndrome

2. Klinefelter's syndrome

3. Turner's syndrome

4. Wolfram's syndrome

5. Friedreich's ataxia

6. Huntington's chorea

7. Laurence-Moon-Biedl syndrome

8. Myotonic dystrophy

9. Porphyria

10.                                     Prader-Willi syndrome

11.                                     Others

4. Gestational diabetes mellitus (GDM)

1Modified from American Diabetes Association: Diabetes Care 1999;22(Suppl 1):1185.
2Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient.
HNF = hepatic nuclear factor.

Glucose Transporter Proteins

Glucose oxidation is a major source of energy for many cells of the body and is especially essential for brain function. Since cell membranes are impermeable to hydrophilic molecules such as glucose, all cells require carrier proteins to transport glucose across the lipid bilayers into the cytosol. While the intestine and kidney have an energy dependent Na+-glucose cotransporter, all other cells have non-energy-dependent transporters that facilitate diffusion of glucose from a higher concentration to a lower concentration across cell membranes. Facilitative glucose transporters comprise a large family including at least 13 members, though some of the recently identified members of the family have not yet been shown to transport glucose. The first four members of the family are the ones that have been best-characterized, and they have distinct affinities for glucose and distinct patterns of expression.

GLUT 1 is present in all human tissues. It appears to mediate basal glucose uptake, since it has a very high affinity for glucose and therefore is able to transport glucose at relatively low concentrations as found in the basal state. For this reason, it is an important component of the brain vascular system (blood-brain barrier) to ensure adequate transport of plasma glucose into the central nervous system. GLUT 3, which is also found in all tissues, is the major glucose transporter on the neuronal surface. It also has a very high affinity for glucose and is responsible for transferring glucose into neuronal cells.

In contrast, GLUT 2 has a very low affinity for glucose and seems to act as a transporter only when plasma glucose levels are relatively high, such as postprandially. It is a major transporter of glucose in hepatic, intestinal, and renal tubular cells, so that diffusion of glucose across these cells increases as glucose levels rise. The low affinity of GLUT 2 for glucose reduces hepatic uptake of glucose during the basal state or during fasting. GLUT 2 is also expressed on the surface of the B cells in rodents, but it is not detected at significant levels on human B cells.

GLUT 4 is found in two major insulin target tissues: skeletal muscle and adipose tissue. It appears to be sequestered mainly within an intracellular compartment of these cells and thus is not able to function as a glucose transporter until a signal from insulin results in translocation of GLUT 4 to the cell membrane, where it facilitates glucose entry into these storage tissues after a meal.

Islet Amyloid Polypeptide (IAPP), or Amylin

IAPP, or amylin, is a peptide made up of 37 amino acids that is produced and stored with insulin in the pancreatic B cell, but only in a low ratio of one molecule of amylin to 100 of insulin. It is cosecreted with insulin in response to glucose and other B cell stimulators. Amylin's function has not been determined, but it produces amyloid deposits in pancreatic islets of most patients with type 2 diabetes of long duration. These amyloid deposits are insoluble fibrillar proteins (containing mainly amylin as well as its precursor peptide) that encroach upon and may even occur within pancreatic B cells. Islets of nondiabetic elderly persons may contain less extensive amyloid deposits. Whether amyloid deposition contributes to the islet dysfunction seen in type 2 diabetes or is simply a consequence of disordered and hyperstimulated islet function remains an unresolved question.

  1. Glucagon

Biochemistry

Pancreatic glucagon, the gene for which is located on human chromosome 2, is a single-chain polypeptide consisting of 29 amino acids with a molecular weight of 3485 (Figure 17-6). It is synthesized in the A cells in the islets of Langerhans and derived from a much larger 160-amino-acid precursor molecule. Within this proglucagon molecule are several other peptides connected in tandem: glicentin-related peptide, glucagon, glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2). The combination of glicentin-related peptide with glucagon consists of 69 amino acids and comprises the hormone glicentin, which is predominantly secreted from the intestine and not the pancreas (Figure 17-6). Both GLP-1 and GLP-2 increase after meals. An endogenous truncated derivative of GLP-1, with the first six of its 37 amino acids absent (GLP-1 [7–37]), is an extremely potent stimulator of pancreatic B cells and is felt to be the major physiologic gut factor (“incretin”) that potentiates glucose-induced insulin secretion after meals. It is released by small intestinal L cells of the duodenum during mixed meals and is several times more potent than glucagon itself as an insulinotropic secretagogue, whereas intact GLP-1 (1–37) and GLP-2 do not stimulate insulin secretion. In healthy humans, the average fasting plasma immunoreactive glucagon level is 75 pg/mL (25 pmol/L). Only 30–40% of this is actually pancreatic glucagon, the remainder being a heterogeneous composite of

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higher-molecular-weight molecules with glucagon immunoreactivity such as proglucagon, glicentin, truncated GLP-1, and GLP-2. The circulation half-life of pancreatic glucagon is 3–6 minutes. Glucagon is mainly removed by the liver and kidney.

 

Figure 17-6. Tissue-specific secretory products of human proglucagon. (GLP-1, glucagon-like peptide-1; GLP-2, glucagon-like peptide-2; GRPP, glicentin-related polypeptide.)

Secretion

Glucagon secretion is inhibited by glucose—in contrast to the effect of glucose on insulin secretion. There are conflicting data about whether the effect of glucose is a direct one on the A cell or whether it is mediated via release of insulin or somatostatin, both of which are known to inhibit the A cell directly (see above).

In addition, since γ-aminobutyric acid (GABA) is released by B cells and its receptors have recently been detected on A cells, GABA may participate in the inhibition of A cells during B cell stimulation.

Many amino acids stimulate glucagon release, although there are differences in their ability to do so. Some, such as arginine, release both glucagon and insulin; others (eg, alanine) stimulate primarily glucagon release. Leucine, a good stimulant for insulin release, does not stimulate glucagon. Other substances that promote glucagon release are catecholamines, the gastrointestinal hormones (cholecystokinin [CCK], gastrin, and gastric inhibitory polypeptide [GIP]), and glucocorticoids. Both sympathetic and parasympathetic (vagal) stimulation promote glucagon release; this is especially important in augmenting the response of the A cell to hypoglycemia. High levels of circulating fatty acid are associated with suppression of glucagon secretion.

Action of Glucagon

In contrast to insulin, which promotes energy storage in a variety of tissues, glucagon is a humoral mechanism for making energy available to the tissues between meals, when ingested food is not available for absorption. Glucagon stimulates the breakdown of stored glycogen, maintains hepatic output of glucose from amino acid precursors (gluconeogenesis), and promotes hepatic output of ketone bodies from fatty acid precursors (ketogenesis). The liver, because of its geographic proximity to the pancreas, represents the major target organ for glucagon, with portal vein glucagon concentrations reaching as high as 300–500 pg/mL (100–166 pmol/L). Binding of glucagon to its receptor on hepatocytes results in activation of adenylyl cyclase and generation of cAMP, which both promotes glycogenolysis and stimulates gluconeogenesis. Uptake of alanine by liver cells is facilitated by glucagon, and fatty acids are directed away from reesterification to triglycerides and toward ketogenic pathways (see below). It is unclear whether physiologic levels of glucagon affect tissues other than the liver.

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The ratio of insulin to glucagon affects key target tissues by mediating phosphorylation or dephosphorylation (either or both) of key enzymes affecting nutrient metabolism. In addition, this ratio increases or decreases actual quantities of certain enzymes, thereby controlling the flux of these nutrients into or out of storage.

  1. Somatostatin

The gene for somatostatin is on the long arm of chromosome 3. It codes for a 116-amino-acid peptide, preprosomatostatin, from whose carboxyl terminal is cleaved the hormone somatostatin, a 14-amino-acid cyclic polypeptide with a molecular weight of 1640 (Figure 17-7). It is present in D cells at the periphery of the human islet (Figure 17-1). It was first identified in the hypothalamus and owes its name to its ability to inhibit release of growth hormone (pituitary somatotropin). Since that time, somatostatin has been identified in a number of tissues, including many areas of the brain, the gastrointestinal tract, and the pancreas. In the central nervous system and the pancreas, somatostatin-14 predominates, but approximately 5–10% of the somatostatin-like immunoreactivity in the brain is due to a 28-amino-acid peptide, somatostatin-28. This consists of an amino terminal region of 14 amino acids and a carboxyl terminal segment containing somatostatin-14. In small intestine, the larger molecule is more prevalent, with 70–75% of the hormone having 28 amino acids and only 25–30% being somatostatin-14. In contrast, pancreatic D cells synthesize only somatostatin-14. The larger peptide somatostatin-28 is ten times more potent than somatostatin-14 in inhibiting growth hormone and insulin, whereas somatostatin-14 is more effective in inhibition of glucagon release.

Almost every known stimulator of release of insulin from pancreatic B cells also promotes somatostatin release from D cells. This includes glucose, arginine, gastrointestinal hormones, and tolbutamide. The importance of circulating somatostatin is unclear, since a major role of this peptide may be as a paracrine regulator of the pancreatic islet and the tissues of the gastrointestinal tract. Physiologic levels of somatostatin in humans seldom exceed 80 pg/mL (49 pmol/L). The metabolic clearance of exogenously infused somatostatin in humans is extremely rapid; the half-life of the hormone is less than 3 minutes.

Recently, molecular cloning has demonstrated the existence of at least five somatostatin receptors (SSTR1–5) which are G protein-coupled receptors with seven membrane-spanning domains. They vary in size from 364 to 418 amino acids (with 105 amino acids invariant) and are found in the central nervous system and in a wide variety of peripheral tissues including the pituitary gland, the small intestine, and the pancreas. These receptors activate tyrosine phosphatases that interfere with the secretory process by dephosphorylating proteins. Inhibition of insulin secretion is due to binding of ligand to SSTR5, whereas inhibition of growth hormone release as well as glucagon release by A cells of the pancreas are due to effects of SSTR2. This explains why an analog of somatostatin, octreotide, which has a much greater affinity for SSTR2 than for SSTR5, can be effective in correcting growth hormone excess without much of an effect on carbohydrate tolerance when used to treat acromegaly.

 

Figure 17-7. Amino acid sequence of somatostatin and its cleavage from dibasic amino acid residue in prosomatostatin and preprosomatostatin.

Somatostatin acts in several ways to restrain the movement of nutrients from the intestinal tract into the

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circulation. It prolongs gastric emptying time, decreases gastric acid and gastrin production, diminishes pancreatic exocrine secretion, decreases splanchnic blood flow, and retards xylose absorption. Neutralization of circulating somatostatin with antisomatostatin serum is associated with enhanced nutrient absorption in dogs. This implies that at least some of the effects of somatostatin are truly endocrine, as opposed to the paracrine effects discussed earlier.

  1. Pancreatic Polypeptide

Pancreatic polypeptide (PP) is found in PP cells located chiefly in islets in the posterior portion of the head of the pancreas. PP is a 36-amino-acid peptide with a molecular weight of 4200. Little is known about its biosynthesis. Circulating levels of the peptide increase in response to a mixed meal; however, intravenous infusion of glucose or triglyceride does not produce such a rise, and intravenous amino acids cause only a small increase. Vagotomy abolishes the response to an ingested meal.

In healthy subjects, basal levels of PP average 24 + 4 pmol/L and may become elevated owing to a variety of factors including old age, alcohol abuse, diarrhea, chronic renal failure, hypoglycemia, or inflammatory disorders. Values above 300 pmol/L are found in most patients with pancreatic endocrine tumors such as glucagonoma or VIPoma and in all patients with tumors of the pancreatic PP cell. As many as 20% of patients with insulinoma and one-third of those with gastrinomas also have pancreatic polypeptide plasma concentrations of greater than 300 pmol/L.

The physiologic action of PP is unknown.

  1. DIABETES MELLITUS

Clinical diabetes mellitus is a syndrome of disordered metabolism with inappropriate hyperglycemia due either to an absolute deficiency of insulin secretion or a reduction in the biologic effectiveness of insulin (or both).

CLASSIFICATION

Traditionally, diabetes was classified according to the patient's age at onset of symptoms (juvenile-onset versus adult-onset). In 1979, the NIH Diabetes Data Group proposed a classification that divided diabetes into two main types—insulin-dependent and non-insulin-dependent—but this “therapeutic classification” proved unsatisfactory as more information on the pathogenesis and etiology of diabetes mellitus accumulated. In 1997, an international committee of diabetologists recommended several changes in the classification of diabetes that have been endorsed by the American Diabetes Association and the World Health Organization (Table 17-4). They include the following:

  1. The terms “insulin-independent diabetes mellitus” and “non-insulin-dependent diabetes mellitus” and their acronyms IDDM and NIDDM were eliminated since they are based upon pharmacologic rather than etiologic considerations.
  2. The terms “type 1 diabetes” and “type 2 diabetes” are retained, with arabic rather than roman numerals. Type 1 diabetes is due to pancreatic islet B cell destruction, which in over 95% of cases is caused by an autoimmune process, while in less than 5% the B cell destruction is idiopathic. Patients with type 1 diabetes are generally prone to ketoacidosis and require insulin replacement therapy. Type 2 diabetes, the much more prevalent form, is a heterogeneous disorder encompassing a spectrum of defects consisting in some cases of defects in B cell function alone but most commonly associated with insulin resistance in the presence of an associated impairment in compensatory insulin secretion.

Of the approximately 16 million patients in the United States who have diabetes, about 1.5 million have type 1. The remainder mainly have type 2 diabetes except for a third group (“other specific types”) recently defined by the ADA who have rare monogenic defects of either pancreatic B cell function or of insulin action, primary diseases of the endocrine pancreas, or drug-induced diabetes (Table 17-4).

TYPE 1 DIABETES MELLITUS

Type 1 is a severe form of diabetes mellitus and is associated with ketosis in the untreated state. About 9% of diabetics in North America and 20% of diabetics in Scandinavian countries have type 1 diabetes. It is most common in young individuals but occurs occasionally in nonobese adults. It is a catabolic disorder in which circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic B cells fail to respond to all known insulinogenic stimuli. In the absence of insulin, the three main target tissues of insulin (liver, muscle, and fat) not only fail to appropriately take up absorbed nutrients but continue to deliver glucose, amino acids, and fatty acids into the bloodstream from their respective storage depots. Furthermore, alterations in fat metabolism lead to the production and accumulation of ketones. This inappropriate persistence of the fasted state postprandially can be reversed by the administration of insulin.

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Genetics of Type 1 Diabetes

Studies in monozygotic twins suggest that genetic influences are less marked in type 1 diabetes than in type 2 diabetes. Only 30–40% of identical twins of type 1 diabetic patients will develop the disease. This also suggests that an environmental factor is required for induction of diabetes in these cases. In contrast, the identical twin of a type 2 diabetic is much more prone to develop diabetes, often with onset within a year after onset of the disease in the sibling.

Type 1 diabetes is believed to result from an infectious or toxic environmental insult to genetically predisposed persons whose aggressive immune system destroys pancreatic B cells while overcoming the invasive agent. Environmental factors that have been associated with altered pancreatic islet cell function include viruses (mumps, rubella, coxsackievirus B4), toxic chemical agents such as vacor (a nitrophenylurea rat poison), and other destructive cytotoxins such as hydrogen cyanide from spoiled tapioca or cassava root.

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At least half of the familial aggregation of type 1 diabetes is accounted for by genes in the major histocompatibility locus on the short arm of chromosome 6. The most important of these are the HLA class II molecules DQ and DR, which code for antigens expressed on the surface of macrophages and B lymphocytes (see Chapter 4 and Figure 4-2). The class II molecules bind to peptide antigens and present them to T cells by binding to the T cell receptor. In contrast to the DR genes, which have polymorphisms only in their beta subunit, the DQ genes have polymorphic alpha and beta subunits, so that in the approved nomenclature a specific DQ allele is identified by an assigned number for each of its A and B subunits. Of approximately 21 known DR genes, only DR3 and DR4 are major susceptibility risk factors for type 1 diabetes. As many as 95% of type 1 diabetic patients have a DR3 or a DR4—or both—compared with 45–50% of Caucasian nondiabetic controls. The highest risk for type 1 diabetes in the United States is borne by individuals who express both a DR3 and a DR4 allele. These are generally in linkage disequilibrium with DQ genes that themselves confer high risk, particularly DQA1*0501, DQB1*0201 (coupled with DR3), and DQA1*0301, DQB1*0302 (coupled with DR4). Only 2% of children born in the United States are DR3 or DR4 heterozygotes, yet they comprise about 40% of all children developing type 1 diabetes.

DQ alleles are associated not only with risk for type 1 diabetes but also with dominant protection, often in linkage with HLA-DR2. The most protective of these—and a quite common allele—is DQA1*0102, DQB1*0602. It occurs in over 20% of individuals but in less than 1% of children developing type 1 diabetes. In fact, in clinical trials for the prevention of type 1 diabetes, subjects with this particular highly protective DQ allele are excluded despite the presence of islet cell antibody-positive first-degree relatives.

It remains a mystery why people with certain HLA types are predisposed to development of type 1 diabetes. The concept of an autoimmune destruction of pancreatic B cells due to selective loss of immune tolerance is supported by evidence that immune suppression therapy interrupts progression to insulin deficiency in a number of newly diagnosed type 1 patients. Moreover, extensive infiltration with both helper and cytotoxic T lymphocytes is present in the islets of children who just developed type 1 diabetes, and their serum contains autoantibodies against structural and secretory proteins of the pancreatic B cells before the onset of type 1 diabetes and for some time after diagnosis.

On the strength of the above evidence, a theory for autoimmune B cell destruction has been proposed based on molecular mimicry, wherein the immune system mistakenly targets B cell proteins that share homologies with certain viral or other foreign peptides (such as partially digested cow's milk dietary proteins). The efficiency of presenting certain proteins depends on the composition of the class II antigens on the surface of the antigen-presenting cells (macrophages). Efficiency of antigen presentation by the class II HLA proteins could play a role during the deletion of self-reactive T cells in the thymus. Failure to properly delete T cells that recognize B cell antigens would predispose to later development of type 1 diabetes. Alternatively, efficiency of antigen presentation could play a role later during the peripheral development of an autoimmune response.

Circulating islet cell autoantibodies, virtually absent in nondiabetics, have been detected in as many as 85% of type 1 diabetics tested in the first few weeks after onset of diabetes. Moreover, when sensitive immunoassays are used, up to 60% of these patients also have detectable antibodies to insulin prior to receiving insulin therapy, and these are especially prevalent with an onset of disease in childhood. The high prevalence of these islet cell and insulin autoantibodies in type 1 diabetes, as well as in certain of their siblings who later develop overt diabetes, supports the concept that autoimmune mechanisms may contribute significantly to progressive B cell destruction.

The most common islet cell antibodies in patients with type 1 diabetes are directed against glutamic acid decarboxylase (GAD), an enzyme localized within pancreatic B cells. This enzyme has isoforms with molecular weights of 65,000 and 67,000 which are also found in central nervous system “inhibitory” neurons that secrete γ-aminobutyric acid. Evidence that a rare neurologic condition, “stiff-man syndrome,” was associated with autoimmunity to neurons containing GAD—and that these patients also had islet cell autoantibodies and a high incidence of type 1 diabetes—led to the discovery that antibodies to GAD made up the bulk of antibodies previously described in type 1 diabetes as being against a 64-kDa antigen in pancreatic B cells.

Manifestations of stiff-man syndrome are not seen in the vast majority of patients with type 1 diabetes even though their islet cell antibodies contain a major component that reacts in vitro with GAD-containing neurons. The blood-brain barrier may have some protective effect against neuronal damage of a degree that might cause stiff-man syndrome in type 1 diabetes. Patients with stiff-man syndrome generally have much higher GAD antibody levels than most patients with type 1 diabetes.

A genetic link to chromosome 11 has been identified in type 1 diabetes. Studies of a polymorphic DNA locus flanking the 5′ region of the insulin gene on chromosome 11 revealed a slight but statistically significant linkage between type 1 diabetes and this genetic locus

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in a Caucasian population of type 1 diabetics. This polymorphic locus, which consists of a variable number of tandem repeats (VNTR) with two common sizes in Caucasians, small (26–63 repeats) or large (140–243 repeats), does not encode a protein. An intriguing proposal to explain how the VNTR might influence susceptibility to type 1 diabetes was based on findings that insulin gene transcription is facilitated in the fetal thymus gland by the presence of the large allele of the VNTR locus flanking the insulin gene. The large VNTR allele might produce a dominant protective effect by promoting negative selection (deletion) by the thymus of insulin-specific T lymphocytes that play a critical role in the immune destruction of their pancreatic B cells.

The established genetic association with the HLA region of chromosome 6 contributes much more (about 50%) to the genetic susceptibility to type 1 diabetes than does this locus flanking the insulin gene on chromosome 11, which contributes about 10%. The recommended nomenclature for these two known susceptibility gene associations are IDDM1 for the HLA region and IDDM2 for the insulin gene region. Approximately 16 other genes with lesser degrees of linkage to type 1 diabetes are being investigated.

Immunomodulation in the Treatment & Prevention of Type 1 Diabetes

Since the destruction of B cells in type 1 diabetes is a progressive, immune-mediated process, therapies that block or modulate the immune response should be able to stop the destruction. Unfortunately, trials of immunosuppression therapies have been generally disappointing. Although some reduction or elimination of insulin requirement in patients with new-onset type 1 diabetes has been observed, most subjects manifest continued carbohydrate intolerance while being exposed to considerable risk from the adverse effects of immunosuppressive drugs. Because of its substantial side effects and increased risks of infection and malignancy, broad immunosuppression is not recommended for the treatment of patients with newly diagnosed type 1 diabetes.

More specific strategies for immunosuppression, such as the use of monoclonal antibodies against particular T cell products, may reduce the hazards of long-term immunotherapy. A trial using a humanized monoclonal antibody against CD3, hOKT3γ1(Ala-Ala), showed efficacy in reducing the decline in insulin production in patients newly diagnosed with type 1 diabetes. CD3 is an antigen expressed on the surface of activated T cells, and the hOKT3γ1(Ala-Ala) monoclonal antibody is believed to modulate the autoimmune response by selectively inhibiting the pathogenic T cells or inducing regulatory T cells. Patients were treated for 14 days with the antibody within 6 weeks after diagnosis of type 1 diabetes. One year later, the majority of patients in the treated group had maintained or increased insulin production and improved glycemic control relative to the control group. This and other approaches that selectively modulate the autoimmune T cell response hold the promise that type 1 diabetes may eventually be preventable without prolonged immunosuppression.

A nonimmunosuppressive modality that showed promise in animal models of type 1 diabetes is nicotinamide, an inhibitor of poly(ADP-ribose) synthetase, an enzyme whose repair of DNA injury tends to deplete the cell of its vital supply of NAD. A series of trials of nicotinamide after the onset of type 1 diabetes have generally been disappointing and inconclusive as regards any benefit. A large randomized trial known as the European Nicotinamide Diabetes Intervention Trial (ENDIT) concluded that nicotinamide provides no protection to islet cell antibody-positive first-degree relatives of patients with type 1 diabetes. Daily exposure to insulin antigen has been shown to delay or prevent the onset of type 1 diabetes in animal models of type 1 diabetes as well as in a small pilot study in nondiabetic humans at high risk to develop type 1 diabetes (first-degree relatives of patients with type 1 diabetes, positive islet cell antibodies, and a blunted insulin release to glucose). Because of these encouraging findings, a large-scale randomized multicenter Diabetes Prevention Trial in type 1 diabetes (DPT-1) has begun under the auspices of the National Institutes of Health to test low-dose insulin injections in nondiabetic relatives of people with type 1 diabetes, who are at high risk to develop type 1 diabetes themselves (having islet cell antibodies and a low serum insulin response to a glucose load). Volunteers with high risk (antibody titer and a low serum insulin response) will be assigned to a control group or to a group receiving 0.25 units of ultralente insulin per kilogram of body weight given in divided doses. Volunteers at intermediate risk, who have islet cell antibodies and also insulin autoantibodies but normal serum insulin responses to glucose loading, will be randomly assigned to a control group or to a group receiving oral insulin. Because of a lower rate of volunteer recruitment and the lower incidence of diabetes in this “intermediate risk” group, this arm of the study had not been completed as of the end of 2002. In addition, intervention trials using other therapies, such as OKT3, are in various stages of development.

TYPE 2 DIABETES

Type 2 diabetes—previously classified as non-insulin-dependent diabetes (NIDDM)—afflicts individuals with insulin resistance who generally have relative rather than absolute insulin deficiency. It accounts for

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80–90% of cases of diabetes in the United States. These patients are usually adults over age 40 with some degree of obesity. They do not require insulin to survive, though over time their insulin secretory capacity tends to deteriorate, and many need insulin treatment to achieve optimal glucose control. Ketosis seldom occurs spontaneously, and if present it is a consequence of severe stress from trauma or infection.

The nature of the primary defect in type 2 diabetes is obscure. Tissue insensitivity to insulin has been noted in most type 2 patients irrespective of weight and has been attributed to several interrelated factors (Table 17-5). These include a putative (as yet undefined) genetic factor, which is aggravated in time by further enhancers of insulin resistance such as aging, a sedentary lifestyle, and abdominal visceral obesity. In addition, there is an accompanying deficiency in the response of pancreatic B cells to glucose, a genetic disorder that may be aggravated by gradual displacement of B cells due to deposition of intra-islet amyloid with aging. Furthermore, both the tissue resistance to insulin and the impaired B cell response to glucose appear to be further aggravated by sustained hyperglycemia, which may impede both insulin signaling and B cell function. Treatment that reduces the hyperglycemia toward normal reduces this acquired defect in insulin resistance and also improves to some degree glucose-induced insulin release. Type 2 diabetes frequently goes undiagnosed for many years, since the hyperglycemia develops quite gradually and is generally asymptomatic initially. Despite this mild presentation, these patients are at increased risk of developing macrovascular and microvascular complications.

The genetics of type 2 diabetes is complex and poorly defined despite the strong genetic predisposition in these patients. This is probably because of the heterogeneous nature of this disorder as well as the difficulty in sorting out the contribution of acquired factors affecting insulin action and glycemic control.

Table 17-5. Factors reducing response to insulin.

Prereceptor inhibitors: Insulin antibodies
Receptor inhibitors:
   Insulin receptor autoantibodies
 “Down-regulation” of receptors by hyperinsulinism:
      Primary hyperinsulinism (B cell adenoma)
      Hyperinsulinism, secondary to a postreceptor defect (obesity, Cushing's syndrome, acromegaly, pregnancy) or prolonged hyperglycemia (diabetes mellitus, post-glucose tolerance test)
Postreceptor influences:
   Poor responsiveness of principal target organs: obesity, hepatic disease, muscle inactivity
   Hormonal excess: glucocorticoids, growth hormone, oral contraceptive agents, progesterone, human chorionic somatomammotropin, catecholamines, thyroxine

Subgroups of Type 2 Diabetes

Two subgroups of patients with type 2 diabetes are currently distinguished by the absence or presence of obesity. It is at present impossible to identify diagnostic characteristics that allow further clear-cut separation into more specific subtypes. Circulating insulin levels vary with the prevailing degree of hyperglycemia and are considered too unreliable to be of use in classifying type 2 diabetes.

  1. OBESE TYPE 2 DIABETES

The prevalence of obesity varies among different racial groups. While obesity is apparent in no more than 30% of Chinese and Japanese patients with type 2 diabetes, it is present in 60–80% of North Americans, Europeans, or Africans with type 2 diabetes and approaches 100% of type 2 patients among Pima Indians or Pacific Islanders from Nauru or Samoa. Patients with type 2 diabetes have an insensitivity to endogenous insulin that is correlated with the presence of a predominantly abdominal distribution of fat, producing an abnormally high waist to hip ratio. In addition, distended adipocytes and overnourished liver and muscle cells may also resist the deposition of additional glycogen and triglycerides in their storage depots. Hyperplasia of pancreatic B cells is often present and probably accounts for the normal or exaggerated insulin responses to glucose and other stimuli seen in the milder forms of this disease. In more severe cases, secondary (but potentially reversible) failure of pancreatic B cell secretion may result after exposure to prolonged fasting hyperglycemia. This phenomenon has been called“desensitization” or “glucose toxicity.” It is selective for glucose, and the B cell can recover some degree of sensitivity to glucose stimulation once the sustained hyperglycemia is corrected by any form of therapy, including diet therapy, sulfonylureas, and insulin.

Not all patients with obesity and insulin resistance develop hyperglycemia, however. An underlying defect in the ability of the B cells to compensate for the increased demand may determine which patients will develop diabetes in the setting of insulin resistance. Furthermore, as noted above, patients with type 2 diabetes suffer from a progressive decline in B cell function that results in worsening hyperglycemia even when the degree of insulin resistance remains stable.

  1. METABOLIC SYNDROME (SYNDROME X)

When type 2 patients predominantly present with insulin resistance, the diabetes may represent only one

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facet of a metabolic syndrome. Hyperglycemia in these patients is frequently associated with hyperinsulinemia, dyslipidemia, andhypertension, which together lead to coronary artery disease and stroke. It has been suggested that this aggregation results from a genetic defect producing insulin resistance, particularly when obesity aggravates the degree of insulin resistance. In this model, impaired action of insulin predisposes to hyperglycemia, which in turn induces hyperinsulinemia. If this hyperinsulinemia is of insufficient magnitude to correct the hyperglycemia, type 2 diabetes will be manifested. The excessive insulin level could also increase sodium retention by renal tubules, thereby contributing to or causing hypertension. Increased VLDL production in the liver, leading to hypertriglyceridemia (and consequently a low HDL-cholesterol level), has also been attributed to hyperinsulinism. Moreover, it has been proposed that high insulin levels can stimulate endothelial and vascular smooth muscle cell proliferation—by virtue of the hormone's action on growth factor receptors—to initiate atherosclerosis.

While there is full agreement on an association of the above disorders, the mechanism of their interrelationship remains speculative and open to experimental investigation. Controversy persists about whether or not hypertension is caused by hyperinsulinism, since these two manifestations, which often coexist in whites, are not highly associated in American blacks or Pima Indians. Moreover, patients with hyperinsulinism due to an insulinoma are generally normotensive, and there is no reduction of blood pressure after surgical removal of the insulinoma restores normal insulin levels.

An alternative unifying hypothesis could be that visceral obesity directly induces the other components of this syndrome. Visceral obesity is an independent risk factor for all of the other components of metabolic syndrome. In addition to the metabolic effects of visceral obesity, adipocytes produce a number of secreted products including TNFα, leptin, adiponectin, and resistin (see Chapter 20). Although the full details of the role of these molecules in causation of the metabolic syndrome are still under investigation, the adipocyte clearly is not just an innocent bystander but plays an active role in the development of systemic insulin resistance, hypertension, and hyperlipidemia. Furthermore, thrombi in atheromatous vessels may be more hazardous in patients with visceral obesity because they also have an associated increase in plasminogen activator inhibitor-1, a circulating factor produced by omental and visceral adipocytes that inhibits clot lysis. This discussion emphasizes the importance of measures such as diet and exercise that reduce visceral adiposity in the management of patients with metabolic syndrome and obese type 2 diabetes.

Australian epidemiologists prefer to group these disorders together as a syndrome, without necessarily implying that a single cause is responsible for the other components. They suggest the acronym CHAOS to signify coronary artery disease, hypertension, adult-onset diabetes, obesity, and stroke. The main value of grouping these disorders as a syndrome, regardless of its nomenclature, is to remind physicians that the therapeutic goals are not only to correct hyperglycemia but also to manage the elevated blood pressure and hyperlipidemia that result in considerable cardiovascular morbidity as well as cardiovascular deaths in these patients. It also raises awareness that indiscriminate therapeutic use of high doses of exogenous insulin may conceivably have adverse effects on a patient's risk profile for cardiovascular disease if the hypothesis behind the insulin resistance syndrome is substantiated. Finally, it reminds physicians that when choosing antihypertensive agents or lipid-lowering drugs to manage one of the components of this syndrome, their possible untoward effects on other components of the syndrome should be carefully considered. For example, physicians aware of this syndrome are less likely to prescribe antihypertensive drugs that raise lipids (diuretics, beta-blockers) or that raise blood sugar (diuretics). Likewise, they will refrain from prescribing drugs that correct hyperlipidemia but increase insulin resistance with aggravation of hyperglycemia (niacin).

  1. NONOBESE TYPE 2 DIABETES

Approximately 20–40% of type 2 diabetic patients are nonobese, though this percentage varies according to the population studied—eg, higher in Asian populations and lower in Pacific Islanders and Pima Indians of the American Southwest and Mexico. Among nonobese type 2 diabetic patients, deficient insulin release by the pancreatic B cell seems to be the major defect, but some insulin resistance may also contribute. However, this degree of insulin resistance does not seem to be clinically relevant to the treatment of most nonobese type 2 patients, who generally respond to appropriate therapeutic supplements of insulin in the absence of rare associated conditions such as lipoatrophy or acanthosis nigricans.

Currently, type 2 diabetes is considered of idiopathic origin. However, with developments in biotechnology, a variety of etiologic genetic abnormalities have been documented within this heterogeneous group, particularly in those presenting with clinical and laboratory manifestations similar to those seen in the nonobese type 2 subgroup. When the genetic defect has been defined, these patients have recently been reclassified within a group designated “other specific types” (Table 17-4). In most of these patients, impaired insulin action at the postreceptor level and an absent or delayed early phase of insulin release in response to glucose can be demonstrated. However, other insulinogenic

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stimuli, such as acute infusion of amino acids, intravenous tolbutamide, or intramuscular glucagon, often remain partially effective in eliciting acute insulin release.

The hyperglycemia in patients with nonobese type 2 diabetes often responds to dietary therapy or to oral antidiabetic agents. Occasionally, insulin therapy is required to achieve satisfactory glycemic control even though it is not needed to prevent ketoacidosis.

OTHER SPECIFIC TYPES OF DIABETES

Genetic Defects of Pancreatic B Cell Function

This subgroup of monogenic disorders is characterized by a diabetes that occurs in late childhood or before the age of 25 years as a result of a partial defect in glucose-induced insulin release and accounts for up to 5% of diabetes in North American and European populations. A strong family history of early-onset diabetes occurring in one parent and in one-half of the parent's offspring suggests autosomal dominant transmission. These patients are generally nonobese, and because they are not ketosis-prone and may initially achieve good glycemic control without insulin therapy, their disease has been called “maturity-onset diabetes of the young” (MODY). Six types have been described with single-gene defects, and all have been shown to produce a defect in glucose-induced insulin release. MODY 2 results from an abnormal glucokinase enzyme. Other forms of MODY are due to mutations of nuclear transcription factors that regulate B cell gene expression (Table 17-6).

MODY 1 includes 74 members of a pedigree known as the R-W family, descendants of a German couple who immigrated to Michigan in 1861. They have been studied prospectively since 1958, and in 1996 the genetic defect was shown to be a nonsense mutation of a nuclear transcription factor found in liver as well as in pancreatic B cells. This gene has been termed hepatocyte nuclear factor-4α (HNF-4α) and is found on chromosome 20. Mutations of this gene are among the rarest of the MODY groups, with very few other mutations reported in families with other than the Michigan pedigree. Its role in reducing glucose-induced insulin secretion has not yet been clarified. These patients display a progressive decline in B cell function and develop chronic complications of diabetes comparable in degree to those with idiopathic type 2 diabetes. They often fare better with insulin therapy.

MODY 2 was first described in French families but has now been found in racial groups from most parts of the world. At least 26 different mutations of the glucokinase gene on chromosome 7 have been identified and characterized. Reduced sensitivity of pancreatic B cell glucokinase to plasma glucose causes impaired insulin secretion, resulting in fasting hyperglycemia and mild diabetes. A reduction in glucokinase activity within the pancreatic B cell is critical in determining the threshold of plasma glucose at which the B cell secretes insulin, since glucokinase acts as a glucose sensor. While some of these mutations can completely block this enzyme's function, others interfere only slightly with its action. In contrast to all the other forms of MODY, patients with one mutated glucokinase allele (heterozygotes) have a benign course with few or no chronic complications and respond well to diet therapy or oral antidiabetic drugs without the need for insulin treatment. On the other hand, rare individuals who inherit two mutated glucokinase alleles have permanent neonatal diabetes, a nonimmune form of absolute insulin deficiency that presents at birth.

Table 17-6. Genetic defects of pancreatic B cell function.

Syndrome

Mutation

Chromosome

MODY 1

Hepatocyte nuclear factor-4α

20q

MODY 2

Glucokinase gene

7p

MODY 3

Hepatocyte nuclear factor-1α

12q

MODY 4

Insulin promoter factor-1

13q

MODY 5

Hepatocyte nuclear factor-1β

17q

MODY 6

NeuroD1

2q

Mitochondrial dys-function

Transfer RNAs (leucine or lysine tRNA)

Mitochondrial DNA

Mutant insulin or proinsulin

Insulin gene

11p

MODY 3 is caused by mutations of hepatocyte nuclear factor-1α (HNF-1α), whose gene is located on chromosome 12. This is the most common form of MODY in European populations, with many different mutations having been reported. Like HNF-4α, the HNF-1α transcription factor is expressed in pancreatic B cells as well as in liver, and its role in glucose-induced insulin secretion has not been clarified. In contrast to most patients with type 2 diabetes, there is no associated insulin resistance, but the clinical course of these two disorders is otherwise similar as to prevalence of microangiopathy and failure to continue to respond to oral agents with time. These patients have been noted to display an exaggerated response to sulfonylureas early in the course of the disease.

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MODY 4 results from mutation of a pancreatic nuclear transcription factor known as insulin promoter factor-1 (IPF-1), whose gene is on chromosome 13. It mediates insulin gene transcription and regulates expression of other B cell-specific genes such as glucokinase and glucose transporter-2. When both alleles of this gene are nonfunctioning, agenesis of the entire pancreas results; but in the presence of a heterozygous mutation of IPF-1, a mild form of MODY has been described in which affected individuals developed diabetes at a later age (mean onset at 35 years) than occurs with the other forms of MODY, in whom onset generally occurs before the age of 25 years.

MODY 5 was initially reported in a Japanese family with a mutation of HNF-1β, a hepatic nuclear transcription factor that acts with HNF-1α to regulate gene expression in pancreatic islets. Mutations in this gene cause a moderately severe form of MODY with progression to insulin treatment and severe diabetic complications in those affected. In addition, congenital kidney defects and nephropathy have been reported in affected individuals prior to the onset of diabetes, suggesting that decreased levels of this transcription factor in the kidney, where it is also normally expressed at high levels, may contribute to renal dysfunction.

MODY 6, a milder form of MODY similar to MODY 4, results from mutations in the gene encoding the islet transcription factor neuroD1. Like IPF-1, neuroD1 plays an important role in the expression of insulin and other B cell genes.

The identification of mutations in multiple genes encoding pancreatic transcription factors in patients with MODY has led to the screening of other genes encoding pancreatic transcription factors in patients with diabetes. Heterozygous mutations in genes encoding several factors, including ISL-1, PAX-6, and PAX-4, have been identified in patients with later-onset diabetes. The association of diabetes with heterozygous mutations in so many B cell genes highlights the critical importance of optimal B cell function in metabolic regulation. Even modest defects in glucose-induced insulin secretion can result in hyperglycemia.

Diabetes Mellitus Associated with a Mutation of Mitochondrial DNA

Since sperm do not contain mitochondria, only the mother transmits mitochondrial genes to her offspring. Diabetes due to a mutation of mitochondrial DNA that impairs the transfer of leucine into mitochondrial proteins has been described in 22 Japanese families involving 52 individuals. Most patients have a mild form of maternally transmitted diabetes that responds to oral hypoglycemic agents, although some patients have a nonimmune form of type 1 diabetes. As many as 63% of patients with this subtype of diabetes have a hearing loss, and a smaller proportion (15%) had a syndrome of myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).

Mutant Insulins

Despite awareness of this disorder over the past 12 years, only eight families have been identified as having abnormal circulating forms of insulin. In three of these families, there is impaired cleavage of the proinsulin molecule; in the other five families, abnormalities of the insulin molecule itself have been reported (Table 17-7).

Analysis of the insulin gene, circulating insulin, and clinical features of family members in these cases indicates that individuals with mutant insulin are heterozygous for this defect, with both a normal and an abnormal insulin molecule being equally expressed. However, because the abnormal insulin binds to receptors poorly, it has very low biologic activity and accumulates in the blood to exceed the concentration of the normal insulin. This decreased removal rate of mutant insulin results in hyperinsulinemia after overnight fasting and a subnormal molar ratio of C peptide to immunoreactive insulin. A mild form of diabetes mellitus may or may not be present in association with mutant insulin, depending on the concentration and bioactivity of circulating normal and abnormal insulins and on the insulin responsiveness of peripheral tissues. Since there is no obvious resistance to insulin in any of these cases, it appears that abnormal insulin does not interfere with binding of normal insulin to receptors; therefore, a feature of this syndrome is the normal response to exogenously administered insulin.

With improved screening techniques becoming available such as the polymerase chain reaction, more cases of mutation of the insulin gene will undoubtedly be detected. However, from present experience it is unlikely that patients with this defect will make up more than a very small fraction of the diabetic population.

Table 17-7. Mutant insulins and proinsulins.

 

Amino Acid Substitution

Insulin Chicago (USA)

B 25 (Phe → Leu)

Insulin Los Angeles (USA)

B 24 (Phe → Ser)

Insulin Wakayama (Japan) I, II, III (three families)

A 3 (Val → Leu)

Proinsulin Tokyo (Japan)

Arg 65 (Arg → His)

Proinsulin Boston (USA)

Arg 65 (Arg → ?)

Proinsulin Providence (USA)

B 10 (His → Asp)

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Genetic Defects of Insulin Action

These are rare and unusual causes of diabetes that result from mutations of the insulin receptor (type A insulin resistance) or from other genetically determined postreceptor abnormalities of insulin action. Metabolic abnormalities associated with these disorders may range from hyperinsulinemia and modest hyperglycemia to severe diabetes. Some individuals have acanthosis nigricans, which seems to be a consequence of very high circulating insulin levels that cross over to bind to insulin-like growth factor receptors on epidermal and melanin-containing cutaneous cells. A similar action of extremely high insulin levels on ovarian hilar cells may cause women with these mutations to become virilized and have enlarged cystic ovaries. Leprechaunism and the Rabson-Mendenhall syndrome are two rare pediatric syndromes characterized by extreme insulin resistance due to inheritance of two mutant insulin receptor alleles.

Alterations in the structure and function of the insulin receptor cannot be demonstrated in patients with insulin-resistant lipoatrophic diabetes, suggesting that the defect must reside in postreceptor pathways. Lipoatrophic insulin resistance in animals can be reversed by replacing the adipocyte products leptin and adiponectin, demonstrating the importance of the adipocyte in regulating insulin function.

Diabetes Due to Diseases of the Exocrine Pancreas

Any process that diffusely damages or displaces at least two-thirds of the pancreas can cause diabetes, though individuals with a predisposition to type 2 diabetes are probably more susceptible to developing diabetes with lesser degrees of pancreatic involvement. Acquired causes include pancreatitis, trauma, infection, pancreatic carcinoma, and pancreatectomy. When extensive enough, hemochromatosis and cystic fibrosis can also displace B cells and cause deficiency in insulin secretion. Fibrocalculous involvement of the pancreas may be accompanied by abdominal pain radiating to the back and associated with pancreatic calcifications on x-ray. Since glucagon-secreting A cells are also damaged or removed by these processes, less insulin is usually required for replacement—as compared with most other forms of diabetes, where A cells are intact.

Endocrinopathies

Excess production of certain hormones—growth hormone (acromegaly), glucocorticoids (Cushing's syndrome or disease), catecholamines (pheochromocytoma), thyroid hormone (thyrotoxicosis), glucagon (glucagonoma), or pancreatic somatostatin (somatostatinoma)—can produce the syndrome of type 2 diabetes by a number of mechanisms. In all but the last instance (somatostatinoma), peripheral responsiveness to insulin is impaired. In addition, excess of catecholamines or somatostatin decreases insulin release from B cells. Diabetes mainly occurs in individuals with preexisting defects in insulin secretion, and hyperglycemia typically resolves when the hormone excess is corrected.

Drug- or Chemical-Induced Diabetes

Many drugs are associated with carbohydrate intolerance or frank diabetes mellitus. Some act by interfering with insulin release from the B cells (thiazides, phenytoin), some by inducing insulin resistance (glucocorticoids, oral contraceptive pills), and some by causing B cell destruction such as vacor (a rat poison) and intravenous pentamidine. Patients receiving alpha interferon have been reported to develop diabetes associated with islet cell antibodies and in certain instances severe insulin deficiency.

While calcium channel blockers as well as clonidine are potent inhibitors of glucose-induced insulin release from in vitro preparations of pancreatic B cells, the inhibitory concentrations required are quite high and are not generally achieved during standard antihypertensive therapy with these agents in humans.

Infections Causing Diabetes

Certain viruses have been associated with direct pancreatic B cell destruction in animals. Diabetes is also known to develop frequently in humans who had congenital rubella, though most of these patients have HLA and immune markers characteristic of type 1 diabetes. In addition, coxsackievirus B, cytomegalovirus, adenovirus, and mumps have been implicated in inducing certain cases of diabetes.

Uncommon Forms of Immune- Mediated Diabetes

These include two rare conditions associated with autoantibodies implicated in causing diabetes.

Stiff-man syndrome is an autoimmune disorder of the central nervous system characterized by stiffness and painful spasm of skeletal muscle. Many patients have high titers of autoantibodies that react with glutamic acid decarboxylase (GAD) in the central nervous system and also in pancreatic B cells. Approximately one-third develop severe B cell destruction and diabetes.

A severe form of insulin resistance has been reported in patients who developed high titers of antibodies that

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bind to the insulin receptor and block the action of insulin in its target tissues. As in other states of extreme insulin resistance, these patients often have acanthosis nigricans. In the past, this form of immune-mediated diabetes was termed type B insulin resistance.

Other Genetic Syndromes Sometimes Associated with Diabetes

A number of genetic syndromes are accompanied by an increased incidence of diabetes mellitus. These include the chromosomal abnormalities of Down's syndrome, Klinefelter's syndrome, and Turner's syndrome.

Wolfram's syndrome (DIDMOAD syndrome) is a rare autosomal recessive disease which in its complete form includes optic atrophy, diabetes insipidus, neural deafness, and a nonimmune form of pancreatic B cell death resulting in insulin deficiency and diabetes mellitus. It has recently been found to be associated with a genetic mutation on the short arm of chromosome 4 and an increased frequency of HLA-DR2 antigen.

CLINICAL FEATURES OF DIABETES MELLITUS

The principal clinical features of the two major types of diabetes mellitus are listed for comparison in Table 17-8.

TYPE 1 DIABETES

Patients with type 1 diabetes present with a characteristic symptom complex, as outlined below. An absolute deficiency of insulin results in excessive accumulation of circulating glucose and fatty acids, with consequent hyperosmolality and hyperketonemia. The severity of the insulin deficiency and the acuteness with which the catabolic state develops determine the intensity of the osmotic and ketotic excess.

Table 17-8. Clinical features of diabetes at diagnosis.

 

Diabetes Type 1

Diabetes Type 2

Polyuria and thirst
Weakness or fatigue
Polyphagia with weight loss
Recurrent blurred vision
Vulvovaginitis or pruritus
Peripheral neuropathy
Nocturnal enuresis
Often asymptomatic

++
++
++
+
+
+
++
-

+
+
-
++
++
++
-
++

Clinical Features

  1. SYMPTOMS

Increased urination is a consequence of osmotic diuresis secondary to sustained hyperglycemia. This results in a loss of glucose as well as free water and electrolytes in the urine. Nocturnal enuresis due to polyuria may signal the onset of diabetes in very young children. Thirst is a consequence of the hyperosmolar state, as is blurred vision, which often develops as the lenses and retinas are exposed to hyperosmolar fluids.

Weight loss despite normal or increased appetite is a common feature of type 1 diabetes when it develops subacutely over a period of weeks. The weight loss is initially due to depletion of water, glycogen, and triglyceride stores. Chronic weight loss due to reduced muscle mass occurs as amino acids are diverted to form glucose and ketone bodies.

Lowered plasma volume produces dizziness and weakness due to postural hypotension when sitting or standing. Total body potassium loss and the general catabolism of muscle protein contribute to the weakness.

Paresthesias may be present at the time of diagnosis of type 1 diabetes, particularly when the onset is subacute. They reflect a temporary dysfunction of peripheral sensory nerves and usually clear as insulin replacement restores glycemic levels closer to normal; thus, their presence suggests neurotoxicity from sustained hyperglycemia.

When insulin deficiency is severe and of acute onset, the above symptoms progress in an accelerated manner. Ketoacidosis exacerbates the dehydration and hyperosmolality by producing anorexia, nausea, and vomiting, thus interfering with oral fluid replacement. As plasma osmolality exceeds 330 mosm/kg (normal, 285–295 mosm/kg), impaired consciousness ensues. With progression of acidosis to a pH of 7.1 or less, deep breathing with a rapid ventilatory rate (Kussmaul respiration) occurs as the body attempts to eliminate carbonic acid. With worsening acidosis (to pH 7.0 or less), the cardiovascular system may be unable to maintain compensatory vasoconstriction; severe circulatory collapse may result.

  1. SIGNS

The patient's level of consciousness can vary depending on the degree of hyperosmolality. When insulin deficiency develops relatively slowly and sufficient water intake is maintained to permit renal excretion of glucose and appropriate dilution of extracellular sodium chloride concentration, patients remain relatively alert and

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physical findings may be minimal. When vomiting occurs in response to worsening ketoacidosis, dehydration progresses and compensatory mechanisms become inadequate to keep plasma osmolality below 330 mosm/kg. Under these circumstances, stupor or even coma may occur. Evidence of dehydration in a stuporous patient, with rapid deep breathing and the fruity breath odor of acetone, suggests the diagnosis of diabetic ketoacidosis.

Postural hypotension indicates a depleted plasma volume; hypotension in the recumbent position is a serious prognostic sign. Loss of subcutaneous fat and muscle wasting are features of more slowly developing insulin deficiency. In occasional patients with slow, insidious onset of insulin deficiency, subcutaneous fat may be considerably depleted. An enlarged liver, eruptive xanthomas on the flexor surface of the limbs and on the buttocks, and lipemia retinalis indicate that chronic insulin deficiency has resulted in chylomicronemia, with circulating triglycerides elevated usually to over 2000 mg/dL (Chapter 19).

TYPE 2 DIABETES

Patients with type 2 diabetes also present with characteristic signs and symptoms. The presence of obesity or a strongly positive family history of mild diabetes also suggests a high risk for the development of type 2 diabetes.

Clinical Features

  1. SYMPTOMS

The classic symptoms of polyuria, thirst, recurrent blurred vision, paresthesias, and fatigue are manifestations of hyperglycemia and osmotic diuresis and are therefore common to both forms of diabetes. However, many patients with type 2 diabetes have an insidious onset of hyperglycemia and may be relatively asymptomatic initially. This is particularly true in obese patients, whose diabetes may be detected only after glycosuria or hyperglycemia is noted during routine laboratory studies. Chronic skin infections are common. Generalized pruritus and symptoms of vaginitis are frequently the initial complaints of women with type 2 diabetes. Diabetes should be suspected in women with chronic candidal vulvovaginitis as well as in those who have delivered large infants (> 9 lb, or 4.1 kg) or have had polyhydramnios, preeclampsia, or unexplained fetal losses. Occasionally, a man with previously undiagnosed diabetes may present with impotence.

  1. SIGNS

Nonobese patients with this mild form of diabetes often have no characteristic physical findings at the time of diagnosis. Obese diabetics may have any variety of fat distribution; however, diabetes seems to be more often associated in both men and women with localization of fat deposits on the upper part of the body (particularly the abdomen, chest, neck, and face) and relatively less fat on the appendages, which may be quite muscular. This centripetal fat distribution has been termed “android”and is characterized by a high waist to hip ratio. It differs from the more centrifugal “gynecoid” form of obesity, in which fat is localized more in the hips and thighs and less in the upper parts of the trunk. Refined radiographic techniques of assessing abdominal fat distribution with CT scans has documented that a “visceral” obesity, due to accumulation of fat in the omental and mesenteric regions, correlates with insulin resistance, whereas fat predominantly in subcutaneous tissues of the abdomen has little, if any, association with insulin insensitivity. Mild hypertension may be present in obese diabetics, particularly when the“android” form of obesity is predominant. In women, candidal vaginitis with a reddened, inflamed vulvar area and a profuse whitish discharge may herald the presence of diabetes.

Laboratory Findings in Diabetes Mellitus

Tests of urine glucose and ketone bodies as well as whole blood or plasma glucose measured in samples obtained under basal conditions and after glucose administration are very important in evaluation of the diabetic patient. Tests for glycosylated hemoglobin have proved useful in both initial evaluation and in assessment of the effectiveness of therapeutic management. In certain circumstances, measurements of insulin or C peptide levels and levels of other hormones involved in carbohydrate homeostasis (eg, glucagon, GH) may be useful. In view of the increased risk of atherosclerosis in diabetics, determination of serum cholesterol (including its beneficial HDL fraction) and triglycerides may be helpful. From these three measurements, an estimate of LDL-cholesterol can be made. (See Chapter 19.)

URINALYSIS

Glycosuria

Several problems are associated with using urine glucose as an index of blood glucose, regardless of the method employed. First of all, the glucose concentration in bladder urine reflects the blood glucose at the time the urine was formed. Therefore, the first voided specimen in the morning contains glucose that was excreted throughout the night and does not reflect the morning blood glucose at all. Some improvement in

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the correlation of urine glucose to blood glucose can be obtained if the patient “double voids”—that is, empties the bladder completely, discards that sample, and then urinates again about one-half hour later, testing only the second specimen for glucose content. However, difficulty in completely emptying the bladder (large residual volumes), problems in understanding the instructions, and the inconvenience impair the usefulness of this test. Self-monitoring of blood glucose has replaced urine glucose testing in most patients with diabetes (particularly those receiving insulin therapy).

Several commercial products are available for determining the presence and amount of glucose in urine. The older and more cumbersome bedside assessment of glycosuria with Clinitest tablets has generally been replaced by the dipstick method, which is rapid, convenient, and glucose-specific. This method consists of paper strips (Clinistix, Tes-Tape) impregnated with enzymes (glucose oxidase and hydrogen peroxidase) and a chromogenic dye that is colorless in the reduced state. Enzymatic generation of hydrogen peroxide oxidizes the dye to produce colors whose intensity depends on the glucose concentration. These dipsticks are sensitive to as little as 0.1% glucose (100 mg/dL) but do not react with the smaller amounts of glucose normally present in nondiabetic urine. The strips are subject to deterioration if exposed to air, moisture, and extreme heat and must be kept in tightly closed containers except when in use. False-negative results may be obtained in the presence of alkaptonuria and when certain substances such as salicylic acid or ascorbic acid are ingested in excess. All of these false-negative results occur because of the interference of strong reducing agents with oxidation of the chromogen.

Differential Diagnosis of Glycosuria

Although glycosuria reflects hyperglycemia in over 90% of patients, two major classes of nondiabetic glycosuria must be considered:

  1. NONDIABETIC GLYCOSURIA DUE TO GLUCOSE

This occurs when glucose appears in the urine despite a normal amount of glucose in the blood. Disorders associated with abnormalities in renal glucose handling include Fanconi's syndrome (an autosomal dominant genetic disorder), dysfunction of the proximal renal tubule, and a benign familial disorder of the renal tubule manifest only by a defect in renal glucose reabsorption (occurs predominantly in males).

In addition, glycosuria is relatively common in pregnancy as a consequence of the increased load of glucose presented to the tubules by the elevated glomerular filtration rate during pregnancy. As many as 50% of pregnant women normally have demonstrable sugar in the urine, especially after the first trimester. This sugar is almost always glucose except during the late weeks of pregnancy, when lactose may be present (see below).

  1. NONDIABETIC GLYCOSURIA DUE TO SUGARS OTHER THAN GLUCOSE

Occasionally, a sugar other than glucose is excreted in the urine. Lactosuria during the late stages of pregnancy and the period of lactation is the most common example. Much rarer are other conditions in which inborn errors of metabolism allow fructose, galactose, or a pentose (1-xylose) to be excreted in the urine. Testing the urine with glucose-specific strips will help differentiate true glucosuria from other glycosurias.

Ketonuria

In the absence of adequate insulin, three major “ketone bodies” are formed and excreted into the urine: β-hydroxybutyric acid, acetoacetic acid, and acetone (see also Serum Ketone Determinations, below). Commercial products are available to test for the presence of ketones in the urine. Acetest tablets, Ketostix, and Keto-Diastix utilize a nitroprusside reaction that measures only acetone and acetoacetate. Although these tests do not detect β-hydroxybutyric acid, which lacks a ketone group, the semiquantitative estimation of the other ketone bodies is nonetheless usually adequate for clinical assessment of ketonuria. Ketostix and Keto-Diastix have short shelf-lives once the containers are opened and thus may give false-negative results.

Other conditions besides diabetic ketoacidosis may cause ketone bodies to appear in the urine; these include starvation, high-fat diets, alcoholic ketoacidosis, fever, and other conditions in which metabolic requirements are increased.

Proteinuria

Proteinuria as noted on a routine dipstick examination of the urine is often the first sign of renal complications of diabetes. If proteinuria is detected, a 24-hour urine collection should be analyzed to quantify the degree of proteinuria (normal individuals excrete < 30 mg of protein per day) and the rate of urinary creatinine excretion; at the same time, serum creatinine levels should be determined so that the creatinine clearance (an estimate of the glomerular filtration rate) can be calculated. In some cases, heavy proteinuria (3–5 g/d) develops later, along with other features of the nephrotic syndrome such as edema, hypoalbuminemia, and hypercholesterolemia.

Microalbuminuria

Urinary albumin can now be detected in microgram concentrations using a radioimmunoassay method that

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is more sensitive than the dipstick method, whose minimal detection limit is 0.3–0.5%. Conventional 24-hour urine collections, in addition to being inconvenient for patients, also show wide variability of albumin excretion, since several factors such as sustained upright posture, dietary protein, and exercise tend to increase albumin excretion rates. For these reasons, many clinics prefer to screen patients by measuring the albumin-creatinine ratio in an early morning spot urine collected upon awakening—prior to breakfast or exercise—and brought in by the patient for laboratory analysis. A ratio of albumin (ľg/L) to creatinine (mg/L) of < 30 is normal, and a ratio of 30–300 indicates abnormal microalbuminuria. When this screening test is positive, a timed overnight urine collection is recommended. This begins at bedtime, when the urine is discarded and the time recorded. The collection is ended at the time the bladder is emptied the next morning, and this urine, as well as any other urine voided overnight, is assayed for albumin. Normal subjects excrete less than 15 ľg/min during overnight urine collections; values between 20 and 200 ľg/min or higher represent abnormal microalbuminuria, which may be an early predictor of the development of diabetic nephropathy.

BLOOD GLUCOSE TESTING

Normal Values

The range of normal fasting plasma or serum glucose is 70–110 mg/dL (3.9–6.1 mmol/L). Plasma or serum from venous blood samples has the advantage over whole blood of providing values for glucose that are independent of hematocrit and reflect levels in the interstitial spaces to which body tissues are exposed. For these reasons—and because plasma and serum lend themselves to automated analytic procedures—they are used in most laboratories. The glucose concentration is 10–15% higher in plasma or serum than in whole blood because structural components of blood cells are absent. Whole blood glucose determinations are seldom used in clinical laboratories but have been used by diabetic patients during self-monitoring of capillary blood glucose, a technique widely accepted in the management of diabetes mellitus (see below). Recently, however, many new reflectance meters have been modified to directly record serum glucose rather than to calculate whole blood glucose concentrations.

Venous Blood Samples

Samples should be collected in tubes containing sodium fluoride, which prevents glycolysis in the blood sample that would artifactually lower the measured glucose level. If such tubes are not available, samples must be centrifuged within 30 minutes of collection and the plasma or serum stored at 4 °C.

The laboratory methods regularly used for determining plasma glucose utilize enzymatic methods (such as glucose oxidase or hexokinase), colorimetric methods (such as o-toluidine), or automated methods. The automated methods utilize reduction of copper or iron compounds by reducing sugars in dialyzed serum. They are convenient but are not specific for glucose, since they react with other reducing substances (which are elevated in azotemia or with high ascorbic acid intake).

Capillary Blood Samples

There are several paper strip methods (glucose oxidase, glucose dehydrogenase or hexokinase) for measuring glucose on capillary blood samples. A reflectance photometer or an amperometric system is then used to measure the reaction that takes place on the reagent strip. The current blood glucose meters require very small volumes of blood (as little as 0.3 ľL); automatically time the entire reaction (as short as 5 seconds); do not require wiping off the strip; and store previous values in an electronic memory for downloading onto a personal computer. Very high or very low hematocrit values can lead to inaccuracies in measurements. It is therefore important to refer to the manufacturer's information sheet regarding hematocrit ranges for particular meters. Some meters such as the FreeStyle (Therasense, Inc) have been approved for measuring glucose in blood samples obtained at alternative sites such as the forearm and thigh. There is, however, a 5- to 20-minute lag in the glucose response on the arm with respect to the glucose response on the finger. Forearm blood glucose measurements could therefore result in a delay in the detection of rapidly developing hypoglycemia. To monitor their own blood glucose levels, patients must prick their fingers with a lancet. Thirty-gauge lancets are now available that reduce discomfort while providing an adequate blood drop for measurement. Automatic spring-loaded devices such as the Autolet or SoftClix are useful in simplifying the finger-pricking technique and ensuring an adequate blood sample. Bedside glucose monitoring in a hospital setting requires rigorous quality control programs and certification of personnel to avoid errors. When properly done, these methods are also of great value to health care professionals in the bedside management of seriously ill hospitalized diabetic patients.

Interstitial Fluid Glucose Samples

Two continuous glucose monitoring systems are currently available for clinical use. The system manufactured by MiniMed Medtronic involves inserting a subcutaneous sensor (rather like an insulin pump cannula)

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that measures glucose concentrations in the interstitial fluid for 72 hours. The glucose values are not available for evaluation at time of measurement—the data are downloaded onto a computer in a physician's office after collection. The other system, Glucowatch, measures glucose in interstitial fluid extracted through intact skin by applying a low electric current (reverse iontophoresis). This process can cause local skin irritation, and sweating invalidates the glucose measurement. Both systems require calibration with finger blood glucose measurements. Their main value appears to be in identifying episodes of asymptomatic hypoglycemia, especially at night.

SERUM KETONE DETERMINATIONS

As noted above in the section on ketonuria, there are three major ketone bodies: β-hydroxybutyrate (often the most prevalent in diabetic ketoacidosis), acetoacetate, and acetone. The same testing materials used for determining urine ketones may be used to measure serum (or plasma) ketones. However, whereas urine readily penetrates “intact” Acetest tablets, more viscous fluids such as serum or plasma do not have access to the bulk of the tablet unless it is first crushed. When a few drops of serum are placed on a crushed Acetest tablet, the appearance of a purple color indicates the presence of ketones. A strongly positive reaction in undiluted serum correlates with a serum ketone concentration of at least 4 mmol/L. It must be kept in mind that Acetest tablets (as well as Ketostix and Keto-Diastix) utilize the nitroprusside reaction, which measures only acetoacetate and acetone. Specific enzymatic techniques are available to quantitate each of the ketone acids, but these techniques are cumbersome and not necessary in most clinical situations.

GLYCATED HEMOGLOBIN ASSAYS

Glycohemoglobin (GHb) is produced by a ketoamine reaction between glucose and the amino terminal amino acid of both beta chains of the hemoglobin molecule. The major form of glycohemoglobin is hemoglobin A1c, which normally comprises only 4–6% of total hemoglobin. The remaining glycohemoglobins (2–4% of total hemoglobin) contain phosphorylated glucose or fructose and are termed hemoglobin A1a and A1b, respectively. The hemoglobin A1c fraction is abnormally elevated in diabetics with chronic hyperglycemia. Specific assays for hemoglobin A1care technically less convenient than assays for total glycohemoglobin and offer little advantage for clinical purposes. Therefore, many laboratories measure the sum of these three glycohemoglobins and report it simply as hemoglobin A1 or “glycohemoglobin.”

The glycation of hemoglobin is dependent on the concentration of blood glucose. The reaction is not reversible, so that the half-life of glycated hemoglobin relates to the life span of red cells (which normally circulate for up to 120 days). Thus, glycohemoglobin generally reflects the state of glycemia over the preceding 8–12 weeks, thus providing a method of assessing chronic diabetic control. A hemoglobin A1close to the normal range (4.5–6%) or a glycated hemoglobin of 5–7% would reflect good control during the preceding 2–3 months, whereas a hemoglobin A1c > 8% or glycated hemoglobin greater than 8% would reflect poor control during the same period.

Conditions Interfering with Glycohemoglobin Measurements (Table 17-9)

The most common laboratory error in measuring glycohemoglobins occurs when chromatographic methods measure an acutely generated intermediary aldimine in blood (prehemoglobin A1c), which fluctuates directly with the prevailing blood glucose level. This artifact can falsely elevate glycohemoglobin by as much as 1–2% during an episode of acute hyperglycemia. It can be eliminated either by washing the red blood cells with saline prior to assay or by dialyzing the hemolysate prior to chromatography. Other substances that falsely elevate “glycohemoglobin” are carbamoylated hemoglobin and hemoglobin F; the former is seen in association with uremia, and the latter circulates in some adults with genetic or hematologic disorders. In these cases, more intricate methodology such as thiobarbituric acid colorimetry or isoelectric focusing is required to distinguish hemoglobin A1c from the interfering substance.

Table 17-9. Factors interfering with chromatographic measurement of glycohemoglobins.

Substances causing falsely high values:
   Prehemoglobin A1c (reversible aldimine intermediate)
   Carbamoylated hemoglobin (uremia)
   Hemoglobin F
Conditions causing falsely low values:
      Hemoglobinopathies (hemoglobins C, D, and S)
      Reduced life span of erythrocytes:1
         Hemorrhage of therapeutic phlebotomies
         Hemolytic disorders

1This causes falsely low values of all methods used to measure HbA1c.

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Hemoglobinopathies such as those associated with hemoglobin C, D, and S will cause falsely low values, since their glycosylated products elute only partially from chromatographic columns. In addition, these hemoglobinopathies are often associated with hemolytic anemias that shorten the life span of red blood cells, thereby further lowering glycohemoglobin measurements. Falsely low values are also seen in patients with chronic or acute blood loss from hemorrhage or from phlebotomies in diabetic patients with hemochromatosis; under these conditions, measurements of glycohemoglobin are not valid for assessment of diabetic therapy.

Glycohemoglobin assays suffer from the lack of universally available reference standards. The National Glycohemoglobin Standardization Program, sponsored in part by the American Diabetes Association to standardize GHb determinations, began in mid 1996 and is currently in progress to certify the manufacturers of GHb assays. Clinical laboratories are urged to use only“certified” assays and to participate also in a proficiency testing survey by the College of American Pathologists. However, in a reliable laboratory where reversible aldimines (prehemoglobin A1c) are routinely removed prior to chromatography, they are useful in assessing the effectiveness of diabetic therapy and particularly helpful in evaluating the reliability of a patient's self-monitoring records of urine or blood glucose values. A glycated hemoglobin test is currently not recommended for diagnostic screening purposes since the test is generally too insensitive to rule out impaired glucose tolerance. However, a value above the normal range in a certified laboratory is generally a specific indicator of diabetes mellitus.

When abnormal hemoglobins or hemolytic states affect the interpretation of glycohemoglobin results or when a narrower time frame is required, eg, when ascertaining glycemic control at the time of conception in a diabetic woman who has recently become pregnant, serum fructosamine assays offer some advantage. Serum fructosamine is formed by nonenzymatic glycosylation of serum proteins (predominantly albumin). Since serum albumin has a much shorter half-life (14–21 days) than hemoglobin, serum fructosamine generally reflects the state of glycemic control for only the preceding 2 weeks. In most circumstances, however, glycohemoglobin assays remain the preferred method for assessing long-term glycemic control in diabetic patients.

LIPOPROTEINS IN DIABETES

Levels of circulating lipoprotein are dependent on normal levels and action of insulin, just as is the plasma glucose. In type 1 diabetes, moderately deficient control of hyperglycemia is associated with only a slight elevation of LDL cholesterol and serum triglycerides and little if any changes in HDL cholesterol. Once the hyperglycemia is corrected, lipoprotein levels are generally normal. However, in obese patients with type 2 diabetes, a distinct “diabetic dyslipidemia” is characteristic of the insulin resistance syndrome. Its features are a high serum triglyceride level (300–400 mg/dL), a low HDL cholesterol (less than 30 mg/dL), and a qualitative change in LDL particles producing a smaller dense LDL whose membrane carries supranormal amounts of free cholesterol. Since a low HDL cholesterol is a major feature predisposing to macrovascular disease, the term“dyslipidemia” has preempted the previous label of “hyperlipidemia,” which mainly described the elevated triglycerides. Measures designed to correct this obesity and hyperglycemia, such as exercise, diet, and hypoglycemic therapy, are the treatment of choice for diabetic dyslipidemia, and in occasional patients in which normal weight was achieved all features of the lipoprotein abnormalities cleared. Since primary disorders of lipid metabolism may coexist with diabetes, persistence of lipid abnormalities after restoration of normal weight and blood glucose should prompt a diagnostic workup and possible pharmacotherapy of the lipid disorder.Chapter 19 discusses these matters in detail.

DIAGNOSIS OF DIABETES MELLITUS

Diagnostic Criteria

  1. Symptoms of diabetes (thirst, increased urination, unexplained weight loss) plus a random plasma glucose concentration > 200 mg/dL (11.1 mmol/L).
  2. Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) after an overnight (at least 8-hour) fast.
  3. Two-hour plasma glucose > 200 mg/dL (11.1 mmol/L) during a standard 75 g oral glucose tolerance test (see below).

These three criteria are the most recent recommendations of an international committee of diabetes experts who have revised previous diagnostic criteria. The diagnosis of diabetes can be based on any one of the above criteria but should be confirmed on a later day with one of the three methods listed above.

A major change from previous criteria is the lowering of the cut-off level of fasting plasma glucose from > 140 mg/dL (7.8 mmol/L) to > 126 mg/dL (7.0 mmol/ L). A new diagnostic category, impaired fasting glucose (IFG), has been added to impaired glucose tolerance

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(IGT). Both terms refer to a stage intermediate between normal glucose homeostasis and diabetes. IFG refers to a level of plasma glucose after an overnight fast that is > 110 mg/dL (above the normal upper limit of 110 mg/dL [6.1 mmol/L]) but less than the level of 126 mg/dL (7.0 mmol /L), which indicates diabetes.

The corresponding category for the IGT when the oral glucose tolerance test is used is as follows:

Two-hour plasma glucose > 140 mg/dL (7.8 mmol/L) but less than 200 mg/dL (11.1 mmol/L).

Many individuals with IGT are euglycemic in their daily lives and may have normal or near-normal glycosylated hemoglobin levels. These subjects may also have fasting plasma glucose levels in the normal range (< 110 mg/dL [6.1 mmol/L]) and often manifest their impaired glucose metabolism only when challenged with a standardized oral glucose tolerance test.

ORAL GLUCOSE TOLERANCE TEST

An oral glucose tolerance test is only rarely indicated, as there is a preference in clinical situations to use fasting plasma glucose levels for diagnosis because they are easier and faster to perform, more convenient and acceptable to patients, more reproducible, and less expensive. Recently, an international committee of diabetologists has recommended simplifying the glucose tolerance test to require only an overnight fasting measurement and one 2 hours after a standard 75 g oral glucose load. Samples at 30, 60, and 90 minutes are no longer required.

If the fasting plasma glucose is between 110 and 126 mg/dL (“impaired fasting glucose”), an oral glucose tolerance test may be considered, especially in men with erectile dysfunction or women who have delivered infants above 9 lb (4.1 kg) birth weight or have had recurrent vaginal yeast infections.

Preparation for Test

In order to optimize insulin secretion and effectiveness, especially when patients have been on a low-carbohydrate diet, a minimum of 150–200 g of carbohydrate per day should be included in the diet for 3 days preceding the test. The patient should eat nothing after midnight prior to the test day.

Testing Procedure

Adults are given 75 g of glucose in 300 mL of water; children are given 1.75 g of glucose per kilogram of ideal body weight. The glucose load is consumed within 5 minutes. Blood samples for plasma glucose are obtained at 0 and 120 minutes after ingestion of glucose.

Interpretation (Table 17-10)

An oral glucose tolerance test is normal if the fasting venous plasma glucose value is less than 110 mg/dL (6.1 mmol/L) and the 2-hour value falls below 140 mg/dL (7.8 mmol/L). A fasting value of 126 mg/dL (7 mmol/L) or higher or a 2-hour value of greater than 200 mg/dL (11.1 mmol/L) is diagnostic of diabetes mellitus. The diagnosis of “impaired glucose tolerance” is reserved for values between the upper limits of normal and those values diagnostic of diabetes. False-positive results may occur in patients who are malnourished at test time, bedridden, or afflicted with an infection or severe emotional stress. Diuretics, oral contraceptives, glucocorticoids, excess thyroxine, phenytoin, nicotinic acid and some of the psychotropic drugs may also cause false-positive results.

Table 17-10. The Diabetes Expert Committee criteria for evaluating the standard oral glucose tolerance test.1

 

Normal Glucose Tolerance

Impaired Glucose Tolerance

Diabetes Mellitus2

Fasting plasma glucose (mg/dL)

< 110

110–125

≥ 126

Two hours after glucose load (mg/dL)

< 140

≥ 140 but < 200

≥ 200

1Give 75 g of glucose dissolved in 300 mL of water after an overnight fast in subjects who have been receiving at least 150–200 g of carbohydrate daily for 3 days before the test.

2A fasting plasma glucose > 126 mg/dL is diagnostic of diabetes if confirmed on a subsequent day to be in the diabetic range after either an overnight fast or 2 hours after a standard glucose load.

INSULIN LEVELS

To measure insulin levels during the glucose tolerance test, serum or plasma must be separated within 30 minutes after collection of the specimen and frozen prior to assay. Normal immunoreactive insulin levels range from 5–20 ľU/mL in the fasting state, reach 50–130 ľU/mL at 1 hour, and usually return to levels below 30 ľU/mL by 2 hours. Insulin levels are rarely of clinical

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usefulness during glucose tolerance testing for the following reasons: When fasting glucose levels exceed 120 mg/dL (6.7 mmol/L), B cells generally have reduced responsiveness to further degrees of hyperglycemia regardless of the type of diabetes. When fasting glucose levels are below 120 mg/dL (6.7 mmol/L), late hyperinsulinism may occur as a result of insulin resistance in type 2 diabetes; however, it also may occur even in mild forms or in the early phases of type 1 diabetes when sluggish early insulin release results in late hyperglycemia that may stimulate excessive insulin secretion at 2 hours.

INTRAVENOUS GLUCOSE TOLERANCE TEST

The intravenous glucose tolerance test is performed by giving a rapid infusion of glucose followed by serial plasma glucose measurements to determine the disappearance rate of glucose per minute. The disappearance rate reflects the patient's ability to dispose of a glucose load. Perhaps its most widespread present use is to screen siblings at risk for type 1 diabetes to determine if autoimmune destruction of B cells has reduced peak early insulin responses (at 1–5 minutes after the glucose bolus) to levels below the normal lower limit of 40 ľU/mL. It has also been used to evaluate glucose tolerance in patients with gastrointestinal abnormalities (such as malabsorption). Caution should be used in clinical interpretation of the results, because the test bypasses normal glucose absorption and associated changes in gastrointestinal hormones that are important in carbohydrate metabolism. Furthermore, the test is relatively insensitive, and adequate criteria for diagnosis of diabetes have not been established for the various age groups.

Preparation for Test

Preparation is the same as for the oral glucose tolerance test (see above).

Testing Procedure

Intravenous access is established and the patient is given a bolus of 50 g of glucose per 1.7 m2 body surface area (or 0.5 g/kg of ideal body weight) as a 25% or 50% solution over 2–3 minutes. Timing begins with injection. Samples for plasma glucose determination are obtained from an indwelling needle in the opposite arm at 0, 10, 15, 20, and 30 minutes. The plasma glucose values are plotted on semilogarithmic paper against time. K, a rate constant that reflects the rate of fall of blood glucose in percent per minute, is calculated by determining the time necessary for the glucose concentration to fall by one-half (t1/2) and using the following equation:

The average K value for a nondiabetic patient is approximately 1.72% per minute; this value declines with age but remains above 1.3% per minute. Diabetic patients almost always have a K value of less than 1% per minute.

Careful attention to venous access is essential, since leakage or infiltration of this hypertonic solution into subcutaneous tissues can cause considerable discomfort which can last for several days.

Clinical Trials in Diabetes

A fundamental controversy regarding whether microangiopathy is related exclusively to the existence and duration of hyperglycemia or whether it reflects a separate genetic disorder has recently been resolved by the findings of the Diabetes Control and Complications Trial (DCCT) and of the United Kingdom Prospective Diabetes Study (UKPDS), which confirmed the beneficial effects of intensive therapy to achieve improved glycemic control in both type 1 and type 2 diabetes, respectively (see below).

With increased understanding of the pathophysiology of both type 1 and type 2 diabetes, large prospective studies have been initiated in attempts to prevent onset of these disorders. Investigators with the Diabetes Prevention Trial 1 (DPT-1) and the Diabetes Prevention Program (DPP) have recently reported their findings (see below).

Clinical Trials in Type 1 Diabetes

  1. THE DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT)

In September 1993, a long-term randomized prospective study involving 1441 type 1 diabetic patients in 29 medical centers reported that “near” normalization of blood glucose resulted in a delay in the onset and a major slowing of the progression of established microvascular and neuropathic complications of diabetes during an up to 10-year follow-up period.

The patients were divided into two study groups with equal numbers of subjects. Approximately half of the total group had no detectable diabetic complications (prevention trial), whereas mild background retinopathy was present in the other half (intervention

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trial). Some patients in the latter group had slightly elevated microalbuminuria and mild neuropathy, but no one with serious diabetic complications was enrolled in the trial. Multiple insulin injections (66%) or insulin pumps (34%) were used in the intensively treated group, and those subjects were trained to modify their therapy in response to frequent glucose monitoring. The conventionally treated group used no more than two insulin injections, and clinical well-being was the goal with no attempt to modify management based on glycated hemoglobin or glucose results. Patients were between the ages of 13 and 19 years, with an average age of 27 years, and half of the subjects were women.

In the intensively treated subjects, a mean glycated hemoglobin of 7.2% (normal, > 6%) and a mean blood glucose of 155 mg/dL were achieved, whereas in the conventionally treated group glycated hemoglobin averaged 8.9%, with an average blood glucose of 225 mg/dL. Over the study period, which averaged 7 years, there was an approximately 60% reduction in risk of diabetic retinopathy, nephropathy, and neuropathy in the intensively treated group.

Intensively treated patients had a threefold greater risk of serious hypoglycemia as well as a greater tendency toward weight gain. However, there were no deaths from hypoglycemia in any subjects in the DCCT study, and no evidence of posthypoglycemic neurologic damage was detected.

The general consensus of the American Diabetes Association is that intensive insulin therapy associated with comprehensive self-management training should become standard therapy in most type 1 patients after the age of puberty. Exceptions include those with advanced renal disease and the elderly, since in these groups the detrimental risks of hypoglycemia outweigh the benefit of tight glycemic control. In children under age 7 years, the extreme susceptibility of the developing brain to damage from hypoglycemia contraindicates attempts at tight glycemic control, particularly since diabetic complications do not seem to occur until some years after the onset of puberty.

  1. THE DIABETES PREVENTION TRIAL-1

This NIH-sponsored multicenter study was designed to determine whether the development of type 1 diabetes could be prevented or delayed by immune intervention therapy. The study recruited 339 first-degree or second-degree relatives of patients with type 1 diabetes who—by genetic, immunologic, and metabolic testing—were deemed to be at high risk of developing diabetes. These subjects lacked a protective HLA haplotype; were islet cell antibody-positive; had impaired first-phase insulin response in an intravenous glucose tolerance test; and had normal or impaired oral glucose tolerance tests. One hundred and sixty-nine test subjects were assigned to the intervention group and received daily low-dose subcutaneous ultralente insulin plus annual 4-day continuous intravenous infusions of insulin. One hundred and seventy subjects were assigned to an observation group. The primary end point was development of diabetes, and the median follow-up was 3.7 years. Unfortunately, the intervention failed to delay or prevent onset of type 1 diabetes—69 subjects in the intervention group and 70 subjects in the observation group developed diabetes.

Although this trial has been discontinued, a related study is still in progress using oral insulin in lower-risk first-degree relatives who have islet cell antibodies but whose early insulin release remains intact.

  1. IMMUNE INTERVENTION TRIALS IN NEW-ONSET TYPE 1 DIABETES

At time of diagnosis of type 1 diabetes, patients still have significant B cell function. This explains why soon after diagnosis patients go into a partial clinical remission (“honeymoon”) requiring little or no insulin. This clinical remission is short-lived, however, and eventually patients lose all B cell function and have more labile glucose control. Attempts have been made to prolong this partial clinical remission using drugs such as cyclosporine, azathioprine, prednisone, and antithymocyte globulin. These agents, however, had limited efficacy, and there were concerns about their toxicity and the need for continuous treatment.

Recently, newer agents that may induce immune tolerance and appear to have few side effects have been used in new-onset type 1 patients. Two small studies, one with a heat shock protein peptide (DiaPep277) and another with an anti-CD3 antibody, have demonstrated that these agents can preserve endogenous insulin production. Larger phase 2 clinical trials are currently in progress.

Clinical Trials in Type 2 Diabetes

  1. KUMAMOTO STUDY

The Kumamoto study involved a relatively small number of type 2 patients (n = 110) who were nonobese and only slightly insulin-resistant, requiring less than 30 units of insulin per day for intensive therapy. Over a 6-year period it was shown that intensive insulin therapy, achieving a mean HbA1c of 7.1%, significantly reduced microvascular end points compared with conventional insulin therapy, achieving a mean HbA1c of 9.4%. Cardiovascular events were neither worsened nor improved by intensive therapy, and weight changes were likewise not influenced by either form of treatment.

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  1. VETERANS AFFAIRS COOPERATIVE STUDY

This study involved 153 obese men who were moderately insulin-resistant and were followed for only 27 months. Intensive insulin treatment resulted in mean HbA1c differences from conventional insulin treatment (7.2% versus 9.5%) that were comparable to those reported in the Kumamoto study. However, a difference in cardiovascular outcome in this study has prompted some concern. While conventional insulin therapy resulted in 26 total cardiovascular events, there were 35 total cardiovascular events in the intensively treated group. This difference in this relatively small population was not statistically significant, but when the total events were broken down to major events (myocardial infarction, stroke, cardiovascular death, congestive heart failure, amputation), the 18 major events in the group treated intensively with insulin were reported to be statistically greater (P = .04) than the ten major events occurring with conventional treatment. While this difference may be a chance consequence of studying too few patients for too short a time, it raises the possibility that insulin-resistant patients with visceral obesity and long-standing type 2 diabetes may develop a greater risk of a serious cardiovascular event when intensively treated with high doses of insulin. At the end of the study, 64% of the intensively treated group were receiving either (1) an average of 113 units of insulin per day when only two injections per day were used or (2) an average of 133 units per day when multiple injections were given. Unfortunately, the UKPDS (see below), which did not find any effect of intensive therapy on cardiovascular outcomes, does not resolve the concern generated by the Veterans Affairs study, since their patient population consisted of newly diagnosed diabetic patients in whom the obese subgroup seemed to be less insulin-resistant, requiring a median insulin dose for intensive therapy of only 60 units per day by the 12th year of the study.

  1. THE UNITED KINGDOM PROSPECTIVE DIABETES STUDY (UKPDS)

This study began in 1977 as a multicenter clinical trial designed to determine in type 2 diabetic patients whether the risk of macrovascular or microvascular complications could be reduced by intensive blood glucose control with oral hypoglycemic agents or insulin and whether any particular therapy was better than the others. Newly diagnosed type 2 diabetic patients aged 25–65 years were recruited between 1977 and 1991, and a total of 3867 were studied over 10 years. Their median age at baseline was 54 years; 44% were overweight (> 20% over ideal weight), and baseline HbA1c was 9.1%. Therapies were randomized to include a control group on diet alone and separate groups intensively treated with either insulin, chlorpropamide, glyburide, or glipizide. Metformin was included as a randomization option in a subgroup of 342 overweight patients, and—much later in the study—an additional subgroup of both normal-weight and overweight patients who were responding unsatisfactorily to sulfonylurea therapy were randomized to either continue on their sulfonylurea therapy alone or to have metformin combined with it.

In 1987, a further modification was made to evaluate whether tight control of blood pressure with stepwise antihypertensive therapy would prevent macrovascular and microvascular complications in 758 hypertensive patients among this UKPDS population—compared with 390 patients whose blood pressure was treated less intensively. The tight control group were randomly assigned to treatment with either an angiotensin-converting enzyme (ACE) inhibitor (captopril) or a beta-blocker (atenolol). Both drugs were stepped up to maximum doses of 100 mg/d, and then, if blood pressure remained higher than the target level of < 150/85 mm Hg, more drugs were added in the following stepwise sequence—a diuretic, slow-release nifedipine, methyldopa, and prazosin—until the target level of tight control was achieved. In the control group, hypertension was conventionally treated to achieve target levels < 180/105 mm Hg, but these patients were not given either ACE inhibitors or beta-blockers.

  1. Results of the UKPDS—Intensive glycemic therapy in the entire group of 3897 newly diagnosed type 2 diabetic patients followed over 10 years showed the following: Intensive treatment with either sulfonylureas, metformin, combinations of these, or insulin achieved mean HbA1clevels of 7.0%. This level of glycemic control decreased the risk of microvascular complications in comparison with conventional therapy (mostly diet alone), which achieved mean levels of HbA1cof 7.9%. Weight gain occurred in intensively treated patients except when metformin was used as monotherapy. No cardiovascular benefits nor adverse cardiovascular outcomes were noted regardless of the therapeutic agent. Hypoglycemic reactions occurred in the intensive treatment groups, but only one death from hypoglycemia was documented out of 27,000 patient-years of intensive therapy.

When therapeutic subgroups were analyzed, some unexpected and paradoxical results were noted. Among the obese patients, intensive treatment with insulin or sulfonylureas did not reduce microvascular complications compared with diet therapy alone. This was in contrast to the significant benefit of intensive therapy with these drugs in the total group. Furthermore, intensive therapy with metformin was more beneficial in obese persons than diet alone with regard to reducing myocardial infarctions, strokes, and diabetes-related

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deaths, but there was no significant reduction of diabetic microvascular complications with metformin as compared with the diet group. Moreover, in the subgroup of obese and nonobese patients in whom metformin was added to sulfonylurea failures, rather than showing a benefit, there was a 96% increase in diabetes-related deaths compared with the matched cohort of patients with unsatisfactory glycemic control on sulfonylureas who remained on sulfonylurea therapy. Chlorpropamide also came out poorly on subgroup analysis in that those receiving it as intensive therapy did less well as regards progression to retinopathy than those conventionally treated with diet.

Intensive antihypertensive therapy to a mean of 144/82 mm Hg had beneficial effects on microvascular disease as well as on all diabetes-related end points, including virtually all cardiovascular outcomes, in comparison with looser control at a mean of 154/87 mm Hg. In fact, the advantage of reducing hypertension by this amount was substantially more impressive than the benefit which accrued by improving the degree of glycemic control from a mean HbA1c of 7.9% to 7.0%. More than half of the patients needed two or more drugs for adequate therapy of their hypertension, and there was no demonstrable advantage of ACE inhibitor therapy over beta-blockers as regards diabetes end points. Use of a calcium channel blocker added to both treatment groups appeared to be safe over the long term in this diabetic population despite some controversy in the literature about its safety in diabetics.

  1. Implications of the UKPDS—It appears that glycemic control to levels of HbA1cto 7.0% shows benefit in reducing total diabetes end points, including a 25% reduction in microvascular disease, as compared with HbA1clevels of 7.9%. This reassures those who have questioned whether the value of intensive therapy, so convincingly shown by the DCCT in type 1 diabetes, can safely be extrapolated to older patients with type 2 diabetes. It also refutes the presence of a “threshold” of glycemic control, since in this group there was a benefit from this modest reduction of HbA1c below 7.9%, whereas in the DCCT a threshold was suggested in that further benefit was less apparent at HbA1c levels below 8%.

Because of the complexity of the overall design in which many of the original therapy groups received additional medications to achieve glycemic goals but remained assigned to their original treatment group, statistical analysis may have been compromised. For instance, in the diet group which was used as a control for all the drug treatment groups, only 58% of their total “patient-years” were actually drug-free, while the remainder consisted of nonintensive therapy with various hypoglycemic drug regimens to avoid unacceptable hyperglycemia. This probably explains in part why the mean HbA1c for this group was only 7.9% on “diet alone” therapy for over 10 years. In view of these crossovers within treatment groups, caution is suggested regarding several subgroup analyses that are controversial. These include the inference that metformin was superior to insulin or sulfonylureas in reducing diabetes-related end points in obese patients compared with diet therapy, even though all three treatment groups achieved the same degree of glycemic control. Conversely, the finding of excess mortality in the subgroup of patients receiving combination therapy with metformin and sulfonylureas need not necessarily preclude this combination in patients doing unsatisfactorily on sulfonylureas alone, though it certainly indicates a need for clarification of this important question.

Probably the most striking and clearest implication of the UKPDS is the remarkable benefit to the hypertensive type 2 diabetic patient of intensive control of blood pressure. Of interest was the observation that there was no demonstrable advantage of ACE-inhibitor therapy on outcome despite a number of short-term reports in smaller populations implying that these drugs have special efficacy in reducing glomerular pressure beyond their general antihypertensive effects. Moreover, slow-release nifedipine showed no evidence of cardiac toxicity in this study despite some previous reports claiming that calcium channel blockers may be hazardous in patients with diabetes. Finally, the greater benefit in diabetes end points from antihypertensive than from antihyperglycemic treatments may be that the difference between the mean blood pressures achieved (144/82 versus 154/87) is therapeutically more influential than the slight difference in HbA1c (7.0% versus 7.9%). Greater hyperglycemia in the control group most likely would have rectified this discrepancy in outcomes. At present, the ADA recommends vigorous treatment of both hyperglycemia and hypertension when they occur, with an expectation that reductions in microvascular and cardiovascular outcomes will be additive.

  1. THE DIABETES PREVENTION PROGRAM (DPP)

This was a randomized clinical trial in 3234 overweight men and women, aged 25–85 years, who showed impaired glucose tolerance. Results from this study indicated that intervention with a low-fat diet and 150 minutes of moderate exercise (equivalent to a brisk walk) per week reduces the risk of progression to type 2 diabetes by 58% as compared with a matched control group. Another arm of this trial demonstrated that use of 850 mg of metformin twice daily reduced the risk of developing type 2 diabetes by 31% but was relatively

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ineffective in those who were either less obese or in the older age group.

TREATMENT OF DIABETES MELLITUS

DIET

A proper diet remains a fundamental element of therapy in all patients with diabetes. However, in over half of cases, diabetics fail to follow their diet. The reasons include unnecessary complexity of dietary instructions and poor understanding of the goals of dietary control by the patient and physician.

ADA Recommendations

The American Diabetes Association releases an annual position statement on medical nutrition therapy that replaces the calculated ADA diet formula of the past with suggestions for an individually tailored dietary prescription based on metabolic, nutritional, and lifestyle requirements. They contend that the concept of one diet for “diabetes” and prescription for an “ADA diet” no longer can apply to both major types of diabetes. In their medical nutrition therapy recommendations for persons with type 2 diabetes, the 55–60% carbohydrate content of previous “ADA” diets has been reduced considerably because of the tendency of high carbohydrate intake to cause hyperglycemia, hypertriglyceridemia, and a lowered HDL cholesterol. In obese type 2 patients, glucose and lipid goals join weight loss as the focus for therapy. These patients are advised to limit their carbohydrate intake by substituting noncholesterologenic monounsaturated oils such as olive oil, rapeseed (canola) oil or the oils in nuts and avocados. This maneuver is also indicated in type 1 patients on intensive insulin regimens in whom near-normoglycemic control is less achievable on diets higher in carbohydrate content. In these patients, the ratio of carbohydrate to fat will vary among individuals in relation to their glycemic responses, insulin regimens, and exercise patterns.

The current recommendations for both types of diabetes continue to limit cholesterol to 300 mg daily and advise a daily protein intake of 10–20% total calories. They suggest that saturated fat be no higher than 8–9% of total calories with a similar proportion of polyunsaturated fat and that the remainder of the caloric needs be made up of an individualized ratio of monounsaturated fat and of carbohydrate containing 20–35 g dietary fiber. Previous recommendations of polyunsaturated fat supplements as part of a prudent diabetic diet have been revised because of their potential hazards. Polyunsaturated fatty acids appear to promote oxidation of LDL and lower HDL cholesterol, both of which may contribute to atherogenesis; furthermore, in large quantities during supplementation, they may promote carcinogenesis. Poultry, veal, and fish continue to be recommended as a substitute for red meats for keeping saturated fat content low. Stearic acid is the least cholesterologenic saturated fatty acid, since it is rapidly converted to oleic acid—in contrast to palmitic acid (found in animal fat as well as coconut oil), which is a major substrate for cholesterol formation. In contrast to previous recommendations, the present ADA position statement adduces no evidence that reducing protein intake below 10% of total caloric intake (about 0.8 g/kg/d) is of any benefit in patients with nephropathy with renal impairment, and in fact the investigators feel it may be detrimental.

Exchange lists for meal planning can be obtained from the American Diabetes Association (1660 Duke Street, Alexandria, VA 22314) and its affiliate associations or from the American Dietetic Association (430 North Michigan Avenue, Chicago, IL 60611). Their Internet address ishttp://www.eatright.org.

Special Considerations in Dietary Control

  1. DIETARY FIBER

Plant components such as cellulose, gum, and pectin are indigestible by humans and are termed dietary “fiber.” Insoluble fibers such as cellulose or hemicellulose, as found in bran, tend to increase intestinal transit time and may have beneficial effects on colonic function. In contrast, soluble fibers such as gums and pectins, as found in beans, oatmeal, or apple skin, tend to decrease gastric and intestinal transit so that glucose absorption is slower and hyperglycemia is diminished. Although the ADA diet does not require insoluble fiber supplements such as added bran, it recommends foods such as oatmeal, cereals, and beans with relatively high soluble fiber content as stable components of the diet in diabetics. High soluble fiber content in the diet may also have a favorable effect on blood cholesterol levels.

  1. GLYCEMIC INDEX

Quantitation of the relative glycemic contribution of different carbohydrate foods has formed the basis of a “glycemic index”(GI), in which the area of blood glucose (plotted on a graph) generated over a 3-hour period following ingestion of a test food containing 50 g of carbohydrate is compared with the area plotted after giving a similar quantity of reference food such as glucose or white bread:

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White bread is preferred to glucose as a reference standard because it is more palatable and has less tendency to slow gastric emptying by high tonicity, as happens when glucose solution is used.

Differences in GI were noted in normal subjects and diabetics when various foods were compared. In comparison to white bread, which was assigned an index of 100, the mean GI for other foods was as follows: baked potato, 135; table sugar (sucrose), 86; spaghetti, 66; kidney beans, 54; ice cream, 52; and lentils, 43. Some investigators have questioned whether the GI for a food ingested alone is meaningful, since the GI may become altered considerably by the presence of fats and protein when the food is consumed in a mixed meal.

Further studies of the reproducibility of the GI in the same person and the relation of a particular food's GI to its insulinotropic action on pancreatic B cells are needed before the utility of the GI in prescribing diabetic diets can be appropriately assessed. At present, however, it appears that small amounts of sucrose—particularly when taken with high-fiber substances such as cereals or whole-grain breads—may have no greater glycemic effects than comparable portions of starch from potatoes, rice, or bread.

  1. SWEETENERS

The nonnutritive sweetener saccharin is widely used as a sugar substitute (Sweet 'N Low) and continues to be available in certain foods and beverages despite warnings by the FDA about its potential long-term bladder carcinogenicity. The latest position statement of the ADA concludes that all nonnutritive sweeteners which have been approved by the FDA are safe for consumption by all people with diabetes.

Aspartame (NutraSweet) may prove to be the safest sweetener for use in diabetics; it consists of two major amino acids, aspartic acid and phenylalanine, which combine to produce a nutritive sweetener 180 times as sweet as sucrose. A major limitation is its heat lability, which precludes its use in baking or cooking. Sucralose (Splenda) and acesulfame potassium (Sunett, Sweet One, DiabetiSweet) are two other nonnutritive sweeteners approved by the FDA as safe for general use. They are both highly stable and, in contrast to aspartame, can be used in cooking and baking.

Other sweeteners such as sorbitol and fructose have recently gained popularity. Except for acute diarrhea induced by ingestion of large amounts of sorbitol-containing foods, their relative risk has yet to be established. Fructose represents a “natural”sugar substance that is a highly effective sweetener which induces only slight increases in plasma glucose levels and does not require insulin for its utilization. However, because of potential adverse effects of large amounts of fructose (up to 20% of total calories) on raising serum cholesterol and LDL cholesterol, the ADA feels it may have no overall advantage as a sweetening agent in the diabetic diet. This does not preclude, however, ingestion of fructose-containing fruits and vegetables or fructose-sweetened foods in moderation.

  1. FISH OIL AND OTHER OILS

Omega-3 fatty acids in high doses have been shown to lower plasma triglycerides and VLDL cholesterol. They may also reduce platelet aggregation. In the Lyon Diet Heart Study in nondiabetics, a high intake of α-linolenic acid was beneficial in secondary prevention of coronary heart disease. This diet, which is rich in vegetables and fruits, also supplies a high intake of natural antioxidants. There is limited clinical information on the use of these oils in patients with diabetes.

ORAL AGENTS FOR THE TREATMENT OF HYPERGLYCEMIA

The drugs for treating type 2 diabetes fall into three categories: (1) Drugs that primarily stimulate insulin secretion. Sulfonylureas remain the most widely prescribed drugs for treating hyperglycemia. The meglitinide analog repaglinide and the D-phenylalanine derivative nateglinide also bind the sulfonylurea receptor and stimulate insulin secretion. (2) Drugs that alter insulin action. Metformin works primarily in the liver. The thiazolidinediones appear to have their main effect on skeletal muscle and adipose tissue. (3) Drugs that principally affect absorption of glucose. The α-glucosidase inhibitors acarbose and miglitol are such currently available drugs.

  1. Drugs That Stimulate Insulin Secretion

Sulfonylureas

This group of drugs contains a sulfonic acid-urea nucleus that can be modified by chemical substitutions to produce agents that have similar qualitative actions but differ widely in potency. The primary mechanism of action of the sulfonylureas is to stimulate insulin release from pancreatic B cells.

  1. MECHANISM OF ACTION

Specific receptors on the surface of pancreatic B cells bind sulfonylureas in the rank order of their insulinotropic potency (glyburide with the greatest affinity and tolbutamide with the least). It has been shown that

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activation of these receptors closes potassium channels, resulting in depolarization of the B cell. This depolarized state permits calcium to enter the cell and actively promote insulin release (Figure 17-8). These ATP-sensitive K+ channel-specific receptors have been characterized and appear to consist of two proteins: a protein that binds the sulfonylurea—the sulfonylurea receptor (SUR)—and an internal rectifying potassium channel (Kir6.2). Four molecules of Kir6.2 form the pore and are associated with four molecules of the SUR.

There is a family of sulfonylurea receptors. SUR1/Kir6.2 is found in B cells and in the brain; it is activated by diazoxide and is sensitive to inhibition by sulfonylureas at low concentrations (IC50 about 1 nm for glyburide). Mutations in SUR1 or Kir6.2 have been identified that result in persistent hyperinsulinemic hypoglycemia of infancy. SUR2A/Kir6.2 is found in cardiac and skeletal muscle. It is insensitive to diazoxide but sensitive to other potassium channel openers such as pinacidil and cromakalim, and it is a hundredfold less sensitive to glyburide. SUR2B/Kir6.2 appears to be widely distributed in vascular smooth muscle. It has not been established that the difference in affinities of these receptors for sulfonylureas is of clinical relevance. Controversy also persists, however, about whether this well-documented insulinotropic action during acute administration is sufficient to explain adequately the hypoglycemic effect of sulfonylureas during chronic therapy. Additional extrapancreatic effects of sulfonylureas, such as their potentiation of the peripheral effects of insulin

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at the receptor or postreceptor level, have been invoked to account for their continued effectiveness during long-term treatment despite a lack of demonstrable increase in insulin secretion. However, several clinical trials have failed to demonstrate any therapeutic benefit on long-term glycemic control when sulfonylureas are added to insulin therapy in the patient with type 1 diabetes. These observations suggest that in vitro evidence for a potentiation by sulfonylureas of the peripheral effects of insulin may have little clinical relevance.

 

Figure 17-8. Proposed mechanism for sulfonylurea stimulation of insulin release by the pancreatic B cell. Energy-dependent pumps maintain a high intracellular concentration of potassium (K+). In the resting B cell, K+ diffuses from the cell through non-energy-dependent potassium channels (A). This current of potassium ions generates an electrical potential that polarizes the resting cell membrane (B) and closes a voltage-gated calcium channel (C), thereby preventing extracellular calcium from entering the cell. When sulfonylureas bind to a specific receptor on the potassium channel (or when glucose metabolism generates ATP), the potassium channel closes. This depolarizes the cell, allowing calcium to enter and cause microtubules to contract (D), moving insulin granules to the cell surface for emeiocytosis. (Modified and reproduced, with permission, from Karam JH: Type II diabetes and syndrome X. Endocrinol Metab Clin North Am 1992;21:339.)

  1. INDICATIONS

Sulfonylureas are not indicated in ketosis-prone type 1 diabetic patients, since these drugs require functioning pancreatic B cells to produce their effect on blood glucose. Moreover, clinical trials show no benefit from the use of sulfonylureas as an adjunct to insulin replacement in type 1 diabetic patients. The sulfonylureas seem most appropriate for use in the nonobese patient with mild maturity-onset diabetes whose hyperglycemia has not responded to diet therapy. In obese patients with mild diabetes and slight to moderate peripheral insensitivity to levels of circulating insulin, the primary emphasis should be on weight reduction. When hyperglycemia in obese diabetics has been more severe, with consequent impairment of pancreatic B cell function, sulfonylureas may improve glycemic control until concurrent measures such as diet, exercise, and weight reduction can sustain the improvement without the need for oral drugs.

  1. SULFONYLUREAS CURRENTLY AVAILABLE IN THE USA (TABLE 17-11)
  2. First-generation sulfonylureas (tolbutamide, tolazamide, acetohexamide, and chlorpropamide)

o   Tolbutamide (Orinase)—Tolbutamide is supplied in tablets of 500 mg. It is rapidly oxidized in the liver to an inactive form. Because its duration of effect is short (6–10 hours), it is usually administered in divided doses (eg, 500 mg before each meal and at bedtime). The usual daily dose is 1.5–3 g; some patients, however, require only 250–500 mg daily. Acute toxic reactions such as skin rashes are rare. Because of its short duration of action, which is independent of renal function, tolbutamide is probably the safest agent to use in elderly patients, in whom hypoglycemia would be a particularly serious risk. Prolonged hypoglycemia has been reported rarely, mainly in patients receiving certain drugs (eg, warfarin, phenylbutazone, or sulfonamides) that compete with sulfonylureas for hepatic oxidation, resulting in maintenance of high levels of unmetabolized active sulfonylureas in the circulation.

o   Tolazamide (Tolinase)—Tolazamide is supplied in tablets of 100, 250, and 500 mg. The average daily dose is 200–1000 mg, given in one or two doses. Tolazamide is comparable to chlorpropamide in potency but is devoid of disulfiram-like or water-retaining effects. Tolazamide is more slowly absorbed than the other sulfonylureas, with effects on blood glucose not appearing for several hours. Its duration of action may last up to 20 hours, with maximal hypoglycemic effect occurring between the fourth and fourteenth hours. Tolazamide is metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d is required, the dose should be divided and given twice daily. Doses larger than 1000 mg/d do not improve the degree of glycemic control.

o   Chlorpropamide (Diabinese)—This drug is supplied in tablets of 100 and 250 mg. It has a half-life of 32 hours and a duration of action of up to 60 hours. It is slowly metabolized by the liver, with approximately 20–30% excreted unchanged in the urine. Since the metabolites retain hypoglycemic activity, elimination of the biologic effect is almost completely dependent on renal excretion, so that its use is contraindicated in patients with renal insufficiency. The average maintenance dose is 250 mg daily (range, 100–500 mg), given as a single dose in the morning. Chlorpropamide is a potent agent, and prolonged hypoglycemia can occur as an adverse effect, especially in elderly patients, who may have impaired renal clearance. Doses in excess of 500 mg/d increase the risk of cholestatic jaundice, which does not occur with the usual dose of 250 mg/d or less. About 15% of patients taking chlorpropamide develop a facial flush when they drink alcohol, and occasionally they may develop a full-blown disulfiram-like reaction, with nausea, vomiting, weakness, and even syncope. There appears to be a genetic predisposition to the development of this reaction.

Other side effects of chlorpropamide include water retention and the development of hyponatremia, effects that are mediated through an ADH mechanism. The hyponatremia is generally a benign condition with sodium values between 125 and 130 mEq/L, but occasional cases of symptomatic hyponatremia with sodium concentrations below 125 mEq/L have been reported, particularly when concomitant diuretic therapy is being used. Chlorpropamide stimulates ADH secretion and also potentiates its action at the renal tubule. Its antidiuretic effect is somewhat unusual, since three other sulfonylureas (acetohexamide, tolazamide, and glyburide) appear to facilitate water excretion in humans.

Since other sulfonylureas have now become available with comparable potency but without the disadvantages

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of depending solely on renal excretion or of causing water retention and alcohol-related flushing, there presently is less need to choose chlorpropamide when prescribing sulfonylurea therapy in type 2 patients.

o   Acetohexamide (Dymelor)—This agent is supplied in tablets of 250 and 500 mg. Its duration of action is about 10–16 hours (intermediate in duration of action between tolbutamide and chlorpropamide). The usual daily dose is 250–1500 mg given in one or two doses. Liver metabolism is rapid, but an active metabolite is produced and excreted by the kidney.

  1. Second-generation sulfonylureas: glyburide, glipizide, and glimepiride—These agents have similar chemical structures, with cyclic carbon rings at each

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end of the sulfonylurea nucleus; this causes them to be highly potent (100- to 200-fold more so than tolbutamide). The drugs should be used with caution in patients with cardiovascular disease as well as in elderly patients, in whom hypoglycemia would be especially dangerous.

o   Glyburide (glibenclamide)—Glyburide is supplied in tablets containing 1.25, 2.5, and 5 mg. The usual starting dose is 2.5 mg/d, and the average maintenance dose is 5–10 mg/d given as a single morning dose. If patients are going to respond to glyburide, they generally do so at doses of 10 mg/d or less, given once daily. If they fail to respond to 10 mg/d, it is uncommon for an increase in dosage to result in improved glycemic control. Maintenance doses higher than 20 mg/d are not recommended and may even worsen hyperglycemia. Glyburide is metabolized in the liver into products with such low hypoglycemic activity that they are considered clinically unimportant unless renal excretion is compromised. Although assays specific for the unmetabolized compound suggest a plasma half-life of only 1–2 hours, the biologic effects of glyburide clearly persist for 24 hours after a single morning dose in diabetic patients. Glyburide is unique among sulfonylureas in that it not only binds to the pancreatic B cell membrane sulfonylurea receptor but also becomes sequestered within the B cell. This may also contribute to its prolonged biologic effect despite its relatively short circulating half-life.

A formulation of “micronized” glyburide, which apparently increases its bioavailability, is now available in “bent” tablet sizes of 1.5 mg, 3 mg, and 6 mg. These are easy to break in half with very mild pressure at the angle of the bend in the tablet.

Glyburide has few adverse effects other than its potential for causing hypoglycemia. It is particularly hazardous in patients over 65 years of age, in whom serious, protracted, and even fatal hypoglycemia can occur even with relatively small daily doses. Drugs with a shorter half-life, eg, tolbutamide or possibly glipizide, are preferable in the treatment of type 2 diabetes in the elderly patient. Glyburide does not cause water retention, as chlorpropamide does, and even slightly enhances free water clearance.

o   Glipizide (glydiazinamide)—Glipizide is supplied in tablets containing 5 and 10 mg. For maximum effect in reducing postprandial hyperglycemia, this agent should be ingested 30 minutes before breakfast, since rapid absorption is delayed when the drug is taken with food. The recommended starting dose is 5 mg/d, with up to 15 mg/d given as a single daily dose. When higher daily doses are required, they should be divided and given before meals. The maximum recommended dose is 40 mg/d, though doses above 10–15 mg probably provide little additional benefit in poor responders and may even be less effective than smaller doses.

At least 90% of glipizide is metabolized in the liver to inactive products, and only a small fraction is excreted unchanged in the urine. Glipizide therapy is contraindicated in patients who have hepatic or renal impairment and who would therefore be at high risk for hypoglycemia, but because of its lower potency and shorter half-life, it is preferable to glyburide in elderly patients.

Glipizide has been marketed as Glucotrol-XL in 5 mg and 10 mg tablets. The medication is enclosed in a nonabsorbable shell that contains an osmotic compartment which expands slowly, thereby slowly pumping out the glipizide in a sustained manner. It provides extended release during transit through the gastrointestinal tract, with greater effectiveness in lowering of prebreakfast hyperglycemia than the shorter-duration immediate-release standard glipizide tablets. However, this formulation appears to have sacrificed glipizide's reduced propensity for severe hypoglycemia compared with longer-acting glyburide without showing any demonstrable therapeutic advantages over glyburide.

o   Glimepiride—This sulfonylurea is supplied in tablets containing 1, 2, and 4 mg. It has a long duration of effect with a half-life of 5 hours, allowing once-daily administration. Glimepiride achieves blood glucose lowering with the lowest dose of any sulfonylurea compound. A single daily dose of 1 mg/d has been shown to be effective, and the maximal recommended dose is 8 mg. It is completely metabolized by the liver to relatively inactive metabolic products.

Table 17-11. Oral antidiabetic drugs.

Drug

Tablet Size

Daily Dose

Duration of Action

Sulfonylureas
   Tolbutamide (Orinase)

250, 500 mg

0.5–2 g in 2 or 3 divided doses

6–12 hours

   Tolazamide (Tolinase)

100, 250, 500 mg

0.1–1 g as single dose or in 2 divided doses

Up to 24 hours

   Acetohexamide1(Dymelor)

250, 500 mg

0.25–1.5 g as single dose or in 2 divided doses

8–24 hours

   Chlorpropamide1(Diabinese)

100, 250 mg

0.1–0.5 g as single dose

24–72 hours

   Glyburide
  (Diaβeta, Micronase)

1.25, 2.5, 5 mg

1.25–20 mg as single dose or in 2 divided doses

Up to 24 hours

  (Glynase)

1.5, 3, 6 mg

1.5–18 mg as single dose or in 2 divided doses

Up to 24 hours

   Glipizide
  (Glucotrol)

5, 10 mg

2.5–40 mg as single dose or in 2 divided doses on an empty stomach.

6–12 hours

  (Glucotrol XL)

5, 10 mg

Up to 20 or 30 mg daily as a single dose

Up to 24 hours

   Glimeperide (Amaryl)

1, 2, 4 mg

1–4 mg as single dose

Up to 24 hours

Meglitinide analogs
   Repaglinide (Prandin)

0.5, 1, 2 mg

4 mg in two divided doses given 15 minutes before break-fast and dinner

3 hours

D-Phenylalanine derivative
   Nateglinide

60, 120 mg

60 or 120 mg 3 times a day before meals

1–5 hours

Biguanides
   Metformin (Glucophage)

500, 850 mg

1–2.5 g. One tablet with meals 2 or 3 times daily

7–12 hours

   Extended-release metformin (Glucophage XR)

500 mg

500–200 mg once a day

Up to 24 hours

Thiazolidinediones
   Rosiglitazone (Avandia)

2, 4, 8 mg

4–8 mg as single dose or in 2 divided doses

24–30 hours

   Pioglitazone (Actos)

15, 30, 45 mg

15–45 mg as single dose

30 hours

Alpha-glucosidase inhibitors
   Acarbose (Precose)

50, 100 mg

75–300 mg in 3 divided doses with first bite of food

4 hours

   Miglitol (Glyset)

25, 50, 100 mg

75–300 mg in 3 divided doses with first bite of food

4 hours

1There has been a decline in use of these formulations. In the case of chlorpropamide, the decline is due to its numerous side effects (see text).

Meglitinide Analogs

Repaglinide is supplied as 0.5, 1, and 2 mg tablets. Its structure is similar to that of glyburide but lacks the sulfonic acid-urea moiety. It also acts by binding to the sulfonylurea receptor and closing the ATP-sensitive potassium channel. It is rapidly absorbed from the intestine and then undergoes complete metabolism in the liver to inactive biliary products, giving it a plasma half-life of less than 1 hour. The drug therefore causes a brief but rapid pulse of insulin. The starting dose is 0.5 mg three times a day 15 minutes before each meal. The dose can be titrated to a maximum daily dose of 16 mg. Like the sulfonylureas, repaglinide can be used in combination with metformin. Hypoglycemia is the main side effect. In clinical trials, when the drug was compared with glyburide, a long-acting sulfonylurea, there was a trend toward less hypoglycemia. Like the sulfonylureas, it causes weight gain. Metabolism is by cytochrome P4503A4 isoenzyme, and other drugs that induce or inhibit this

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isoenzyme may increase or inhibit the metabolism of repaglinide, respectively. The drug may be useful in patients with renal impairment or in the elderly. It remains to be shown whether this drug has significant advantages over short-acting sulfonylureas.

δ-Phenylalanine Derivative

Nateglinide is supplied in tablets of 60 and 120 mg. This drug binds the sulfonylurea receptor and closes the ATP-sensitive potassium channel. The drug is rapidly absorbed from the intestine, reaching peak plasma levels within 1 hour. It is metabolized in the liver and has a plasma half-life of about 1.5 hours. Like repaglinide, it causes a brief rapid pulse of insulin, and when given before a meal it reduces the postprandial rise in blood glucose. The 60 mg dose is used in patients with mild elevations in HbA1c. For most patients, the recommended starting and maintenance dosage is 120 mg three times a day before meals. Like the other insulin secretagogues, its main side effects are hypoglycemia and weight gain.

  1. Drugs That Alter Insulin Action

Biguanides

Unlike sulfonylureas, the biguanides (Table 17-11) do not require functioning pancreatic B cells for reduction of hyperglycemia. Use ofphenformin was discontinued in the USA because of its association with the development of lactic acidosis in patients with coexisting liver or kidney disease. Metformin, a biguanide that is much less likely to produce lactic acidosis, has generally replaced phenformin in the treatment of diabetics.

  1. CLINICAL PHARMACOLOGY

The exact mechanism of action of metformin (1,1-dimethylbiguanide hydrochloride) remains unclear. It reduces both the fasting level of blood glucose and the degree of postprandial hyperglycemia in patients with type 2 diabetes but has no effect on fasting blood glucose in normal subjects. Metformin does not stimulate insulin action, yet it is particularly effective in reducing hepatic gluconeogenesis. Other proposed mechanisms include a slowing down of gastrointestinal absorption of glucose and increased glucose uptake by skeletal muscle, which have been reported in some but not all clinical studies. Because of its very high concentration in intestinal cells after oral administration, metformin increases glucose-to-lactate turnover in these cells, and this also contributes to its action in reducing hyperglycemia.

Metformin has a half-life of 1.5–3 hours, is not bound to plasma proteins, and is not metabolized in humans, being excreted unchanged by the kidneys.

  1. INDICATIONS AND DOSAGE

Metformin may be used as an adjunct to diet for the control of hyperglycemia and its associated symptomatology in patients with type 2 diabetes, particularly those who are obese or are not responding optimally to maximal doses of sulfonylureas. A side benefit of metformin therapy is its tendency to improve both fasting and postprandial hyperglycemia and hypertriglyceridemia in obese diabetics without the weight gain associated with insulin or sulfonylurea therapy. For this reason—and because of its ability to correct hyperglycemia while having an insulin-sparing action—metformin has particular potential in treating patients with the insulin resistance syndrome (syndrome X, or metabolic syndrome). Metformin is not indicated for patients with type 1 diabetes and is contraindicated in diabetics with renal insufficiency, since failure to excrete this drug would produce high blood and tissue levels of metformin that would stimulate lactic acid overproduction. Likewise, patients with hepatic insufficiency or abusers of ethanol should not receive this drug since lactic acid production from the gut and other tissues, which rises during metformin therapy, could result in lactic acidosis when defective hepatocytes cannot remove the lactate or when alcohol-induced reduction of nucleotides interferes with lactate clearance. Finally, metformin is relatively contraindicated in patients with cardiorespiratory insufficiency, since they have a propensity to develop hypoxia which would aggravate the lactic acid production already occurring from metformin therapy. The “age” cutoff for prescribing metformin has not been defined and remains relative to the overall health of the patient, but generally there is concern that after the age of 65–70 years, the potential for progressive impairment of renal function or development of a cardiac event while taking metformin raises the risk enough to outweigh the benefits of prescribing metformin to the elderly patient with type 2 diabetes.

Metformin is dispensed as 500 mg, 850 mg, and 1000 mg tablets. A 500 mg extended-release preparation is also available. The dosage range is from 500 mg to a maximum of 2550 mg daily, with the lowest possible effective dose being recommended. Eighty-five percent of the maximal glucose-lowering effect is achieved by a daily dose of 1500 mg, and there is little benefit from giving more than 2000 mg daily. It is important to begin with a low dose and increase the dosage very gradually in divided doses—taken with meals—to reduce minor gastrointestinal upsets. A common schedule would be one 500 mg tablet three times a day with meals or one 850

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mg or 1000 mg tablet twice daily at breakfast and dinner. The maximum recommended dose is 850 mg three time a day. One to four tablets of the extended-release preparation can be given once a day.

  1. ADVERSE REACTIONS

The most frequent side effects of metformin are gastrointestinal symptoms (anorexia, nausea, vomiting, abdominal discomfort, diarrhea), which occur in up to 20% of patients. These effects are dose-related, tend to occur at onset of therapy, and often are transient. However, in 3–5% of patients, therapy may have to be discontinued because of persistent diarrheal discomfort. Absorption of vitamin B12 appears to be reduced during chronic metformin therapy, and annual screening of serum B12 levels and red blood cell parameters has been encouraged by the manufacturer.

Hypoglycemia does not occur with therapeutic doses of metformin, which permits its description as a “euglycemic” or“antihyperglycemic” drug rather than an oral hypoglycemic agent. Dermatologic or hematologic toxicity is rare.

Lactic acidosis (see below) has been reported as a side effect but is uncommon with metformin in contrast to phenformin, and almost all reported cases have involved subjects with associated risk factors that should have contraindicated its use (renal, hepatic, or cardiorespiratory insufficiency, alcoholism, advanced age).

Thiazolidinediones

Drugs of this new class of antihyperglycemic agents sensitize peripheral tissues to insulin. They bind to a nuclear receptor called peroxisome proliferator-activated receptor-gamma (PPAR-γ) and affect the expression of a number of genes that regulate the release of adipokines—resistin and adiponectin—from adipocytes. Adiponectin secretion is stimulated, which sensitizes tissues to the effects of insulin; and resistin secretion is inhibited, which reduces insulin resistance. Observed effects of thiazolidinediones include increased glucose transporter expression (GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased hepatic glucose output, and increased differentiation of preadipocytes into adipocytes. Like the biguanides, this class of drugs does not cause hypoglycemia.

Troglitazone (Rezulin) was the first drug in this class to go into widespread clinical use. Unfortunately, about 1.9 % of patients taking this drug developed elevations in liver enzymes over three times normal, which resolved when the drug was stopped. Liver failure, however, occurred if the drug was continued—at least 90 cases have been reported, and 63 of these patients have died. The drug has therefore been withdrawn from clinical use.

Two other drugs in the same class are available for clinical use: Rosiglitazone (Avandia) and pioglitazone (Actos). Both of these drugs are effective as monotherapy and in combination with sulfonylureas, metformin, and insulin. When used as monotherapy, these drugs lower HbA1c by about 1 or 2 percentage points. When used in combination with insulin, they can result in a 30–50% reduction in insulin dosage, and some patients can come off insulin completely. Combination therapy with a thiazolidinedione and metformin has the advantage of not causing hypoglycemia. Patients inadequately managed on sulfonylureas can do well on a combination of sulfonylurea with rosiglitazone or pioglitazone. About 25% of patients in clinical trials fail to respond to these drugs, presumably because they are significantly insulinopenic.

Rosiglitazone therapy is associated with increases in total cholesterol, LDL cholesterol (14–18%), and HDL cholesterol (11–14%). There is reduction in free fatty acids of about 8–15%. The changes in triglycerides were generally not different from changes reported with placebo. The increase in the LDL cholesterol need not necessarily be detrimental—studies with troglitazone showed that there is a shift from the atherogenic small dense LDL particles to larger, less dense LDL particles. Pioglitazone in clinical trials lowered triglycerides (9%) and increased HDL cholesterol (12–19%) but did not result in a consistent change in total cholesterol and LDL cholesterol levels. A prospective randomized comparison of the metabolic effects of pioglitazone and rosiglitazone on patients who had previously been on troglitazone showed similar effects on HbA1c and weight gain. Pioglitazone-treated subjects, however, had lower total cholesterol, LDL cholesterol, and triglycerides when compared with rosiglitazone. Anemia occurs in 3–4% of patients treated with these drugs, but this effect may be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs, especially when the drug is combined with a sulfonylurea or with insulin.

The dosage of rosiglitazone is 4–8 mg daily and of pioglitazone 15–45 mg daily, and the drugs do not have to be taken with food. Rosiglitazone is primarily metabolized by the CYP2C8 isoenzyme, and unlike troglitazone it does not appear to affect CYP3A4 and has no significant effect on oral contraceptives. Pioglitazone is metabolized by CYP2C8 and CYP3A4. The pharmacokinetics of coadministration of pioglitazone and oral contraceptives has not been evaluated.

These two agents in clinical trials did not—unlike troglitazone—show evidence of drug-induced liver function test abnormalities or hepatotoxicity: The FDA

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has recommended, however, that patients should not initiate drug therapy with these agents if the ALT is 2.5 times greater than the upper limit of normal. Obviously, caution should be used in initiation of therapy in patients with even mild ALT elevations. Liver function tests should be performed once every 2 months for the first year and periodically thereafter.

  1. Drugs That Affect Glucose Absorption

Alpha-Glucosidase Inhibitors

Drugs of this family are competitive inhibitors of intestinal brush border alpha-glucosidases. Two of these drugs, acarbose and miglitol, are available for clinical use. Both are potent inhibitors of glucoamylase, α-amylase, and sucrase. They are less effective on isomaltase and are ineffective on trehalase or lactase. Acarbose binds 1000 times more avidly to the intestinal disaccharidases than do products of carbohydrate digestion or sucrose. A fundamental difference exists between acarbose and miglitol in their absorption. Acarbose has the molecular mass and structural features of a tetrasaccharide, and very little (about 2%) crosses the microvillar membrane. Miglitol, however, is structurally similar to glucose and is absorbable. Both drugs delay the absorption of carbohydrates and reduce postprandial glycemic excursion.

  1. ACARBOSE

Acarbose is available as 50 and 100 mg tablets. The recommended starting dose is 50 mg twice daily, gradually increasing to 100 mg three times daily. For maximal benefit on postprandial hyperglycemia, acarbose should be given with the first mouthful of food ingested. In diabetic patients it reduces postprandial hyperglycemia by 30–50%, and its overall effect is to lower the HbA1c by 0.5–1%. The principal adverse effect, seen in 20–30% of patients, is flatulence. This is caused by undigested carbohydrate reaching the lower bowel, where gases are produced by bacterial flora. In 3% of cases, troublesome diarrhea occurs. This gastrointestinal discomfort tends to discourage excessive carbohydrate consumption and promotes improved compliance of type 2 diabetes patients with their diet prescriptions. When acarbose is given alone, there is no risk of hypoglycemia. However, if combined with insulin or sulfonylureas, it might increase risk of hypoglycemia from these agents. A slight rise in hepatic aminotransferases has been noted in clinical trials (5% versus 2% in placebo controls, and particularly with doses greater than 300 mg/d). This generally returns to normal on stopping this drug. In the UKPDS, approximately 2000 patients on diet, sulfonylurea, metformin, or insulin therapy were randomized to acarbose or placebo therapy. By 3 years, 60% of the patients had discontinued the drug, mostly because of gastrointestinal symptoms. In the 40% of patients who remained on the drug acarbose was associated with an 0.5% lowering of HbA1c compared with placebo.

  1. MIGLITOL

Miglitol is similar to acarbose in terms of its clinical effects. It is indicated for use in diet- or sulfonylurea-treated patients with type 2 diabetes. Therapy is initiated at the lowest effective dosage of 25 mg three times a day. The usual maintenance dose is 50 mg three times a day, though some patients may benefit from increasing the dose to 100 mg three times a day. Gastrointestinal side effects occur as with acarbose. The drug is not metabolized and is excreted unchanged by the kidney. Theoretically, absorbable α-glucosidase inhibitors could induce a deficiency of one or more of the α-glucosidases involved in cellular glycogen metabolism and biosynthesis of glycoproteins. This does not occur in practice because—unlike the intestinal mucosa, which is exposed to a high concentration of the drug—circulating plasma levels are 200-fold to 1000-fold lower than those needed to inhibit intracellular α-glucosidases. Miglitol should not be used in renal failure since its clearance is impaired in this setting.

Drug Combinations

A glyburide and metformin combination (Glucovance) is available in dose forms of 1.25 mg/250 mg, 2.5 mg/ 500 mg, and 5 mg/500 mg. This combination, however, limits the clinician's ability to optimally adjust dosage of the individual drugs and for that reason is of questionable merit.

Safety of Oral Hypoglycemic Agents

The University Group Diabetes Program (UGDP) reported that the number of deaths due to cardiovascular disease in diabetic patients treated with tolbutamide or phenformin was excessive when compared to either insulin-treated patients or to patients receiving placebos. At present, a warning label outlining their cardiovascular risk is inserted in each packet of sulfonylureas and metformin dispensed. However, the United Kingdom Prospective Diabetes Study of type 2 diabetes has refuted these conclusions regarding sulfonylureas. It did not confirm any cardiovascular hazard among over 1500 patients treated intensively with sulfonylureas for more than 10 years, compared with a comparable number who received either insulin or diet therapy. Analysis of a subgroup of obese patients receiving metformin also showed no hazard—and even a slight reduction in

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cardiovascular deaths compared with conventional (diet) therapy.

The question of safety of thiazolidinediones (see above) remains to be resolved regarding the frequency of life-threatening hepatic toxicity and whether monthly monitoring during the first 10 months of treatment adequately protects the patient. Lactic acidosis from metformin (see above) is quite rare and probably not a major consideration for its use—in the absence of major risk factors such as impaired renal function or hepatic function or conditions predisposing to hypoxia.

INSULIN

Insulin is indicated for type 1 diabetics as well as for those type 2 diabetics whose hyperglycemia does not respond to diet therapy and oral hypoglycemic drugs.

Insulin replacement in patients with type 1 diabetes has been less than optimal because subcutaneous injections cannot completely reproduce the normal physiologic pattern of insulin secretion into the portal vein. With the help of appropriate modifications of diet and exercise and careful monitoring of capillary blood glucose levels at home, however, it is possible to achieve acceptable control of blood glucose by using multiple injections of ultrashort-, short-, intermediate-, and long-acting insulins. In some patients, a portable insulin infusion pump may be required for optimal control.

With the development of highly purified human insulin preparations, immunogenicity has been markedly reduced, thereby decreasing the incidence of therapeutic complications such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the injection site.

Characteristics of Currently Available Insulin Preparations

Commercial insulin preparations differ with regard to the animal species from which they are obtained; their purity, concentration, and solubility; and their time of onset and duration of biologic action (Figure 17-9; Table 17-12). Eighteen different formulations of insulin are available in the USA (Table 17-14).

  1. SPECIES OF INSULIN

Human insulin is now produced by recombinant DNA techniques (biosynthetic human insulin). Eli Lilly and Novo Nordisk dispense human insulin as regular (R), NPH (N), lente (L), or ultralente (U) formulations (Table 17-14). Three analogs of human insulin—two rapidly acting (insulin lispro, insulin aspart) and one very long-acting (insulin glargine) are now available for clinical use. A limited supply of monospecies pork insulin (Iletin II) remains available for use by certain patients who may benefit from the slightly more prolonged and sustained effect of animal insulin compared with human insulin.

  1. PURITY OF INSULIN

Improvements in purification techniques for insulins have reduced or eliminated contaminating insulin precursors that were capable of inducing anti-insulin antibodies. “Purified” insulin is defined by the FDA as containing less than 10 ppm of proinsulin, whether

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extracted from animal pancreas or produced from biosynthetic proinsulin. All human and pork insulins currently available contain less than 10 ppm of proinsulin and are labeled as “purified.”

 

Figure 17-9. Extent and duration of action of various types of insulin (in a fasting diabetic). Duration of action is extended considerably when the dose of a given insulin formulation increases above the average therapeutic doses depicted here. (Modified, with permission, from Katzung BG [editor]: Basic & Clinical Pharmacology, 2nd ed. McGraw-Hill, 1985.)

Table 17-12. Summary of bioavailability characteristics of the insulins.

 

Insulin Type

Onset

Peak Action

Duration

Ultrashort-acting

Insulin lispro, insulin aspart

5–15 minutes

1–1.5 hours

3–4 hours

Short-acting

Regular, Velosulin

15–30 minutes

1–3 hours

5–7 hours

Intermediate-acting

Lente, NPH

2–4 hours

8–10 hours

18–24 hours

Long-acting

Ultralente

4–5 hours

8–14 hours

25–36 hours

 

Insulin glargine

6–8 hours

24 hours

The more highly purified insulins currently in use preserve their potency quite well; therefore, refrigeration while in use is not necessary. During travel, reserve supplies of insulin can be readily transported without significant loss of potency provided they are protected from extremes of heat or cold.

Table 17-13. Examples of intensive insulin regimens using insulin lispro or insulin aspart and ultralente, NPH, or insulin glargine in a 70 kg man with type 1 diabetes.1,2,3,4

 

Pre-Breakfast

Pre-Lunch

Pre-Dinner

At Bedtime

Insulin lispro or aspart

5 units

4 units

6 units

Ultralente insulin

8 units

8 units

OR

Insulin lispro or aspart

5 units

4 units

6 units

NPH insulin

3 units

3 units

2 units

8–14 units

Insulin lispro or aspart

5 units

4 units

6 units

Insulin glargine

15–16 units

1Reproduced, with permission, from Tierney LM Jr, McPhee SJ, Papadakis MA: Current Medical Diagnosis & Treatment 2003. McGraw-Hill, 2003.

2Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g at lunch and 90 g at dinner.

3The dose of insulin lispro or insulin aspart can be raised by 1 or 2 units if extra carbohydrate (15–30 g) is ingested or if premeal blood glucose is > 170 mg/dL. Insulin lispro or insulin aspart can be mixed in the same syringe with ultralente or NPH insulin.

4Insulin glargine cannot be mixed with any of the available insulins and must be given as a separate injection.

Concentrations of Insulins (Table 17-14)

At present, insulins in the USA are available only in a concentration of 100 units/mL (U100); all are dispensed in 10-mL vials. To accommodate children and the occasional adult who may require small quantities of insulin, “low-dose” (0.3 mL) disposable insulin syringes have been introduced so that U100 insulin can now be measured accurately in doses as low as 1 or 2 units. This has eliminated the need for lower concentrations of insulin and has resulted in the phasing out of all U40 insulins in the United States. For use in rare cases of severe insulin resistance in which large quantities of insulin are required, a limited supply of U500 (500 units/mL) regular human insulin is available from Eli Lilly.

Bioavailability Characteristics

Four principal types of insulin are available: (1) ultrashort-acting insulin, with very rapid onset and short duration of action; (2) short-acting insulin, with rapid onset of action; (3) intermediate-acting insulin; and (4) long-acting insulin, with slow onset of action (Table 17-14). Ultrashort-acting and short-acting insulins are dispensed as clear solutions at neutral pH. The long-acting insulin analog insulin glargine is also dispensed as a clear solution but at acidic pH. Other intermediate-acting and long-acting insulins are dispensed as opaque suspensions at neutral pH with either protamine (derived from fish sperm) in phosphate buffer (NPH) or varying concentrations of zinc in acetate buffer (ultralente and lente insulins).

The characteristics of these various insulins are discussed below and summarized in Table 17-12. It is important

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to recognize that values given for time of onset of action, peak effect, and duration of action are only approximate ones and that there is great variability in these parameters from patient to patient and even in a given patient depending on the size of the dose, the site of injection, the degree of exercise, the avidity of circulating anti-insulin antibodies, and other less well defined variables.

Table 17-14. Some insulin preparations available in the USA.1

Preparation

Species Source

Concentration

Ultrashort-acting insulins
      Insulin lispro (Humalog, Lilly)

Human analog (recombinant)

U100

      Insulin aspart

Human analog (recombinant)

U100

Short-acting insulins Purified2
      Regular (Novo Nordisk)3

Human

U100

      Regular Humulin (Lilly)

Human

U100, U500

      Regular Iletin II (Lilly)

Pork

U100

      Velosulin (Novo Nordisk)4

Human

U100

Intermediate-acting insulins Purified3
      Lente Humulin (Lilly)

Human

U100

      Lente Iletin II (Lilly)

Pork

U100

      Lente (Novo Nordisk) Novolin

Human

U100

   NPH Humulin (Lilly)

Human

U100

   NPH Iletin II (Lilly)

Pork

U100

   NPH (Novo Nordisk) Novolin

Human

U100

Premixed insulins % NPH, % regular
      Novolin 70/30 (Novo Nordisk)

Human

U100

      Humulin 70/30 and 50/50 (Lilly)

Human

U100

 % NPL, % insulin lispro
      Humalog Mix 75/25 (Lilly)

Human analog (recombinant)

U100

 % insulin aspart protamine, % insulin aspart
      NovoLogMix 70/30

Human

U100

Long-acting insulins Purified3
      Ultralente Humulin (Lilly)
      Insulin glargine (Lantis, Aventis)

Human
Human analog (recombinant)

U100
U100

1All of these agents (except insulin lispro and U500) are available without a prescription.

2Less than 10 ppm proinsulin.

3Novo Nordisk human insulins are termed Novolin R, L, and N.

4Velosulin contains phosphate buffer, which favors its use to prevent insulin aggregation in pump tubing but precludes its being mixed with lente insulin.

  1. ULTRASHORT-ACTING INSULINS

Insulin lispro is an insulin analog wherein two amino acids near the terminal end of the B chain have been reversed in position: the proline at position B28 has been moved to position B29, and the lysine has been moved from B29 to B28. Insulin aspart is a single substitution of proline by aspartic acid at position B28. These changes result in these two analogs having less tendency

P.701


to form hexamers—in contrast to human insulin. When injected subcutaneously, the analogs quickly dissociate into monomers and are absorbed very rapidly, reaching peak serum values as early as 1 hour—in contrast to regular insulin, whose hexamers require considerably more time to dissociate and become absorbed. The amino acid changes in these analogs do not interfere with their binding to the insulin receptor, with its circulating half-life, or with its immunogenicity, which are all identical with that of human regular insulin. The optimal times of preprandial subcutaneous injection of comparable doses of ultrashort-acting analogs and regular human insulin are 20 and 60 minutes before the meal, respectively. Diabetic patients who have had to wait up to an hour after injecting regular human insulin before they can begin a meal appreciate this more rapid onset of action. Patients do need to understand that when using the ultrashort-acting insulins they must ingest adequate absorbable carbohydrate early in the meal to avoid hypoglycemia immediately after a meal. Regular insulin's duration of action is proportionate to the dose, with larger doses lasting much longer. This effect is much less pronounced with insulin lispro and insulin aspart, so that regardless of dose, its duration of action is close to 4 hours, and this reduces the risk of late hypoglycemia. The structural differences between insulin lispro and human insulin may be sufficient to prevent insulin lispro from binding to human insulin antibodies in some patients, and there have been case reports of successful use of insulin lispro in those rare patients who have a generalized allergy to human insulin or who have severe antibody insulin resistance. Unlike the over-the-counter insulins, the analogs do require a physician's prescription.

  1. SHORT-ACTING INSULINS

Regular insulin is a short-acting, soluble crystalline zinc insulin whose hypoglycemic effect appears within 15 minutes after subcutaneous injection, peaks at 1–3 hours, and lasts for about 5–7 hours when usual quantities, eg, 5–15 units, are administered. Regular insulin is the only type that can be administered intravenously, and insulin infusions are particularly useful in the treatment of diabetic ketoacidosis and during postoperative management of insulin-requiring diabetics. Because regular insulin when infused intravenously is monomeric and has an immediate effect, there is no advantage to using the more expensive ultrashort-acting insulin analogs for intravenous use.

Regular insulin produced by Novo Nordisk and Eli Lilly is dispensed without a buffer. When it is used in reservoirs or infusion pumps, stability is improved when regular insulin is buffered with disodium phosphate (Velosulin).

  1. INTERMEDIATE-ACTING INSULINS
  2. Lente insulin—This is a mixture of 30% short-acting semilente with 70% ultralente insulin. Its onset of action is delayed to 2–4 hours, and its peak response is generally reached in about 8–10 hours. Because its duration of action is often less than 24 hours (with a range of 18–24 hours), most patients require at least two injections daily to maintain a sustained insulin effect. The supernatant of the lente suspension contains an excess of zinc ions, which may precipitate regular insulin if it is added to lente.
  3. NPH (neutral protamine Hagedorn, or isophane) insulin—This is an intermediate-acting insulin in which the onset of action is delayed by combining two parts of soluble crystalline zinc insulin with one part protamine zinc insulin. The mixture is reported to have equivalent concentrations of protamine and insulin, so that neither is in excess (“isophane”). The peak action and duration of action of NPH insulin are similar to those of lente insulin, however, in contrast to lente insulin, regular insulin retains its solubility and independent rapid action when mixed with NPH.

Flocculation of suspended particles may occasionally “frost” the sides of a bottle of NPH insulin or “clump” within bottles from which multiple small doses are withdrawn over a prolonged period. This instability is a rare phenomenon and might occur less frequently if NPH human insulin were refrigerated when not in use and if bottles were discarded after 1 month of use. Patients should be vigilant for early signs of frosting or clumping of the NPH insulin, because it indicates a pronounced loss of potency. Several cases of diabetic ketoacidosis have been reported in type 1 diabetes patients who had been inadvertently injecting this denatured insulin.

  1. LONG-ACTING INSULINS
  2. Human ultralente insulin—Ultralente insulin is a relatively insoluble crystal of zinc and insulin suspended in an acetate buffer. Its onset of action is less than that of the previously available beef ultralente. It is generally recommended that the daily dose be split into two equal doses given 12 hours apart. Its peak activity is less than that of NPH insulin, and it is often used to provide basal coverage while the short-acting insulins are used to cover the glucose rise associated with meals.
  3. Insulin glargine—Insulin glargine is an insulin analog in which the asparagine at position 21 of the A chain of the human insulin molecule is replaced by glycine and two arginines are added to the carboxyl terminal of the B chain. The arginines raise the isoelectric point of the molecule close to neutral, making it more

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soluble in an acidic environment. In contrast, human insulin has an isoelectric point of pH 5.4. Insulin glargine is a clear insulin which, when injected into the neutral pH environment of the subcutaneous tissue, forms microprecipitates that slowly release the insulin into the circulation. It lasts for about 24 hours without any pronounced peaks and is given once a day to provide basal coverage. This insulin cannot be mixed with the other insulins because of its acidic pH. When this insulin was given as a single injection at bedtime to type 1 diabetes patients, fasting hyperglycemia was better controlled when compared with bedtime NPH insulin. The clinical trials also suggest that there may be less nocturnal hypoglycemia with this insulin when compared with NPH insulin.

In one clinical trial involving type 2 patients, insulin glargine was associated with a slightly more rapid progression of retinopathy when compared with NPH insulin. The frequency was 7.5% with the analog and 2.7% with the NPH. This finding, however, was not seen in other clinical trials with this analog. In in vitro studies, insulin glargine has a sixfold greater affinity for IGF-I receptor compared with the human insulin. There has also been a report that insulin glargine has increased mitogenicity compared with human insulin in a human osteosarcoma cell line. Circulating levels of insulin glargine, however, are low, and the clinical significance of these observations is not yet clear.

  1. INSULIN MIXTURES

Since intermediate insulins require several hours to reach adequate therapeutic levels, their use in type 1 patients requires supplements of regular insulin or insulin lispro or insulin aspart preprandially. It is well established that insulin mixtures containing increased proportions of lente to regular insulins may retard the rapid action of admixed regular insulin. The excess zinc in lente insulin binds the soluble insulin and partially blunts its action, particularly when a relatively small proportion of regular insulin is mixed with lente (eg, 1 part regular to 1.5 or more parts lente). NPH preparations do not contain excess protamine and so do not delay absorption of admixed regular insulin. They are therefore preferable to lente when mixtures of intermediate and regular insulins are prescribed. For convenience, regular or NPH insulin may be mixed together in the same syringe and injected subcutaneously in split dosage before breakfast and supper. It is recommended that the regular insulin be withdrawn first, then the NPH insulin. No attempt should be made to mix the insulins in the syringe, and the injection is preferably given immediately after the syringe is loaded. Stable premixed insulins (70% NPH and 30% regular or 50% of each) are available as a convenience to patients who have difficulty mixing insulin because of visual problems or insufficient manual dexterity. These include Novolin 70:30 (Novo Nordisk) and Humulin 70:30 and 50:50 (Lilly).

With increasing use of ultrashort-acting insulin analogs as a preprandial insulin, it has become evident that combination with an intermediate-acting or long-acting insulin is essential to maintain postabsorptive glycemic control. It has been demonstrated that insulin lispro can be acutely mixed with either NPH or ultralente insulin without affecting its rapid absorption. Premixed preparations of insulin lispro and NPH insulin are unstable because of exchange of insulin lispro with the human insulin in the protamine complex. Consequently, the soluble component becomes over time a mixture of regular and insulin lispro at varying ratios. In an attempt to remedy this, an intermediate insulin composed of isophane complexes of protamine with insulin lispro was developed and given the name NPL (neutral protamine lispro). A premixed combination of NPL (75%) and insulin lispro (25%) is now available for clinical use (Humalog Mix 75/25). This mixture has a more rapid onset of glucose-lowering activity compared with 70% NPH/30% regular human insulin mixture and can be given within 15 minutes before or after starting a meal. Similarly, a 70% insulin aspart protamine/30 insulin aspart (NovoLogMix 70/30) is now available.

  1. INSULIN ANALOGS IN CLINICAL TRIALS

Albumin in subcutaneous tissue fluid has a slow disappearance rate, and insulin analogs that bind albumin would have delayed absorption and prolonged action. Insulin analogs with nonesterified fatty acids coupled to B29 Lys bind to albumin, and in clinical trials these fatty acid-acylated insulins show prolonged duration of action without a peak.

Methods of Insulin Administration

  1. INSULIN SYRINGES AND NEEDLES

Disposable plastic syringes with needles attached are available in 1-mL, 0.5-mL, and 0.3-mL sizes. Their finely honed 30-gauge attached needles have greatly reduced the pain of injections. They are light, not susceptible to damage, and convenient when traveling. Moreover, their clear markings and tight plungers allow accurate measurement of insulin dosage. The “low-dose”syringes have become increasingly popular, because most patients take less than 30 units at one injection. Two lengths of needles are available: short (8 mm) and long (12.7 mm). Long needles are preferable in obese patients to reduce the variability of insulin absorption. Disposable syringes may be reused until blunting of the needle occurs (usually after three to five

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injections). Sterility adequate to avoid infection with reuse appears to be maintained by recapping syringes between uses. Cleansing the needle with alcohol may not be desirable, since it can dissolve the silicon coating and increase the pain of skin puncturing.

  1. SITES FOR INJECTION

Any part of the body covered by loose skin can be used as an injection site, including the abdomen, thighs, upper arms, flanks, and upper outer quadrants of the buttocks. In general, regular insulin is absorbed more rapidly from upper regions of the body such as the deltoid area or the abdomen rather than from the thighs or buttocks. Exercise appears to facilitate insulin absorption when the injection site is adjacent to the exercising muscle. Rotation of sites continues to be recommended to avoid delayed absorption when fibrosis or lipohypertrophy occurs owing to repeated use of a single site. However, considerable variability of absorption rates from different regions, particularly with exercise, may contribute to the instability of glycemic control in certain type 1 patients if injection sites are rotated indiscriminately over different areas of the body. Consequently, diabetologists recommend limiting injection sites to a single region of the body and rotating sites within that region. It is possible that some of the stability of glycemic control achieved by infusion pumps may be related to the constancy of the region of infusion from day to day. For most patients the abdomen is the recommended region for injection, since it provides a considerable area in which to rotate sites and there may be less variability of absorption with exercise than when the thigh or deltoid areas are used. The effect of anatomic regions appears to be much less pronounced with the analogs.

  1. INSULIN PUMPS

Several small portable “open loop” devices for the delivery of insulin are on the market. These devices contain an insulin reservoir and a pump programmed to deliver regular insulin subcutaneously; they do not contain a glucose sensor. With improved methods for self-monitoring ofblood glucose at home (see below), these pump systems are becoming increasingly popular. In the United States, MiniMed, Disetronic (Deltec), and Animas insulin infusion pumps are available for subcutaneous delivery of insulin. These pumps are small (about the size of a pager) and easy to program. They have many features, including the ability to record a number of different basal rates throughout a 24-hour period and adjust the time over which bolus doses are given. They are able also to detect pressure build-up if the catheter is kinked. Improvements have also been made in the infusion sets. The catheter connecting the insulin reservoir to the subcutaneous cannula can be disconnected so the patient can remove the pump temporarily (eg, for bathing). The great advantage of continuous subcutaneous insulin infusion (CSII) is that it allows for establishment of a basal profile tailored to the patient. The patient therefore is able to eat with less regard to timing because the basal insulin infusion should maintain a constant blood glucose level between meals.

CSII therapy is appropriate for patients who are motivated, mechanically adept, educated about diabetes (diet, insulin action, treatment of hypo- and hyperglycemia), and willing to monitor their blood glucose four to six times a day. Known complications of CSII include ketoacidosis, which can occur when insulin delivery is interrupted, and skin infections. Another major disadvantage is the cost and the time demanded of physicians and staff in initiating therapy. Increasingly, patients are using the ultrashort-acting analogs in the insulin pumps. In a double-blind crossover study comparing insulin lispro with regular insulin in insulin pumps, subjects using insulin lispro had lower HbA1cvalues and improved postprandial glucose control with the same frequency of hypoglycemia. There does remain a concern that in the event of pump failure, the insulin analogs could result in more rapid onset of hyperglycemia and ketosis.

Implantable insulin pumps delivering insulin into the peritoneum and portal circulation have been examined in clinical trials. The published results suggest that insulin requirements are lower and there is less hypoglycemia with this form of insulin delivery compared with intensive insulin therapy by injections, but safety considerations have not yet been sufficiently resolved to justify FDA approval.

To facilitate treatment of patients who are adhering to a regimen of multiple preprandial injections of regular insulin that supplement a single injection of long-acting insulin delivered by a conventional syringe, portable pen injectors have been introduced. Cartridges containing insulin lispro, insulin aspart, regular insulin, and NPH insulin are available for use with these pens. The devices (eg, Novo-Pen, BD pens) eliminate the need to carry an insulin bottle and syringes during the day. Eli Lilly also makes disposable pens containing insulin lispro, NPH, or 70/30 mixtures.

A novel method for delivering preprandial insulin by inhalation is in clinical trials. Several short-term trials have reported that inhaled insulin is as efficacious as subcutaneously delivered insulin in controlling postmeal glucose excursions. The bioavailability of inhaled insulin is about 10%, and so patients would need to inhale about 300–400 units of insulin a day. The current clinical studies excluded patients with pulmonary disorders, and there remain questions about the effects of long-term use on pulmonary tissues.

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Pancreas transplantation at the time of renal transplantation is becoming more widely accepted. Patients undergoing simultaneous pancreas and kidney transplantation have an 85% chance of pancreatic graft survival and a 92% chance of renal graft survival after 1 year. Solitary pancreatic transplantation in the absence of a need for renal transplantation should be considered only in those rare patients who fail all other insulin therapeutic approaches and who have life-threatening complications related to lack of metabolic control.

Islet cell transplantation is a minimally invasive procedure, and investigators in Edmonton, Canada, have reported insulin independence in a small number of patients with type 1 diabetes who underwent this procedure. Using islets from multiple donors and steroid-free immunosuppression, over 20 subjects have undergone percutaneous transhepatic portal vein transplantation of islets. All were able to achieve insulin independence, in some cases for more than 2 years of follow-up. All patients had complete correction of severe hypoglycemic reactions, leading to a marked improvement in overall quality of life. All patients continue to have persistent and detectable levels of C-peptide.

Despite these remarkable advances achieved by the Edmonton group, wide application of this procedure for the treatment of type 1 diabetes is limited by the dependence on multiple donors and the requirement for potent long-term immunotherapy.

STEPS IN THE MANAGEMENT OF THE DIABETIC PATIENT

Diagnostic Examination

  1. HISTORY AND PHYSICAL EXAMINATION

A complete history is taken and physical examination is performed for diagnostic purposes and to rule out the presence of coexisting or complicating disease. Nutritional status should be noted, particularly if catabolic features such as progressive weight loss are present despite a normal or increased food intake. The family history should include not only the incidence but also the age at onset of diabetes in other members of the family, and it should be noted whether affected family members were obese and whether they required insulin. Other factors that increase cardiovascular risk, such as a smoking history, presence of hypertension or hyperlipidemia, or oral contraceptive pill use should be documented.

A careful physical examination should include baseline height and weight, pulse rate, and blood pressure. If obesity is present, it should be characterized as to its distribution and a waist to hip ratio should be recorded. All peripheral arterial pulses should be examined, noting whether bruits or other signs of atherosclerotic disease are present. Neurologic and ophthalmologic examinations should be performed, with emphasis on investigation of abnormalities that may be related to diabetes, such as neovascularization of the retina or stocking/glove sensory loss in the extremities.

  1. LABORATORY DIAGNOSIS

(See also Laboratory Findings in Diabetes Mellitus, above.) Laboratory diagnosis should include documentation of the presence of fasting hyperglycemia (plasma glucose > 126 mg/dL [7 mmol/L]) or postprandial (post-glucose tolerance test) values consistently above 200 mg/dL (11.1 mmol/L). An attempt should be made to characterize the diabetes as type 1 or type 2, based on the clinical features present and on whether or not ketonuria accompanies the glycosuria. For the occasional patient, measurement of islet cell, glutamic acid decarboxylase (GAD), insulin antibodies, and ICA 512 antibodies can help in distinguishing between type 1 and type 2 diabetes. Many newly diagnosed patients with type 1 diabetes still have significant endogenous insulin production, and C peptide levels may not reliably distinguish between type 1 and type 2 diabetes. With current emphasis on home blood glucose monitoring, laborious attempts to document the renal threshold for glucose are no longer necessary in the initial evaluation of diabetic patients, particularly since “double-voided” urine specimens are difficult to obtain and since acceptable control of glycemia now allows only rare episodes of glycosuria.

Other baseline laboratory measurements that should be made part of the record include either glycohemoglobin or hemoglobin A1c, total and HDL cholesterol, plasma triglycerides, electrocardiogram, chest x-ray, complete blood count, complete urinalysis, and renal function studies (serum creatinine, blood urea nitrogen, and, if necessary, creatinine clearance).

Patient Education & Self-Management Training

Education is the most important task of the physician who provides care to diabetic patients. It must be remembered that education is necessary not only for newly diagnosed diabetic patients and their families but also for patients with diabetes of any duration who may never have been properly educated about their disorder or who may not be aware of advances in diabetes management. The “teaching curriculum” should include explanations of the nature of diabetes, its potential acute and chronic complications, and information on how these complications can be prevented or at least recognized and treated early. The importance of self-monitoring of blood glucose should be emphasized, particularly

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in all insulin-requiring diabetic patients, and instructions on proper testing and on recording of data should be provided. Patients should be trained in self-management and taught to use algorithms to adjust the timing and quantity of their insulin dose, food, and exercise in response to their recorded blood glucose values, so that optimal blood glucose control is achieved. Patients must be helped to accept the fact that they have diabetes; until this difficult adjustment has been made efforts to cope with the disorder are likely to be futile. Counseling should be directed at avoidance of extremes such as compulsive rigidity or self-destructive neglect. All patients should be made aware of community agencies (Diabetes Association chapters, etc.) that serve as resources for continuing education.

  1. DIET INSTRUCTION

All diabetic patients should receive individual instruction on diet, as described earlier in this chapter. Unrestricted diets are not advised for insulin requiring diabetics. Until new methods of insulin replacement are available to provide more normal patterns of insulin delivery in response to metabolic demands, multiple small feedings restricted in simple sugars will continue to be recommended.

  1. INSULIN

Give the patient an understanding of the actions of the various insulins and the methods of administration of insulin. Since infections, particularly pyogenic ones with fever and toxemia, provoke a marked increase in insulin requirements, patients must be taught how to appropriately administer supplemental rapid-acting insulin as needed to correct hyperglycemia during infections. Patients and their families or friends should also be taught to recognize signs and symptoms of hypoglycemia and how to institute appropriate therapy for hypoglycemic reactions (see Acute Complications of Diabetes Mellitus, below).

  1. ORAL DRUGS FOR HYPERGLYCEMIA

Information must be provided on the principles of hypoglycemic therapy (including information about time of onset, peak action, duration of action, and any adverse effects of pharmacologic agents being used). Patients should be made aware of the maximum recommended dose of the oral agent they are taking and should learn to inquire about possible drug interactions whenever any new medications are added to their regimens.

  1. EFFECT OF EXERCISE

Exercise increases the effectiveness of insulin, and regular daily moderate exercise is an excellent means of improving utilization of fats and carbohydrates in diabetic patients. A judicious balance of the size and frequency of meals with moderate regular exercise can often stabilize the insulin dosage in diabetics who tend to slip out of control easily. Strenuous exercise, however, can precipitate hypoglycemia in an unprepared patient, and diabetics must therefore be taught to reduce their insulin dosage or take supplemental carbohydrate in anticipation of strenuous activity. Injection of insulin into a site farthest away from the muscles most involved in exercise may help ameliorate exercise-induced hypoglycemia, since insulin injected into exercising muscle is much more rapidly mobilized. With more knowledge regarding the relationship between caloric intake and expenditure and insulin requirements, the patient can become liberated from much of the regimentation imposed by the disorder.

  1. GOOD HYGIENE

All diabetic patients must receive adequate instruction on personal hygiene, especially with regard to care of the feet, skin, and teeth.

  1. INFECTIONS

Infections with fever and severe illness provoke the release of high levels of insulin antagonists that will bring about a marked increase in insulin requirements. It is essential to limit the period of infection, since infection raises the blood glucose level and this, in turn, can impair the general defense mechanisms that the body uses against bacterial and even viral organisms. Thus, the early and sufficient use of bactericidal antibiotics is imperative. Type 1 diabetics must be taught how to supplement the regimen with regular insulin if persistent glycosuria and ketonuria occur—especially if associated with infection. Patients must understand that insulin therapy should never be withheld in the presence of gastric upset and vomiting if glycosuria with ketonuria is present. When food intake is limited by nausea or vomiting, the patient should take ginger ale, apple juice, or grape juice in small sips and should notify the physician in case supplemental intravenous fluids might be required.

  1. SELF-MONITORING OF BLOOD GLUCOSE LEVELS

Patients on insulin therapy and oral agents that can cause hypoglycemia should be instructed in techniques for self-monitoring of blood glucose (see above under blood glucose testing). Self-monitoring is useful in educating patients about the glycemic effects of specific foods in their diet and exercise and reduces the likelihood of unexpected episodes of severe hypoglycemia. Knowledge of the level of blood glucose has been particularly helpful at bedtime in ascertaining the need for

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supplementary feedings to avoid nocturnal hypoglycemia. Initially, blood glucose levels should be checked at least four times a day in patients taking multiple insulin injections. Generally, these measurements are taken before each meal and at bedtime. In addition, patients should be taught to check their blood glucose level whenever they develop symptoms that could represent a hypoglycemic episode. All blood glucose levels and their timing and corresponding insulin doses should be recorded in an organized fashion and brought with the patient for physician review during regularly scheduled checkups.

  1. IDENTIFICATION BRACELET

All patients receiving hypoglycemic therapy should wear a Medic-Alert bracelet or necklace that clearly states that insulin or an oral sulfonylurea drug is being taken. A card in the wallet or purse is less useful, since legal problems may arise if a victim's person and belongings are searched without permission. (Information on how to obtain a Medic-Alert identification device can be obtained from the Medic-Alert Foundation, PO Box 1009, Turlock, CA 95380.)

  1. RESTRICTIONS ON OCCUPATION

Certain occupations potentially hazardous to the diabetic patient or others will continue to be prohibited (eg, piloting airplanes, operating cranes).

Avoidance of Stress & Emotional Turmoil

Prevention of psychologic turmoil is of great importance in the control of diabetes, particularly when the disease is difficult to stabilize. One reason blood glucose control in diabetics may be particularly sensitive to emotional upset is that their pancreatic A cells are hyperresponsive to physiologic levels of epinephrine, producing excessive levels of glucagon with consequent hyperglycemia.

Specific Therapy

With the publication of data from the DCCT and the UKPDS, there has been a shift in the guidelines regarding acceptable levels of control. The ADA recommends that for both type 1 and type 2 patients, the goal is to achieve preprandial blood glucose values of 80–120 mg/dL and an average bedtime glucose of 100–140 mg/dL and HbA1c of < 7% (nondiabetic range: 4–6%). Obviously, these goals should be modified taking into account the patient's ability to carry out the treatment regimen, the risk of severe hypoglycemia, and other patient factors that may reduce the benefit of such tight control.

Type 1 Diabetes

Type 1 patients require replacement therapy with exogenous insulin. This should be instituted under conditions of an individualized diabetic diet with multiple feedings and normal daily activities so that an appropriate dosage regimen can be developed.

At the onset of diabetes, many type 1 patients recover some pancreatic B cell function and may temporarily need only low doses of exogenous insulin to supplement their own endogenous insulin secretion. This is known as the “honeymoon period.” Within 8 weeks to 2 years, however, most of these patients show either absent or negligible pancreatic B cell function. At this point, these patients should be switched to a more flexible insulin regimen with a combination of short-acting or ultrashort-acting insulin together with intermediate-acting or long-acting insulin. At a minimum, the patient should be on a three-injection regimen, and frequently four or more injections. Twice-daily split-dose insulin mixtures cannot maintain near-normalization of blood glucose without hypoglycemia (particularly at night) and are not recommended. Self-monitoring of blood glucose levels is a requisite for determining the optimal adjustment of insulin dosage and the modulation of food intake and exercise in type 1 diabetes.

  1. INSULIN REGIMENS

Certain caveats should be kept in mind regarding insulin treatment. Considerable variations in absorption and bioavailability exist, even when the same dose is injected in the same region on different days in the same individual. Such variation often can be minimized by injecting smaller quantities of insulin at each injection and consequently using multiple injections. Furthermore, a given insulin dosage may demonstrate considerable variability in pharmacokinetics in different individuals, either because of insulin antibodies that bind insulin with different avidity or for other as yet unknown reasons. A properly educated patient should be taught to adjust insulin dosage by observing the pattern of recorded self-monitored blood glucose levels and correlating it with the approximate duration of action and the time to peak effect after injection of the various insulin preparations (Table 17-15). Adjustments should be made gradually—not more often than every 2 or 3 days if possible.

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meals with one injection of NPH insulin at bedtime is a commonly used regimen (Table 17-16). The advent of pen injectors has made such multiple injection regimens more convenient.

Table 17-15. Typical patterns of overnight blood glucose levels and serum free immunoreactive insulin levels in prebreakfast hyperglycemia due to various causes in patients with type 1 diabetes.

 

Blood Glucose Levels (mg/dL)

Serum Free Immunoreactive Insulin Levels (ľU/mL)

10 PM

3 AM

7 AM

10 PM

3 AM

7 AM

Somogyi effect

90

40

200

High

Slightly high

Normal

“Dawn phenomenon”

110

110

150

Normal

Normal

Normal

Waning of circulating insulin levels plus “dawn phenomenon”

110

190

220

Normal

Low

Low

Waning of circulating insulin levels plus “dawn phenomenon” plus Somogyi effect

110

40

380

High

Normal

Low

The ultrashort-acting insulin analogs have been advocated as a safer and much more convenient alternative to regular insulin for preprandial use in regimens of intensive insulin therapy. In clinical studies, combinations of ultrashort-acting insulin analogs (insulin lispro or insulin aspart) with meals together with intermediate-acting (NPH) or longer-acting insulin (ultralente, insulin glargine) for basal coverage have now been shown to have improved HbA1c values with less hypoglycemia when compared with a regimen of regular insulin with meals and NPH at night.

Table 17-13 illustrates some regimens that might be appropriate for a 70 kg person with type 1 diabetes eating meals of standard carbohydrate intake and moderate to low fat content.

o   Etiology and diagnosis—One of the more difficult therapeutic problems in managing patients with type 1 diabetes is determining the proper adjustment of insulin dose when the early morning blood glucose level is high before breakfast. Prebreakfast hyperglycemia is sometimes due to the Somogyi effect, in which nocturnal hypoglycemia evokes a surge of counterregulatory hormones to produce high blood glucose levels by 7 AM. However, a more common cause of prebreakfast hyperglycemia is the waning of circulating insulin levels, which requires use of more (rather than less) intermediate insulin in the evening. These two

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phenomena are not mutually exclusive and can occur together to produce a greater magnitude of hyperglycemia in affected patients with type 1 diabetes. A third phenomenon—the dawn phenomenon—has been reported to occur in as many as 75% of type 1 patients and in the majority of type 2 patients and normal subjects as well. It is characterized by a reduced tissue sensitivity to insulin between 5 AM and 8 AM (dawn), and apparently is evoked by spikes of growth hormone released hours before, at onset of sleep. When the “dawn phenomenon” occurs alone, it may produce only mild hyperglycemia in the early morning; however, when it is associated with either or both of the other phenomena, it can further aggravate the hyperglycemia (Table 17-15). Diagnosis of the cause of prebreakfast hyperglycemia can be facilitated by asking the patient to self-monitor blood glucose levels at 3 AM in addition to monitoring at the usual times, bedtime and 7 AM. When this was done, the Somogyi effect was found to be much less prevalent and of lower magnitude as a cause of prebreakfast hyperglycemia than had been previously suspected. In insulin-treated patients, serum levels of free immunoreactive insulin (particularly in the basal or low ranges) are difficult to quantitate accurately because of technical interference from circulating insulin antibodies. In specialized research laboratories, however, free insulin levels have been measured in hospitalized patients with prebreakfast hyperglycemia (Table 17-15).

o   Treatment—When a particular pattern emerges from monitoring blood glucose levels at 10 PM, 3 AM, and 7 AM, appropriate therapeutic measures can be taken. Prebreakfast hyperglycemia due to the Somogyi effect can be treated by either reducing the dose of intermediate insulin at supper, giving a portion of it at bedtime, or supplying more food at bedtime. When the“dawn phenomenon” alone is present, shifting a portion of the intermediate insulin from dinnertime to bedtime often suffices. Insulin glargine given at bedtime results in lower fasting glucose values when compared with bedtime NPH. When insulin pumps are used, the “dawn phenomenon” can be controlled by stepping up the basal infusion rate (eg, from 0.8 unit/h to 1 unit/h) from 6 AM until breakfast. Finally, in cases in which the circulating insulin level is waning, either increasing the evening insulin dose or, preferably, shifting it from dinnertime to bedtime (or both) may be efficacious. Switching to ultralente insulin or insulin glargine or insulin pump administration can also solve this problem.

 

Table 17-16. Guidelines for regular and NPH insulin regimens in patients with type 1 diabetes mellitus.

  1. TYPE 2 DIABETES

The principles of therapy are less well defined in this heterogeneous group of diabetic patients than is the case with type 1 diabetes. Therapeutic recommendations are based upon the relative contributions of B cell insufficiency and insulin insensitivity in individual patients. With prolonged duration of type 2 diabetes, deposits of amyloid accumulate in islets and encroach on pancreatic B cells, resulting in progressive diminution of insulin-secretory capacity.

  1. The obese patient—The most common type of patient with type 2 diabetes is obese with insulin insensitivity. Characteristically, obese patients compensate for their insulin resistance with increased basal levels of circulating insulin and are capable of responding to a glucose load with hypersecretion of insulin. However, as hyperglycemia progresses, the insulin response to a glucose load decreases. This refractoriness of the B cell may be partially reversed with therapeutic correction of the hyperglycemia and seems to be selectively related to the hyperglycemic stimulation, since other B cell-stimulating agents such as sulfonylureas, arginine, and glucagon still provoke rapid insulin release.

o   Weight reduction—One of the primary modes of therapy in the obese type 2 diabetic patient is weight reduction. Normalization of glycemia can be achieved by reducing adipose stores, with consequent restoration of tissue sensitivity to insulin. A combination of caloric restriction, increased exercise, modification of behavior, and consistent reinforcement of good eating habits is required if a weight reduction program is to be successful. Knowledge of the symptoms of diabetes and an understanding of the risks and complications of diabetes often increase the patient's motivation for weight reduction. Even so, significant weight loss is seldom achieved and even more difficult to maintain in the morbidly obese patient. Weight control is variable in moderately obese patients depending on the enthusiasm of the therapist and the motivation of the patient. Orlistat is a reversible inhibitor of gastric and pancreatic lipases and prevents the hydrolysis of dietary triglycerides. These triglycerides are then excreted in the feces. In a 1-year study in obese patients with type 2 diabetes, those taking orlistat had lost more weight, had lower HbA1c values, and had improved lipid profiles. The main adverse reactions were gastrointestinal, with oily spotting, oily stool, flatus, and fecal urgency and frequency. Malabsorption of fat-soluble vitamins also occurs, and patients should take a multivitamin tablet containing fat-soluble vitamins at least 2 hours before or 2 hours after the administration of orlistat.

o   Hypoglycemic agents—Hypoglycemic agents, including insulin as well as the oral hypoglycemic drugs are generally not indicated for long-term use in the obese patient with mild diabetes. A weight reduction program can be disrupted by real or imagined hypoglycemic reactions when insulin therapy is used, and

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weight gain is quite common in the insulin-treated obese diabetic patient. Metformin, an insulin-sparing agent and one that does not increase weight or provoke hypoglycemia, offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in obese patients.

If metformin therapy (combined with a weight reduction regimen) is inadequate in achieving target glucose values, a thiazolidinedione or a sulfonylurea should be added. Some individuals may require metformin, a thiazolidinedione, and a sulfonylurea to achieve adequate glycemic control. Insulin therapy should be instituted if the combination of these three drugs fails to restore euglycemia. Weight-reducing interventions should continue and may allow for simplification of this regimen in the future.

  1. The nonobese patient—In the nonobese type 2 diabetic with moderately severe hyperglycemia, pancreatic B cells are refractory to glucose stimulation. Peripheral insulin resistance is also detectable but is considerably less intense than in obese diabetics who have a comparable degree of hyperglycemia; it is also of less therapeutic import, since insulin-treated nonobese patients do not generally need an excessive dosage of insulin.
  2. Diet—If hyperglycemia is mild (fasting blood glucose levels of < 200 mg/dL [11.1 mmol/L]), normal metabolic control can occasionally be restored by a diet devoid of simple sugars and with calories calculated to maintain ideal body weight. Restriction of saturated fats and cholesterol is also strongly advised. An individualized diet with a recommended exchange list should be prescribed for these nonobese type 2 patients.
  3. Oral agents for hyperglycemia—When diet therapy alone is not sufficient to correct hyperglycemia, a trial of oral antihyperglycemic drugs is indicated to supplement the dietary regimen. In the nonobese type 2 patient, sulfonylureas are generally the first-line oral drug of choice, and metformin or thiazolidinediones (or both) are added later if glycemic control is inadequate. Failing this, these individuals will require insulin.
  4. Insulin—When the combination of metformin, a sulfonylurea, and a thiazolidinedione fails and type 2 patients require insulin, various insulin regimens may be effective (Table 17-13). There is no consensus about how insulin therapy should be instituted. One proposed regimen adds a bedtime intermediate-acting insulin to reduce excessive nocturnal hepatic glucose output while continuing daytime sulfonylurea therapy. If the patient remains hyperglycemic during the day, an additional insulin dosage can be added in the morning and the daytime sulfonylurea can be discontinued. The most popular insulin regimen under these circumstances is to use a split dose of a fixed 70:30 mixture of NPH:regular insulin before breakfast and before dinner, and this can be adjusted appropriately depending on premeal and bedtime blood glucose values. If more than 50 units per day does not achieve satisfactory glycemic control, these patients may benefit from more intensive multiple-injection regimens as described for type 1 patients. Metformin principally reduces hepatic glucose output and the thiazolidinediones improve peripheral resistance, and it is a reasonable option to continue these drugs when insulin therapy is instituted because they may permit the use of lower doses of insulin and simpler regimens.

Immunopathology of Insulin Therapy

At least five molecular classes of insulin antibodies are produced during the course of insulin therapy: IgA, IgD, IgE, IgG, and IgM. Human insulin is much less antigenic than the older animal (especially beef) insulins, but because of its hexameric presentation at therapeutic injection doses, it is also treated as a foreign substance by the immune system and results in detectable—albeit low—titers of insulin antibodies in most patients.

  1. INSULIN ALLERGY

Insulin allergy, a hypersensitivity reaction of the immediate type, is a rare condition in which local or systemic urticaria occurs immediately after insulin injection. This reaction is due to histamine release from tissue mast cells sensitized by adherence of IgE antibodies to their surface. In severe cases, anaphylaxis can occur. The appearance of a subcutaneous nodule at the site of insulin injection, occurring several hours after the injection and lasting for up to 24 hours, has been attributed to an IgG-mediated complement-binding Arthus reaction. Because sensitivity was often due to noninsulin protein contaminants, the highly purified insulins have markedly reduced the incidence of insulin allergy, especially of the local variety. Antihistamines, cortico-steroids, and even desensitization may be required, espe-cially for systemic hypersensitivity in an insulin-dependent patient. A protocol for allergy testing and insulin desensitization is available from the Eli Lilly Company. A trial of insulin analogs should also be considered. There is a case report of successful use of insulin lispro in the face of generalized allergy to human insulin.

  1. IMMUNE INSULIN RESISTANCE

All patients who receive insulin (including insulin analogs) develop a low titer of circulating IgG antibodies,

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and this neutralizes to a small extent the rapid action of insulin. With the old animal insulins, a high titer of circulating antibodies sometimes developed, resulting in extremely high insulin requirements, often to more than 200 units/d. This is now very rarely seen with the switch to the highly purified pork or human insulins and has not been reported with use of the analogs.

  1. LIPODYSTROPHY AT INJECTION SITES

Rarely, a disfiguring atrophy of subcutaneous fatty tissue occurs at the site of insulin injection. Although the cause of this complication is obscure, it seems to represent a form of immune reaction, particularly since it occurs predominantly in females and is associated with lymphocyte infiltration in the lipoatrophic area. This complication has become even less common since the development of highly purified insulin preparations of neutral pH. Injection of highly purified preparations of insulin directly into the atrophic area often results in restoration of normal contours.

Lipohypertrophy, on the other hand, is not a consequence of immune responses; rather, it seems to be due to the pharmacologic effects of depositing insulin in the same location repeatedly. It can occur with purified insulins and is best treated with localized liposuction of the hypertrophic areas by an experienced plastic surgeon. It is prevented by rotation of injection sites. There is a case report of a patient who had intractable lipohypertrophy (fatty infiltration of injection site) with human insulin but no longer had the problem when he switched to insulin lispro.

ACUTE COMPLICATIONS OF DIABETES MELLITUS

HYPOGLYCEMIA

Hypoglycemic reactions (see below and Chapter 18) are the most common complications that occur in insulin-treated diabetic patients. They may also occur in patients taking oral sulfonylureas, especially older patients or those with impaired liver or kidney function treated with long-acting and highly potent agents such as chlorpropamide or glyburide. Hypoglycemia may result from delay in taking a meal or from unusual physical exertion without supplemental calories or a decrease in insulin dose.

Clinical Features

Signs and symptoms of hypoglycemia may be divided into those resulting from neuroglycopenia (insufficient glucose for normal central nervous system function leading to confusion and coma) and those resulting from stimulation of the autonomic nervous system. There is great variation in the pattern of hypoglycemic signs and symptoms from patient to patient; however, individual patients tend to experience the same pattern from episode to episode. In older diabetics, in patients with frequent hypoglycemic episodes, and in those with diabetic autonomic neuropathy, autonomic responses may be blunted or absent, so that hypoglycemia may be manifested only by signs and symptoms of neuroglycopenia. The gradual onset of hypoglycemia with intermediate-acting or long-acting insulin also makes recognition more difficult in older patients.

  1. NEUROGLYCOPENIA

Signs and symptoms of neuroglycopenia include mental confusion with impaired abstract and, later, concrete thought processes; this may be followed by bizarre antagonistic behavior. Stupor, coma, and even death may occur with profound hypoglycemia. Full recovery of central nervous system function does not always occur if treatment is delayed.

  1. AUTONOMIC HYPERACTIVITY

Signs and symptoms of autonomic hyperactivity can be both adrenergic (tachycardia, palpitations, sweating, tremulousness) and parasympathetic (nausea, hunger). Except for sweating, most of the sympathetic symptoms of hypoglycemia are blunted in patients receiving beta-blocking agents for angina or hypertension. Though not absolutely contraindicated, these drugs must be used with great caution in insulin-requiring diabetics.

  1. COUNTERREGULATORY RESPONSES TO HYPOGLYCEMIA

(Table 17-17.)

  1. 1. Normal counterregulation—When plasma glucose is acutely lowered in normal subjects by intravenous insulin, a rapid surge of both glucagon and epinephrine acts to counterregulate the hypoglycemia. The hormonal responses tend to begin after plasma glucose falls below 70 mg/dL (3.9 mmol/L). If they fail to correct the decline of plasma glucose, symptoms of autonomic hyperactivity usually become apparent once plasma glucose falls below 60 mg/dL (3.3 mmol/L). Plasma glucagon is considered the first line of defense against acute hypoglycemia, while the role of epinephrine and the sympathetic system is to provide a backup system. The latter helps to restore euglycemia and serves as an

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alarm system to warn the subject of the urgent need for carbohydrate intake in case the counterregulatory response is inadequate to prevent the potentially disastrous consequences of life-threatening neuroglycopenia.

  1. 2. Defective counterregulation in diabetes—For unexplained reasons, patients with type 1 diabetes uniformly lose their ability to secrete glucagon in response to acute insulin-induced hypoglycemia (but not in the presence of amino acids in protein-containing meals) within a few years after developing diabetes. After that time, they are solely dependent upon triggered autonomic adrenergic responses to counteract an impending hypoglycemic crisis as well as for early warning. It is well documented that with advanced age these autonomic responses may be blunted considerably, and in diabetic patients with clinical autonomic neuropathy as a complication of diabetes they may be absent. In these circumstances, reduced awareness of hypoglycemia can lead to potentially life-threatening sequelae from neuroglycopenic convulsions or coma.
  2. 3. Iatrogenic autonomic failure—Cryer has proposed that frequent and recurrent hypoglycemic episodes such as may be encountered in patients receiving intensive insulin therapy to achieve normoglycemia may result in failure of the sympathetic nervous system to respond to hypoglycemia. Adaptation of the central nervous system to recurrent hypoglycemic episodes is associated with increased glucose transport into the brain despite subnormal levels of plasma glucose. This results from up-regulation of glucose transporter 1 at the blood-brain barrier induced by recurrent hypoglycemia. The threshold for recognizing hypoglycemia is thereby altered, so that much lower plasma glucose levels are needed to trigger an autonomic response—and by the time this occurs, cognition may already be impaired in some cases, with onset of neuroglycopenia. That this adaptation and autonomic failure is a consequence of chronic hypoglycemia and not diabetes is evidenced by reports of patients with insulinomas who had chronic recurrent episodes of hypoglycemia of which they often were unaware. These were patients who had loss of epinephrine responses and symptoms during acute insulin-induced hypoglycemia and whose symptoms and adrenergic responses during repeat testing returned to normal after euglycemia had been restored following resection of the insulinomas. This documented reversibility of the syndrome of hypoglycemia unawareness due to chronic hypoglycemia has exciting implications for therapy of those diabetic patients whose unawareness may be iatrogenic as a result of recurrent hypoglycemia during attempts at normalization of blood glucose with intensive insulin therapy.
  3. 4. Human insulin and hypoglycemic unawareness—In 1987, a preliminary report contended that hypoglycemia unawareness became more prevalent in diabetics transferred from beef-pork to human insulin. Although occasional studies gave support to this claim, most investigators failed to find evidence for a detrimental effect of human insulin on recognition of hypoglycemia. There is some evidence that many of the anecdotal reports of loss of hypoglycemic awareness after changing from animal to human insulin may be a consequence of an increased number of hypoglycemic episodes. The latter may occur on switching from animal to human insulin if the switch is made at equivalent or nearly equivalent dosages without taking the precaution of using a lower human insulin dose to compensate for the reduced neutralization of the injected insulin by preexisting anti-beef or anti-pork insulin antibodies. Another possible cause of more frequent hypoglycemic episodes is the inclination of patients and their physicians to attempt tighter glycemic control when switching from animal to

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human insulin as part of a general upgrading of diabetes care. As evidenced by the results of the Diabetes Control and Complications Trial (DCCT), the risk of frequent hypoglycemic episodes is greatly increased when “normalization” of the blood glucose is attempted with present suboptimal methods of insulin delivery, and this was independent of the species of insulin used in the DCCT. Although the controversy has not been completely resolved, most authorities do not recommend restricting the use of human insulin because of fear of hypoglycemia.

Table 17-17. Counterregulatory responses to hypoglycemia.

Normal Counterregulation

Defective Counterregulation in Type 1 Diabetes1

Glucagon rises rapidly to three to five times baseline after insulin-induced hypoglycemia, provoking hepatic glyco-genolysis.

Glucagon response to insulin-induced hypoglycemia is lost after onset of type 1 diabetes.

Adrenergic discharge (1) raises hepatic glucose output by glycogenolysis and (2) provides warning to subject of impending hypoglycemic crisis.

Blunted or absent adrenergic response may occur as a result of-

1. Neural damage associated with advanced age or autonomic neuropathy

2. Neural dysfunction (iatrogenic) from frequent hypoglycemia or (?) human insulin therapy

1Type 2 diabetics are less well characterized as to their defective counterregulation of glucagon loss but appear to have the same frequency and causes of adrenergic loss as do type 1 diabetics.

  1. MANAGEMENT OF HYPOGLYCEMIC UNAWARENESS

(Table 17-18.) Avoiding recurrent hypoglycemia is the main principle of therapy to restore hypoglycemic awareness. Many insulin-treated diabetics have nocturnal episodes of hypoglycemia of which they are often unaware. These may be detected only with screening by capillary blood testing at least once a week at 2–3 AM. If such episodes do occur, appropriate reduction of evening insulin doses or an increase in the amount of food taken as a snack at bedtime should be advised.

When hypoglycemic unawareness occurs while the patient is awake, two patterns of presentation have been described. In some cases, patients appear perfectly alert with no obvious neuroglycopenia or adrenergic symptoms when a scheduled preprandial capillary blood glucose measurement indicates a level below 40 or 50 mg/dL (2.2 or 2.7 mmol/L). This suggests some degree of adaptation with probable provision of increased glucose transporter-1 proteins among brain capillaries to provide minimum requirements of glucose to the brain despite the hypoglycemia. These patients are at increased risk, however, of developing severe neuroglycopenia if hypoglycemia progresses.

Table 17-18. Hypoglycemic unawareness in type 1 diabetes mellitus.

1. Sleeping patient (nocturnal hypoglycemia)

2. Hypoglycemia with unawareness while awake—

1. Manifestations:

1. Without detectable neuroglycopenia:

1. Adaptation to chronic hypoglycemia (increased brain glucose transporter I)

2. With neuroglycopenia:

1. Maladaptation to hypoglycemia

2. Mechanisms:

1. Defective autonomic response:

1. Due to diabetic autonomic neuropathy

2. Iatrogenic

1. Frequent hypoglycemia

2. Human insulin therapy (?)

3. Management:

1. Identify patients at risk and reevaluate glycemic goals

2. Advise frequent self-monitoring of blood glucose

3. Learn to detect subtle symptoms of neuroglycopenia

4. Avoid recurrent hypoglycemia

5. Frequent snacks should be prescribed

6. Multiple small doses of insulin may be needed

7. Injectable glucagon made available to family

In the second pattern of presentation, patients exhibit neuroglycopenia and progress to require assistance for recovery without having had any awareness of the impending crisis. This form of unawareness is life-threatening and requires immediate measures to prevent recurrences.

When either of these patterns of hypoglycemic unawareness presents while the patient is awake, careful evaluation for autonomic neuropathy with reduced or absent adrenergic responses is indicated. Evidence for this condition consists of orthostatic hypotension or a fixed heart rate measured during a change in position, during respiration, or after a Valsalva maneuver.

If autonomic neuropathy is detected, glycemic target goals should be appropriately raised by lowering the daily insulin dosage and ensuring that it is administered in multiple small doses, which have a more predictable pharmacokinetic pattern than do larger depot injections. To further lower the risk of severe hypoglycemic episodes, the frequency of self-monitoring of blood glucose should be increased to provide awareness of glycemic status at regular intervals, and patients should be trained to detect subtle signs or symptoms of autonomic responses they might otherwise overlook.

In patients without obvious autonomic neuropathy who have lost awareness to hypoglycemia, special efforts should be made to avoid hypoglycemia for weeks or months in order to reverse central nervous system adaptation to recurrent hypoglycemia. This can be done by increasing the frequency of self-monitoring of blood glucose, raising the mean blood glucose level to be targeted, eating frequent small snacks, and reducing the size of insulin doses at any one injection.

Treatment

All of the manifestations of hypoglycemia are rapidly relieved by glucose administration. Because of the danger of insulin reactions, diabetic patients should carry packets of table sugar or a candy roll at all times for use at the onset of hypoglycemic symptoms. Tablets containing 3 g of glucose are available. The educated patient soon learns to take the amount of glucose needed to correct symptoms without ingesting excessive quantities of orange juice or candy, which can provoke very high glycemic levels. Family members or friends of the patient should be provided with a glucagon emergency kit (Lilly), which contains a syringe, diluent, and a 1

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mg ampule of glucagon that can be injected intramuscularly if the patient is found unconscious; these kits are available by prescription. Detailed instructions in the use of glucagon are an essential part of the diabetic education program. An identification MedicAlert bracelet, necklace, or card in the wallet or purse should be carried by every diabetic receiving hypoglycemic drug therapy. The telephone number for the Medic-Alert Foundation International in Turlock, California, is 800-ID-ALERT.

  1. THE CONSCIOUS PATIENT

Patients with symptoms of hypoglycemia who are conscious and able to swallow should eat or drink orange juice, glucose tablets, or any sugar-containing beverage or food except pure fructose (which does not cross the blood-brain barrier).

  1. THE UNCONSCIOUS PATIENT

In general, oral feeding is contraindicated in stuporous or unconscious patients. The preferred treatment is 50 mL of 50% glucose solution given rapidly over 3–5 minutes. If trained personnel are not available to administer intravenous glucose, the treatment of choice is for a family member or friend to administer 1 mg of glucagon intramuscularly (see above), which will usually restore the patient to consciousness within 10–15 minutes; the patient should then be given an oral form of sugar to ingest. If glucagon is not available, small amounts of honey, syrup, or glucose gel can be rubbed into the buccal mucosa. Rectal administration of syrup or honey (30 mL per 500 mL of warm water) has also been used effectively.

COMA

Coma is a medical emergency calling for immediate evaluation to determine its cause so that proper therapy can be started. There are several causes of coma that result directly from diabetes mellitus or its treatment. When evaluating a comatose diabetic patient, these must be considered in addition to the myriad causes included in the differential diagnosis of coma (cerebrovascular accidents, head trauma, intoxication with alcohol or other drugs, etc).

Etiologic Classification of Diabetic Coma

The causes of coma resulting directly from diabetes mellitus or its treatment include the following:

  1. HYPERGLYCEMIC COMA

Hyperglycemic coma may be associated with either severe insulin deficiency (diabetic ketoacidosis) or with mild to moderate insulin deficiency (hyperglycemic, hyperosmolar, nonketotic coma).

  1. HYPOGLYCEMIC COMA

This results from excessive doses of insulin or certain oral hypoglycemic agents (see above).

  1. LACTIC ACIDOSIS

Lactic acidosis in diabetics is particularly apt to occur in association with severe tissue anoxia, sepsis, or cardiovascular collapse.

Emergency Management of Coma

The standard approach to any comatose patient is outlined below. Prompt action is required.

  1. Establish an airway.
  2. Establish intravenous access. About 30 mL of blood should be drawn and sent for complete blood count, serum electrolyte determinations, renal function and liver function tests, and blood glucose measurements.
  3. Administer 50 mL of 50% dextrose in water to all comatose patients, unless bedside monitoring of blood glucose shows hyperglycemia.
  4. Administer 1 ampule (0.4 mg) of naloxone intravenously and 100 mg of thiamine intravenously. (See also Chapter 24.)

Diagnosis of Coma

After emergency measures have been instituted, a careful history (from family, friends, paramedics, etc), physical examination, and laboratory evaluation are required to resolve the differential diagnosis. Patients in deep coma from a hyperosmolar nonketotic state or from hypoglycemia are generally flaccid and have quiet breathing—in contrast to patients with acidosis, whose respirations are rapid and deep if the pH of arterial blood has dropped to 7.1 or below. When hypoglycemia is a cause of the coma, hypothermia is usually present and the state of hydration is usually normal. Although the clinical laboratory remains the final arbiter in confirming the diagnosis, a rapid estimationof blood glucose and ketones can be obtained by the use of bedside glucose and ketone meters (see Laboratory Findings in Diabetes Mellitus, above). Table 17-19 is a summary of some laboratory abnormalities found in diabetic patients with coma attributable to diabetes or its treatment. The individual clinical syndromes are discussed in detail on the following pages.

  1. Diabetic Ketoacidosis

This acute complication of diabetes mellitus may be the first manifestation of previously undiagnosed type 1 diabetes or may result from increased insulin requirements in type 1 diabetes patients during the course of infection, trauma, myocardial infarction, or surgery. It

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is a life-threatening medical emergency with a mortality rate just under 5% in individuals under 40 years of age but with a more ominous prognosis in the elderly, who have mortality rates over 20%. In all cases, precipitating factors such as infection should be searched for and treated appropriately. Poor compliance, either for psychological reasons or because of inadequate patient education, is probably the most common cause of diabetic ketoacidosis, particularly when episodes are recurrent. In adolescents with type 1 diabetes, recurrent episodes of severe ketoacidosis often indicate the need for counseling to alter this behavior.

Table 17-19. Summary of some laboratory abnormalities in patients with coma directly attributable to diabetes or its treatment.

 

Urine

Plasma

Glucose

Acetone

Glucose

Bicarbonate

Acetone

Osmolality

Hyperglycemia, hyperosmolar coma
Diabetic ketoacidosis

++ to ++++

++++

High

Low

++++

+++

Hyperglycemic nonketotic coma

++ to ++++

0 or +1

High

Normal or slightly low2

0

++++

Hypoglycemia

03

0 or +

Low

Normal

0

Normal

Lactic acidosis

0 to +

0 or +

Normal, low, or high

Low

0 or +

Normal

1A small degree of ketonuria may be present if the patient is severely stressed or has not been eating because of illness.

2A patient may be acidotic if there is severe volume depletion with cardiovascular collapse or if sepsis is present.

3Leftover urine in bladder might still contain sugar from earlier hyperglycemia.

Diabetic ketoacidosis has been found to be one of the more common serious complications of insulin pump therapy, occurring in approximately one per 80 patient months of treatment. Many patients who monitor capillary blood glucose regularly ignore urine ketone measurements, which would signal the possibility of insulin leakage or pump failure before serious illness develops.

Patients with type 2 diabetes may also develop ketoacidosis under severe stress such as sepsis, trauma, or major surgery.

Pathogenesis

Acute insulin deficiency results in rapid mobilization of energy from stores in muscle and fat depots, leading to an increased flux of amino acids to the liver for conversion to glucose and of fatty acids for conversion to ketones (acetoacetate, β-hydroxybutyrate, and acetone). In addition to this increased availability of precursor, there is a direct effect of the low insulin:glucagon ratio on the liver that promotes increased production of ketones as well as of glucose. In response to both the acute insulin deficiency and the metabolic stress of ketosis, the levels of insulin-antagonistic hormones (corticosteroids, catecholamines, glucagon, and GH) are consistently elevated. Furthermore, in the absence of insulin, peripheral utilization of glucose and ketones is reduced. The combination of increased production and decreased utilization leads to an accumulation of these substances in blood, with plasma glucose levels reaching 500 mg/dL (27.8 mmol/L) or more and plasma ketones reaching levels of 8–15 mmol/L or more.

The hyperglycemia causes osmotic diuresis leading to depletion of intravascular volume. As this progresses, impaired renal blood flow reduces the kidney's ability to excrete glucose, and hyperosmolality is worsened. Severe hyperosmolality (> 330 mosm/kg) correlates closely with central nervous system depression and coma.

In a similar manner, impaired renal excretion of hydrogen ions aggravates the metabolic acidosis that occurs as a result of the accumulation of the ketone acids, β-hydroxybutyrate and acetoacetate. The accumulation of ketones may cause vomiting, which exacerbates the intravascular volume depletion. In addition, prolonged acidosis can compromise cardiac output and reduce vascular tone. The result may be severe cardiovascular collapse with generation of lactic acid, which then adds to the already existent metabolic acidosis.

Clinical Features

  1. SYMPTOMS AND SIGNS

As opposed to the acute onset of hypoglycemic coma, the appearance of diabetic ketoacidosis is usually preceded by a day or more of polyuria and polydipsia associated with marked fatigue, nausea, and vomiting.

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Eventually, mental stupor ensues and can progress to frank coma. On physical examination, evidence of dehydration in a stuporous patient with rapid and deep respirations and the “fruity” breath odor of acetone would strongly suggest the diagnosis. Postural hypotension with tachycardia indicates profound dehydration and salt depletion. Abdominal pain and even tenderness may be present in the absence of abdominal disease, and mild hypothermia is usually present.

  1. LABORATORY FINDINGS

Four-plus glycosuria, strong ketonuria, hyperglycemia, ketonemia, low arterial blood pH, and low plasma bicarbonate (5–15 mEq/L) are typical laboratory findings in diabetic ketoacidosis. Serum potassium is usually normal or slightly elevated (5–8 mEq/L) despite total body potassium depletion, because of the shift of potassium from the intracellular to extracellular spaces that occurs in systemic acidosis. The average total body potassium deficit resulting from osmotic diuresis, acidosis, and gastrointestinal losses is about 5–10 mEq/kg body weight. Similarly, serum phosphate is elevated (6–7 mg/dL), but total body phosphate is generally depleted. Serum sodium is generally reduced (to about 125–130 mEq/L) because severe hyperglycemia pulls intercellular water into the interstitial compartment, thereby diluting the already depleted sodium ions lost by polyuria and vomiting. (For every 100 mg/dL of plasma glucose above normal, serum sodium decreases by 1.6 mEq/L.) Serum osmolality can be directly measured by standard tests of freezing-point depression or can be estimated by calculating the molarity of sodium, chloride, and glucose in the serum. A convenient formula for estimating effective serum osmolality is as follows (physiologic values in humans are generally between 280 and 300 mosm/kg):

These calculated estimates are usually 10–20 mosm/kg lower than values recorded by standard cryoscopic techniques. Blood urea nitrogen and serum creatinine are invariably elevated because of dehydration. While urea exerts an effect on freezing point depression as measured in the laboratory, it is freely permeable across cell membranes and therefore not included in calculations of effective serum osmolality. In the presence of keto acids, values from multichannel chemical analysis of serum creatinine may be falsely elevated and therefore quite unreliable. However, most laboratories can correct for these interfering chromogens by using a more specific method if asked to do so.

The nitroprusside reagents (Acetest and Ketostix) used for the bedside assessment of ketoacidemia and ketoaciduria measure only acetoacetate and its by-product, acetone. The sensitivity of these reagents for acetone, however, is quite poor, requiring over 10 mmol/L, which is seldom reached in the plasma of ketoacidotic subjects—although this detectable concentration is readily achieved in urine. Thus, in the plasma of ketotic patients, only acetoacetate is measured by these reagents. The more prevalent β-hydroxybutyrate has no ketone group and is therefore not detected by the conventional nitroprusside tests. This takes on special importance in the presence of circulatory collapse during diabetic ketoacidosis, wherein an increase in lactic acid can shift the redox state to increase β-hydroxybutyrate at the expense of the readily detectable acetoacetate. Bedside diagnostic reagents would then be unreliable, suggesting no ketonemia in cases where β-hydroxybutyric acid is a major factor in producing the acidosis.

In about 90% of cases, serum amylase is elevated. However, this often represents salivary as well as pancreatic amylase and correlates poorly with symptoms of pancreatitis, such as pain and vomiting. Therefore, in patients with diabetic ketoacidosis, an elevated serum amylase does not justify a diagnosis of acute pancreatitis; serum lipase may be useful if the diagnosis of pancreatitis is being seriously considered.

  1. DATA RECORDING ON A FLOW SHEET

The need for frequent evaluation of the patient's status cannot be overemphasized. Patients with moderately severe diabetic ketoacidosis (pH < 7.2) are best managed in an intensive care unit. Essential baseline blood chemistries include glucose, ketones, electrolytes, arterial blood gases, blood urea nitrogen, and serum creatinine. Serum osmolality should be estimated and tabulated during the course of therapy.

Typically, the patient with moderately severe diabetic ketoacidosis will have a plasma glucose of 350–900 mg/dL (19.4–50 mmol/L), the presence of serum ketones at a dilution of 1:8 or greater, slight hy-ponatremia of 130 mEq/L, hyperkalemia of 5–8 mEq/L, hyperphosphatemia of 6–7 mg/dL, and an elevated blood urea nitrogen and creatinine. Acidosis may be severe (pH ranging from 6.9 to 7.2 and bicarbonate ranging from 5 to 15 mEq/L); PCO2 is low (15–20 mm Hg) from hyperventilation.

A comprehensive flow sheet that includes vital signs, serial laboratory data, and therapeutic interventions should be meticulously maintained by the physician responsible for the patient's care (Figure 17-10). Plasma glucose should be recorded hourly and electrolytes and pH at least every 2–3 hours during the initial treatment period. Insulin therapy is greatly facilitated when

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plasma glucose results are available within a few minutes of sampling. This can be achieved by the use of bedside glucose meters for measurements of capillary blood glucose (see Blood Glucose Testing, above). Fluid intake and output as well as details of insulin therapy and the administration of other medications should also be carefully recorded on the flow sheet.

 

Figure 17-10. Flow sheet for treatment of diabetic ketoacidosis.

Treatment

  1. IMMEDIATE RESUSCITATION AND EMERGENCY MEASURES

If the patient is stuporous or comatose, immediately institute the emergency measures outlined in the section on coma (see above). Once the diagnosis of diabetic ketoacidosis is established in the emergency room, administration of at least 2 L of isotonic saline (0.9% saline solution) in an adult patient in the first 2–3 hours is necessary to help restore plasma volume and stabilize blood pressure while acutely reducing the hyperosmolar state. In addition, by improving renal plasma flow, fluid replacement also restores the renal capacity to excrete hydrogen ions, thereby ameliorating the acidosis as well. Immediately after the initiation of fluid replacement, a rapid bolus of 0.3 unit of regular insulin per kilogram of body weight should be given intravenously. This will inhibit both gluconeogenesis and ketogenesis while promoting utilization of glucose and keto acids. If arterial blood pH is 7.0 or less, intravenous bicarbonate may be administered (details of administration are outlined below). Gastric intubation is recommended in the comatose patient to prevent vomiting and aspiration that may occur as a result of gastric atony, a common complication of diabetic ketoacidosis. An indwelling bladder catheter is required in all comatose patients but should be avoided, if possible, in a fully cooperative diabetic patient because of the risk of bladder infection. In patients with preexisting cardiac or renal failure or those in severe cardiovascular collapse, a central venous pressure catheter or a Swan-Ganz catheter should be inserted to evaluate the degree of hypo-volemia and to monitor subsequent fluid administration.

  1. SPECIFIC MEASURES

Each case must be managed individually depending on the specific abnormalities present and subsequent response to initial therapy.

  1. Insulin—Only regular insulin, and preferably human insulin, should be used in the management of diabetic ketoacidosis. As noted above, a “loading” dose of 0.3 unit/kg body weight of regular insulin is given initially as an intravenous bolus to prime the tissue insulin receptors. Following the initial bolus, doses of insulin as low as 0.1 unit/kg, given hourly by slow intravenous drip—or even when given intramuscularly—are as effective in most cases as the much higher doses previously recommended, and they appear to be safer. When a continuous infusion of insulin is used, 25 units of regular human insulin should be placed in 250 mL of isotonic saline and the first 50 mL of solution flushed through to saturate the tubing before connecting it to the intravenous line. An I-Vac or Harvard pump provides a reliable infusion rate. The insulin dose should be“piggy-backed” into the fluid line so the rate of fluid replacement can be changed without altering the insulin delivery rate. If the plasma glucose level fails to fall at least 10% in the first hour, a repeat loading dose is recommended. Rarely, a patient with insulin resistance is encountered; this requires doubling the insulin dose every 2–4 hours if severe hyperglycemia does not improve after the first two doses of insulin and fluid replacement.

Insulin therapy, either as a continuous infusion or as injections given every 1–2 hours, should be continued until arterial pH has normalized.

  1. Fluid replacement—In most adult patients, the fluid deficit is 4–5 L. Initially, isotonic saline is preferred for restoration of plasma volume and, as noted above, should be infused rapidly to provide 1 L/h over the first 1–2 hours. After the first 2 L of fluid have been given, the fluid should be changed to 0.45% saline solution given at a rate of 300–400 mL/h; this is because water loss exceeds sodium loss in uncontrolled diabetes with osmotic diuresis. Failure to give enough volume replacement (at least 3–4 L in 8 hours) to restore normal perfusion is one of the most serious therapeutic shortcomings affecting satisfactory recovery. In the same way, excessive fluid replacement (more than 5 L in 8 hours) may contribute to acute respiratory distress syndrome or cerebral edema. When blood glucose falls to approximately 250 mg/dL, the fluids should be changed to a 5% glucose solution to maintain plasma glucose in the range of 250–300 mg/dL. This will prevent the development of hypoglycemia and will also reduce the likelihood of cerebral edema, which could result from too rapid decline of blood glucose. Intensive insulin therapy should be continued until the ketoacidosis is corrected.
  2. Sodium bicarbonate—The use of sodium bicarbonate in management of diabetic ketoacidosis has been questioned since clinical benefit was not demonstrated in one prospective randomized trial and because of the following potentially harmful consequences: (1) development of hypokalemia from rapid shift of potassium into cells if the acidosis is overcorrected; (2) tissue anoxia from reduced dissociation of oxygen from hemoglobin when acidosis is rapidly reversed (leftward shift of the oxygen dissociation curve); and (3) cerebral acidosis resulting from lowering of cerebrospinal fluid

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pH. It must be emphasized, however, that these considerations are less important when severe acidosis exists. It is therefore recommended that bicarbonate be administered to diabetic patients in ketoacidosis if the arterial blood pH is 7.0 or less with careful monitoring to prevent overcorrection.

One to two ampules of sodium bicarbonate (one ampule contains 44 mEq/50 mL) should be added to 1 L of 0.45% saline. (Note:Addition of sodium bicarbonate to 0.9% saline would produce a markedly hypertonic solution that could aggravate the hyperosmolar state already present.) This should be administered rapidly (over the first hour). It can be repeated until the arterial pH reaches 7.1, but it should not be given if the pH is 7.1 or greater since additional bicarbonate would increase the risk of rebound metabolic alkalosis as ketones are metabolized. Alkalosis shifts potassium from serum into cells, which could precipitate a fatal cardiac arrhythmia. As noted earlier, serious consideration should be given to placement of a central venous or Swan-Ganz catheter when administering fluids to severely ill patients with cardiovascular compromise.

  1. Potassium—Total body potassium loss from polyuria and vomiting may be as high as 200 mEq. However, because of shifts of potassium from cells into the extracellular space as a consequence of acidosis, serum potassium is usually normal to slightly elevated prior to institution of treatment. As the acidosis is corrected, potassium flows back into the cells, and hypokalemia can develop if potassium replacement is not instituted. If the patient is not uremic and has an adequate urine output, potassium chloride in doses of 10–30 mEq/h should be infused during the second and third hours after beginning therapy as soon as the acidosis starts to resolve. Replacement should be started sooner if the initial serum potassium is inappropriately normal or low and should be delayed if serum potassium fails to respond to initial therapy and remains above 5 mEq/L, as in cases of renal insufficiency. Cooperative patients with only mild ketoacidosis may receive part or all of their potassium replacement orally.

An ECG can be of help in monitoring the patient's potassium status: high peaked T waves are a sign of hyperkalemia, and flattened T waves with U waves are a sign of hypokalemia.

Foods high in potassium content should be prescribed when the patient has recovered sufficiently to take food orally. Tomato juice has 14 mEq of potassium per 240 mL, and a medium-sized banana has about 10 mEq.

  1. Phosphate—Phosphate replacement is seldom required in treating diabetic ketoacidosis. However, if severe hypophosphatemia of less than 1 mg/dL (< 0.35 mmol/L) develops during insulin therapy, a small amount of phosphate can be replaced per hour as the potassium salt. Correction of hypophosphatemia helps to restore the buffering capacity of the plasma, thereby facilitating renal excretion of hydrogen. It also corrects the impaired oxygen dissociation from hemoglobin by regenerating 2,3-diphosphoglycerate. However, three randomized studies in which phosphate was replaced in only half of a group of patients with diabetic ketoacidosis did not show any apparent clinical benefit from phosphate administration. Moreover, attempts to use the phosphate salt of potassium as the sole means of replacing potassium have led to a number of reported cases of severe hypocalcemia with tetany. To minimize the risk of inducing tetany from too rapid replacement of phosphate, the average deficit of 40–50 mmol of phosphate should be replaced intravenously at a rate no greater than 34 mmol/hin a 60- to 70-kg person. A stock solution (Abbott) provides a mixture of 1.12 g KH2PO4and 1.18 g K2HPO4 in a 5-mL single-dose vial (this equals 22 mmol of potassium and 15 mmol of phosphate). One-half of this vial (2.5 mL) should be added to 1 L of either 0.45% saline or 5% dextrose in water. Two liters of this solution, infused at a rate of 400 mL/h, will correct the phosphate deficit at the optimal rate of 3 mmol/h while providing 4.4 mEq of potassium per hour. (Additional potassium should be administered as potassium chloride to provide a total of 10–30 mEq of potassium per hour, as noted above.) If the serum phosphate remains below 2.5 mg/dL after this infusion, a repeat 5-hour infusion can be given.

It remains controversial whether phosphate replacement is beneficial. Several clinics prohibit its use in the routine treatment of diabetic ketoacidosis, since the risk of inducing hypocalcemia is thought to outweigh its potential benefits. However, potential hazards of phosphate replacement can be greatly reduced by administering phosphate at a rate no greater than 3–4 mmol/h. To prevent errors of overreplacement, phosphate should be administered separately rather than included as a component of potassium replacement.

  1. Hyperchloremic acidosis during therapy—Because of the considerable loss of keto acids in the urine during the initial phase of therapy, substrate for subsequent regeneration of bicarbonate is lost and correction of the total bicarbonate deficit is hampered. A portion of the bicarbonate deficit is replaced with chloride ions infused in large amounts as saline to correct the dehydration. In most patients, as the ketoacidosis clears during insulin replacement, a hyperchloremic, low-bicarbonate pattern emerges with a normal anion gap. This is a relatively benign condition that reverses itself over the subsequent 12–24 hours once intravenous saline is no longer being administered.

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Prognosis

Insulin and fluid and electrolyte replacement combined with careful monitoring of patients' clinical and laboratory responses to therapy have dramatically reduced the morbidity and mortality rates of diabetic ketoacidosis. However, this complication still represents a potential threat to survival, especially in older people with cardiovascular disease. Even in specialized centers, the mortality rate may approach 5–10%. Therefore, physicians treating diabetic ketoacidosis must not be lured into adopting“cookbook” approaches that lessen their attentiveness to changes in the patient's condition. Signs to be watched for include failure of improvement in mental status after a period of treatment, continued hypotension with minimal urine flow, or prolonged ileus (which may suggest bowel infarction). Laboratory abnormalities to be watched include failure of blood glucose to fall by 80–100 mg/dL during the first hour of therapy, failure to increase serum bicarbonate or arterial pH appropriately, serum potassium above 6 or below 2.8 mEq/L, and electrocardiographic evidence of cardiac arrhythmias. Any of these signs call for a careful search for the cause of the abnormality and prompt specific therapy.

Disposition

After recovery and stabilization, patients should receive intensive detailed instructions about how to avoid this potentially disastrous complication of diabetes mellitus. They should be taught to recognize the early symptoms and signs of ketoacidosis.

Urine ketones should be measured in patients with signs of infection or in those using an insulin pump when capillary blood glucose is unexpectedly and persistently high. A combined glucose and ketone meter (Precision, Medisense) that is able to measure blood betahydroxybutyrate concentration on capillary blood is available and provides an alternative to monitoring for ketonuria. When heavy ketonuria and glycosuria persist on several successive examinations, supplemental regular insulin should be administered and liquid foods such as lightly salted tomato juice and broth should be ingested to replenish fluids and electrolytes. Patients should be instructed to contact the physician if ketonuria persists, and especially if vomiting develops or if appropriate adjustment of the infusion rate on an insulin pump does not correct the hyperglycemia and ketonuria. In adolescents, recurrent episodes of severe diabetic ketoacidosis often indicate poor compliance with the insulin regimen, and these patients should receive intensive family counseling.

  1. Hyperglycemic, Hyperosmolar, Nonketotic State

This form of hyperglycemic coma is characterized by severe hyperglycemia, hyperosmolality, and dehydration in the absence of significant ketosis. It occurs in middle-aged or elderly patients with non-insulin-dependent diabetes which is often mild or occult. Lethargy and confusion develop as serum osmolality exceeds 300 mosm/kg, and coma can occur if osmolality exceeds 330 mosm/kg. Underlying renal insufficiency or congestive heart failure is common, and the presence of either worsens the prognosis. A precipitating event such as pneumonia, cerebrovascular accident, myocardial infarction, burns, or recent operation can often be identified. Certain drugs, such as phenytoin, diazoxide, glucocorticoids, and thiazide diuretics, have been implicated in its development, as have procedures associated with glucose loading, eg, peritoneal dialysis.

Pathogenesis

A partial or relative insulin deficiency may initiate the syndrome by reducing glucose utilization by muscle, fat, and the liver while at the same time inducing hyperglucagonemia and increasing hepatic glucose output. The result is hyperglycemia that leads to glycosuria and osmotic diuresis with obligatory water loss. The presence of even small amounts of insulin is believed to prevent the development of ketosis by inhibiting lipolysis in the adipose stores. Therefore even though a low insulin:glucagon ratio promotes ketogenesis in the liver, the limited availability of precursor free fatty acids from the periphery restricts the rate at which ketones are formed. If a patient is unable to maintain adequate fluid intake because of an associated acute or chronic illness or has suffered excessive fluid loss (eg, from burns or therapy with diuretics), marked dehydration results. As plasma volume contracts, renal insufficiency develops; this, then, limits renal glucose excretion and contributes markedly to the rise in serum glucose and osmolality. As serum osmolality exceeds 320–330 mosm/kg, water is drawn out of cerebral neurons, resulting in mental obtundation and coma.

Clinical Features

  1. SYMPTOMS AND SIGNS

The onset of the hyperglycemic, hyperosmolar, nonketotic state may be insidious, preceded for days or weeks by symptoms of weakness, polyuria, and polydipsia. A history of reduced fluid intake is common, whether due to inappropriate absence of thirst, gastrointestinal upset, or, in the case of elderly or bedridden patients,

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lack of access to water. A history of ingestion of large quantities of glucose-containing fluids, such as soft drinks or orange juice, can occasionally be obtained; these patients are usually less hyperosmolar than those in whom fluid intake was restricted. The absence of toxic features of ketoacidosis may retard recognition of the syndrome and thus delay institution of therapy until dehydration is profound. Because of this delay in diagnosis, the hyperglycemia, hyperosmolality, and dehydration in hyperglycemic, hyperosmolar, nonketotic coma is often more severe than in diabetic ketoacidosis.

Physical examination will reveal the presence of profound dehydration (orthostatic fall in blood pressure and rise in pulse, supine tachycardia or even frank shock, dry mucous membranes, decreased skin turgor). The patient may be lethargic, confused, or comatose. Kussmaul respirations are absent unless the precipitating event for the hyperosmolar state has also led to the development of metabolic acidosis (eg, sepsis or myocardial infarction with shock).

  1. LABORATORY FINDINGS

Severe hyperglycemia is present, with blood glucose values ranging from 800 to as high as 2400 mg/dL (44.4–133.2 mmol/L). In mild cases, where dehydration is less severe, dilutional hyponatremia as well as urinary sodium losses may reduce serum sodium to about 120–125 mEq/L—this protects, to some extent, against extreme hyperosmolality. Once dehydration progresses further, however, serum sodium can exceed 140 mEq/L, producing serum osmolalities of 330–440 mosm/kg* (normal, 280–295 mosm/kg). Ketosis is usually absent or mild; however, a small degree of ketonuria may be present if the patient has not been eating because of illness. Acidosis is not a part of the hyperglycemic, hyperosmolar state, but it may be present (usually lactic acidosis) because of other acute underlying conditions (sepsis, acute renal failure, myocardial infarction, etc). (See Lactic Acidosis, below.)

Treatment

There are some differences in fluid, insulin, and electrolyte replacement in this disorder, as compared to diabetic ketoacidosis. However, in common with the treatment of ketoacidotic patients, careful monitoring of the patient's clinical and laboratory response to therapy is essential.

  1. FLUID REPLACEMENT

Fluid replacement is of paramount importance in treating nonketotic hyperglycemic coma. If circulatory collapse is present, fluid therapy should be initiated with isotonic saline. In all other cases, initial replacement with hypotonic (usually 0.45%) saline is preferable, because these patients are hyperosmolar with considerable loss of body water and excess solute in the vascular compartment. As much as 4–6 L of fluid may be required in the first 8–10 hours. Careful monitoring of fluid quantity and type, urine output, blood pressure, and pulse is essential. Placement of a central venous pressure or Swan-Ganz catheter should be strongly considered to guide replacement of fluid, especially if the patient is elderly or has underlying renal or cardiac disease. Because insulin therapy will decrease plasma glucose and therefore serum osmolality, a change to isotonic saline may be necessary at some time during treatment in order to maintain an adequate blood pressure and a urine output of at least 50 mL/h. Once blood glucose reaches 250 mg/dL, 5% dextrose in 0.45% or 0.9% saline solution should be substituted for the sugar-free fluids. When consciousness returns, oral fluids should be encouraged.

  1. ELECTROLYTE REPLACEMENT

Hyperkalemia is less marked and much less potassium is lost in the urine during the osmotic diuresis of hyperglycemic, hyperosmolar, nonketotic coma than in diabetic ketoacidosis. There is, therefore, less severe total potassium depletion, and less potassium replacement is needed to restore potassium stores to normal. However, because the initial serum potassium usually is not elevated and because it declines rapidly as insulin therapy allows glucose and potassium to enter cells, it is recommended that potassium replacement be initiated earlier than in ketotic patients: 10 mEq of potassium chloride can be added to the initial liter of fluid administered if the initial serum potassium is not elevated and if the patient is making urine. When serum phosphate falls below 1 mg/dL during insulin therapy, phosphate replacement can be given intravenously with the same precautions as those outlined for ketoacidotic patients (see above). If the patient is awake and cooperative, part or all of the potassium and phosphate replacement can be given orally.

  1. INSULIN THERAPY

In general, less insulin is required to reduce the hyperglycemia of nonketotic patients than is the case for patients in diabetic ketoacidosis. In fact, fluid replacement alone can decrease glucose levels considerably. An initial

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dose of 15 units of regular insulin given intravenously and 15 units given intramuscularly is usually quite effective in lowering blood glucose. In most cases, subsequent doses need not be greater than 10–25 units every 4 hours. (Insulin should be given intramuscularly or intravenously until the patient has stabilized; it may then be given subcutaneously.) Some patients—especially those who are severely ill because of other underlying diseases—may require continuous intravenous administration of insulin (in a manner similar to that described for ketoacidosis) with careful monitoring, preferably in an intensive care setting.

  1. SEARCH FOR THE PRECIPITATING EVENT

The physician must initiate a careful search for the event that precipitated the episode of hyperglycemic, hyperosmolar, nonketotic coma if it is not obvious after the initial history and physical examination. Chest x-rays and cultures of blood, urine, and other body fluids should be obtained to look for occult sources of sepsis; empiric antibiotic coverage should be considered in the seriously ill patient. Cardiac enzymes and serial ECGs can be ordered to look for evidence of “silent” myocardial infarction.

Prognosis

The overall mortality rate of hyperglycemic, hyperosmolar, nonketotic coma is over ten times that of diabetic ketoacidosis, chiefly because of its higher incidence in older patients, who may have compromised cardiovascular systems or associated major illnesses. (When patients are matched for age, the prognoses of these two forms of hyperosmolar coma are reasonably comparable.)

Disposition

After the patient is stabilized, the appropriate form of long-term management of the diabetes must be determined. This must include patient education on how to recognize situations (gastrointestinal upset, infection) that will predispose to recurrence of hyperglycemic, hyperosmolar, nonketotic coma as well as detailed information on how to prevent the escalating dehydration (small sips of sugar-free liquids, increase in usual hypoglycemic therapy, or early contact with the physician) that culminates in hyperosmolar coma. For a detailed discussion of therapeutic alternatives for type 2 diabetic patients, see Steps in the Management of the Diabetic Patient (above).

  1. Hypoglycemic Coma

Hypoglycemia is a common complication of insulin replacement therapy in diabetic patients. In most cases, it is detected and treated by patients or their families before coma results. However, it remains the most frequent cause of coma in the insulin-treated diabetic patient. In addition, it can occur in any patient taking oral agents that stimulate pancreatic B cells (eg, sulfonylureas, meglitinide, D-phenylalanine analog), particularly if the patient is elderly, has renal or liver disease, or is taking certain other medications that alter metabolism of the sulfonylureas (eg, phenylbutazone, sulfonamides, or warfarin). It occurs more frequently with the use of long-acting sulfonylureas than when shorter-acting agents are used.

Clinical Findings & Treatment

The clinical findings and emergency treatment of hypoglycemia are discussed at the beginning of this section.

Prognosis

Most patients who arrive at emergency rooms in hypoglycemic coma appear to recover fully; however, profound hypoglycemia or delays in therapy can result in permanent neurologic deficit or even death. Furthermore, repeated episodes of hypoglycemia may have a cumulative adverse effect on intellectual functioning.

Disposition

The physician should carefully review with the patient the events leading up to the hypoglycemic episode. Associated use of other medications, as well as alcohol or narcotics, should be noted. Careful attention should be paid to diet, exercise pattern, insulin or sulfonylurea dosage, and general compliance with the prescribed diabetes treatment regimen. Any factors thought to have contributed to the development of the episode should be identified and recommendations made in order to prevent recurrences of this potentially disastrous complication of diabetes therapy.

If the patient is hypoglycemic from use of a long-acting oral hypoglycemic agent (eg, chlorpropamide or glyburide) or from high doses of a long-acting insulin, admission to hospital for treatment with continuous intravenous glucose and careful monitoring of blood glucose is indicated.

  1. Lactic Acidosis

When severely ill diabetic patients present with profound acidosis and an anion gap over 15 mEq/L but relatively low or undetectable levels of keto acids in plasma, the presence of excessive plasma lactate (> 5 mmol/L) should be considered, especially if other causes of acidosis such as uremia are not present.

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Pathogenesis

Lactic acid is the end product of anaerobic metabolism of glucose. Normally, the principal sources of this acid are the erythrocytes (which lack the enzymes for aerobic oxidation), skeletal muscle, skin, and brain. The chief pathway for removal of lactic acid is by hepatic (and to some degree renal) uptake for conversion first to pyruvate and eventually back to glucose, a process that requires oxygen. Lactic acidosis occurs when excess lactic acid accumulates in the blood. This can be the result of overproduction (tissue hypoxia), deficient removal (hepatic failure), or both (circulatory collapse). Lactic acidosis is not uncommon in any severely ill patient suffering from cardiac decompensation, respiratory or hepatic failure, septicemia, or infarction of the bowel or extremities.

With the discontinuance of phenformin therapy in the USA, lactic acidosis in patients with diabetes mellitus has become uncommon, but it still must be considered in the acidotic diabetic if the patient is seriously ill, and especially if the patient is receiving metformin therapy as well.

Clinical Features

  1. SYMPTOMS AND SIGNS

The main clinical features of lactic acidosis are marked hyperventilation and mental confusion, which may progress to stupor or coma. When lactic acidosis is secondary to tissue hypoxia or vascular collapse, the clinical presentation is variable, being that of the prevailing catastrophic illness. In the rare instance of idiopathic or spontaneous lactic acidosis, the onset is rapid (usually over a few hours), the cardiopulmonary status is stable, and mentation may be relatively normal.

  1. LABORATORY FINDINGS

Plasma glucose can be low, normal, or high in diabetic patients with lactic acidosis, but usually it is moderately elevated. Plasma bicarbonate and arterial pH are quite low. An anion gap will be present (calculated by subtracting the sum of the plasma bicarbonate and chloride from the plasma sodium; normal is 12–15 mEq/L). Ketones are usually absent from plasma, but small amounts may be present in urine if the patient has not been eating recently. Other causes of “anion gap” metabolic acidosis should be excluded—eg, uremia, diabetic or alcoholic ketoacidosis, and salicylate, methanol, ethylene glycol, or paraldehyde intoxication. In the absence of azotemia, hyperphosphatemia may be a clue to the presence of lactic acidosis.

The diagnosis is confirmed by demonstrating, in a sample of blood that is promptly chilled and separated, a plasma lactate concentration of 6 mmol/L or higher (normal is about 1 mmol/L). Failure to rapidly chill the sample and separate the plasma can lead to falsely high plasma lactate values as a result of continued glycolysis by the red blood cells. Frozen plasma remains stable for subsequent assay.

Treatment

The cornerstone of therapy is aggressive treatment of the precipitating cause. An adequate airway and good oxygenation should be ensured. If hypotension is present, fluids and, if appropriate, pressor agents must be given to restore tissue perfusion. Appropriate cultures and empiric antibiotic coverage should be instituted in any seriously ill patient with lactic acidosis in whom the cause is not immediately apparent. Alkalinization with intravenous sodium bicarbonate to keep the pH above 7.2 has been recommended in the emergency treatment of severe lactic acidosis. However, there is no evidence that the mortality rate is favorably affected by administering bicarbonate and the matter is at present controversial, particularly because of the hazards associated with bicarbonate therapy. Hemodialysis may be useful in those cases in which metformin accumulation and the attendant lactic acidosis occurred in patients with renal insufficiency. Dichloroacetate, an anion that facilitates pyruvate removal by activating pyruvate dehydrogenase, reverses certain types of lactic acidosis in animals, but in a prospective controlled clinical trial involving 252 patients with lactic acidosis, dichloroacetate failed to alter either hemodynamics or survival.

CHRONIC COMPLICATIONS OF DIABETES MELLITUS (Table 17-20)

In most patients with diabetes, a number of pathologic changes occur at variable intervals during the course of the disease. These changes involve the vascular system for the most part; however, they also occur in the nerves, the skin, and the lens.

In addition to the above complications, diabetic patients have an increased incidence of certain types of infections and may handle their infections less well than the general population.

Classifications of Diabetic Vascular Disease

Diabetic vascular disease is conveniently divided into two main categories: microvascular disease and macrovascular disease.

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  1. MICROVASCULAR DISEASE

Disease of the smallest blood vessels, the capillary and the precapillary arterioles, is manifested mainly by thickening of the capillary basement membrane. Microvascular disease involving the retina leads to diabetic retinopathy, and disease involving the kidney causes diabetic nephropathy. Small vessel disease may also involve the heart, and cardiomegaly with heart failure has been described in diabetic patients with patent coronary arteries.

Table 17-20. Chronic complications of diabetes mellitus.

Eyes
   Diabetic retinopathy
      Nonproliferative (background)
      Proliferative
   Cataracts
      Subcapsular (snowflake)
      Nuclear (senile)
Kidneys
   Intercapillary glomerulosclerosis
      Diffuse
      Nodular
   Infection
      Pyelonephritis
      Perinephric abscess
      Renal papillary necrosis
   Renal tubular necrosis
      Following dye studies (urograms, arteriograms)
Nervous system
   Peripheral neuropathy
      Distal, symmetric sensory loss
      Motor neuropathy
         Foot drop, wrist drop
         Mononeuropathy multiplex (diabetic amyotrophy)
   Cranial neuropathy
Crania  l nerves III, IV, VI, VII
   Autonomic neuropathy
      Postural hypotension
      Resting tachycardia
      Loss of sweating
      Gastrointestinal neuropathy
         Gastroparesis
         Diabetic diarrhea
      Urinary bladder atony
      Impotence (may also be secondary to pelvic vascular disease)
Skin
   Diabetic dermopathy (shin spots)
   Necrobiosis lipoidica diabeticorum
   Candidiasis
   Foot and leg ulcers
      Neurotropic
      Ischemic
Cardiovascular system
   Heart disease
      Myocardial infarction
      Cardiomyopathy
   Gangrene of the feet
      Ischemic ulcers
      Osteomyelitis
Bones and joints
   Diabetic cheirarthropathy
   Dupuytren's contracture
   Charcot joint
Unusual infections
   Necrotizing fasciitis
   Necrotizing myositis
 Mucor meningitis
   Emphysematous cholecystitis
   Malignant otitis externa

  1. MACROVASCULAR DISEASE

Large vessel disease in diabetes is essentially an accelerated form of atherosclerosis. It accounts for the increased incidence of myocardial infarction, stroke, and peripheral gangrene in diabetic patients. Just as in the case of atherosclerosis in the general population, the exact cause of accelerated atherosclerosis in the diabetic population remains unclear. Abnormalities in vessel walls, platelets and other components of the clotting system, red blood cells, and lipid metabolism have all been postulated to play a role. In addition, there is evidence that coexistent risk factors such as cigarette smoking and hypertension may be important in determining the course of the disease.

Prevalence of Chronic Complications by Type of Diabetes

Although all of the known complications of diabetes can be found in both types of the disease, some are more common in one type than in the other. Renal failure due to severe microvascular nephropathy is the major cause of death in patients with type 1 diabetes, whereas macrovascular disease is the leading cause in type 2. Although blindness occurs in both types, it occurs

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more commonly as a result of severe proliferative retinopathy, vitreous hemorrhages, and retinal detachment in type 1 disease, whereas macular edema and ischemia are the usual cause in type 2. Similarly, although diabetic neuropathy is common in both type 1 and type 2 diabetes, severe autonomic neuropathy with gastroparesis, diabetic diarrhea, resting tachycardia, and postural hypotension is much more common in type 1.

Relationship of Glycemic Control to Development of Chronic Complications

The cause of chronic microvascular complications in diabetic patients has now been resolved. A compelling argument for its being a consequence of impaired metabolic control was initially made by observations in Korean patients who ingested a B cell-toxic rodenticide, vacor, during a suicide attempt and developed persistent diabetes. As many as 44% of these patients developed retinopathy during a 6- to 7-year follow-up of their acquired diabetes, while 28% had clinical proteinuria and more than half showed significant thickening of their quadriceps capillary basement membrane width.

However, in patients with idiopathic diabetes mellitus, the most compelling argument for the view that chronic diabetic complications relate to poor glycemic control is based on the findings of the Diabetes Control and Complications Trial (discussed above). This study of 1441 type 1 patients over a 7- to 10-year period conclusively demonstrated that near normalization of blood glucose with intensive therapy was able to substantially prevent or delay the development of diabetic retinopathy, nephropathy, and neuropathy.

Genetic Factors in Susceptibility to Development of Chronic Complications of Diabetes

Although no genetic susceptibility genes have been identified as yet, three unrelated observations indicate that roughly 40% of people may be unusually susceptible to the ravages of hyperglycemia or other metabolic sequelae of an inadequate insulin effect.

(1) In one retrospective study of 164 juvenile-onset diabetics with a median age at onset of 9 years, 40% were incapacitated or dead from end-stage renal disease with proliferative retinopathy after a 25-year follow-up, while the remaining subjects were either mildly affected (40%) or had no clinically detected microvascular disease (20%). This study was completed long before the availability of glycemic self-monitoring methodology, so it is unlikely that any of these patients were near optimal glycemic control.

(2) Data from renal transplantation indicate that only about 40% of normal kidneys developed evidence of moderate to severe diabetic nephropathy within 6–14 years of being transplanted into diabetic subjects with end-stage renal failure, whereas as many as 60% were only minimally affected.

(3) Among children under 21 years of age with type 1 diabetes, 40% had thickening of the capillary basement membrane width (CBMW) of the quadriceps muscle, while 60% had vessels within the normal range. This finding was unrelated to the severity or duration of diabetes and is in contrast to results in diabetic adults 21 years of age or older, in whom virtually 100% have thickened CBMWs.

These three observations support the hypothesis that while approximately 60% of people suffer only minimal consequences from hyperglycemia and other metabolic hazards of insulin insufficiency, 40% or so suffer severe, potentially catastrophic microvascular complications if the disease is poorly controlled. The genetic mechanisms for this increased susceptibility are as yet unknown but could relate to overproduction or reduced removal of accelerated glycosylation end products in particular tissues. If further studies indicate that the presence of early thickening of the CBMW—found in 40% of children—represents a marker of this susceptibility gene and a predictor of severe microvascular disease, it could justify more intensive insulin therapy in that group to achieve near-normalization of blood glucose. The remaining 60% of less susceptible individuals might then be spared the inconveniences of strict glycemic control as well as the risks of hypoglycemia inherent in present methods of intensive insulin therapy.

SPECIFIC CHRONIC COMPLICATIONS OF DIABETES MELLITUS (Table 17-20)

  1. Ophthalmologic Complications

Diabetic Retinopathy

For early detection of diabetic retinopathy, adolescent or adult patients who have had type 1 diabetes for more than 5 years and all type 2 diabetic patients should be referred to an ophthalmologist for examination and follow-up. When hypertension is present in a patient with diabetes, it should be treated vigorously, since hypertension is associated with an increased incidence and accelerated progression of diabetic retinopathy.

  1. PATHOGENESIS AND CLINICAL FEATURES

Two main categories of diabetic retinopathy exist: nonproliferative and proliferative.

Nonproliferative (background) retinopathy represents the earliest stage of retinal involvement by

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diabetes and is characterized by such changes as microaneurysms, dot hemorrhages, exudates, and retinal edema. During this stage, the retinal capillaries leak proteins, lipids, or red cells into the retina. When this process occurs in the macula, the area of greatest concentration of visual cells, there will be interference with visual acuity; this is the most common cause of visual impairment in type 2 diabetes and occurs in up to 18% of these patients over time.

Proliferative retinopathy involves the growth of new capillaries and fibrous tissue within the retina and into the vitreous chamber. It is a consequence of small vessel occlusion, which causes retinal hypoxia; this in turn stimulates new vessel growth. Proliferative retinopathy can occur in both types of diabetes but is more common in type 1, developing about 7–10 years after onset of symptoms, with a prevalence of 25% after 15 years' duration. Prior to proliferation of new capillaries, a preproliferative phase often occurs in which arteriolar ischemia is manifested as cotton-wool spots (small infarcted areas of retina). Vision is usually normal until vitreous hemorrhage or retinal detachment occurs. Proliferative retinopathy is a leading cause of blindness in the USA, particularly since it increases the risk of retinal detachment. After 10 years of diabetes, half of all patients have at least some degree of retinopathy, and this proportion increases to more than 80% after 15 years of diabetes.

  1. TREATMENT

Once maculopathy or proliferative changes are detected, panretinal xenon or argon laser photocoagulation therapy is indicated. Destroying retinal tissue with photocoagulation means that surviving tissue receives a greater share of the available oxygen supply, thereby abolishing hypoxic stimulation of new vessel growth. Results of a large-scale clinical trial (the Diabetic Retinopathy Study) have verified the effectiveness of photocoagulation, particularly when recent vitreous-hemorrhages have occurred or when extensive new vessels are located near the optic disk.

The best results with photocoagulation are achieved if proliferative retinopathy is detected early. This is best done by obtaining a baseline fluorescein angiogram within 5–10 years after onset of type 1 diabetes and then repeating this study at intervals of 1–5 years, depending on the severity of the retinal involvement found. Prepubertal children do not develop diabetic retinopathy regardless of the duration of their diabetes. They need not be scheduled for routine ophthalmologic examination until several years after the onset of puberty.

Pituitary ablation, which has been associated with delay in progression of severe retinopathy in the past, is rarely used today because photocoagulation therapy is just as effective and avoids the risks associated with destruction of the pituitary. Occasional cases of rapidly progressive (“florid”) proliferative retinopathy in type 1 adolescent diabetics have been reported in which photocoagulation was less effective than pituitary ablation in preventing blindness. Clinical trials have shown that aspirin does not influence the course of proliferative retinopathy, and there is no contraindication for its use to achieve cardiovascular benefit in diabetic patients who have proliferative retinopathy.

Cataracts

Two types of cataracts occur in diabetic patients: subcapsular and senile. Subcapsular cataract occurs predominantly in type 1 diabetics, may come on fairly rapidly, and has a significant correlation with the hyperglycemia of uncontrolled diabetes. This type of cataract has a flocculent or “snowflake” appearance and develops just below the lens capsule.

Senile cataract represents a sclerotic change of the lens nucleus. It is by far the most common type of cataract found in either diabetic or nondiabetic adults and tends to occur at a younger age in diabetic patients, particularly when glycemic control is poor.

Two separate abnormalities found in diabetic patients, both of which are related to elevated blood glucose levels, may contribute to the formation of cataracts: (1) glycosylation of the lens protein and (2) an excess of sorbitol, which is formed from the increased quantities of glucose found in the insulin-independent lens. Accumulation of sorbitol leads to osmotic changes in the lens that ultimately result in fibrosis and cataract formation.

Glaucoma

Glaucoma occurs in approximately 6% of persons with diabetes. It is generally responsive to the usual therapy for open-angle disease. Closed-angle glaucoma can result from neovascularization of the iris in diabetics, but this is relatively uncommon except after cataract extraction, when accelerated new vessel growth may occur that involves the angle of the iris and obstructs outflow.

  1. Renal Complications

Diabetic Nephropathy

  1. PATHOGENESIS AND CLINICAL FINDINGS

About 4000 cases of end-stage renal disease due to diabetic nephropathy occur annually among diabetic patients in the USA. This represents about one-third of all patients being treated for renal failure. The cumulative incidence of nephropathy differs between the two

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major types of diabetes. Patients with type 1 diabetes who have not received intensive insulin therapy and have had only fair to poor glycemic control have a 30–40% chance of having nephropathy after 20 years—in contrast to the much lower frequency in type 2 diabetes patients not receiving intensive therapy, in whom only about 15–20% develop clinical renal disease. However, since so many more individuals are affected with type 2 diabetes, end-stage renal disease is much more prevalent in type 2 diabetes in the United States and especially throughout the rest of the world. There is no question that improved glycemic control and more effective therapeutic measures to correct hypertension can reduce the incidence of end-stage renal disease in both types of diabetes in the future.

Diabetic nephropathy is initially manifested by proteinuria; subsequently, as kidney function declines, urea and creatinine accumulate in the blood. Thickening of capillary basement membranes and of the mesangium of renal glomeruli produces varying degrees of glomerulosclerosis and renal insufficiency. Diffuse glomerulosclerosis is more common than nodular intercapillary glomerulosclerosis (Kimmelstiel-Wilson lesions); both produce heavy proteinuria.

  1. Microalbuminuria—New methods of detecting small amounts of urinary albumin have permitted detection of microgram concentrations—in contrast to the less sensitive dipstick strips, whose minimal detection limit is 0.3–0.5% (weight:volume). Conventional 24-hour urine collections, in addition to being inconvenient for patients, also show wide variability of albumin excretion, since several factors such as sustained erect posture, dietary protein, and exercise tend to increase albumin excretion rates. For these reasons, a timed overnight urine collection or albumin-creatinine ratio in early morning spot urine collected upon awakening is preferable. Normal subjects excrete less than 15 ľg/min during overnight urine collections; values of 20 ľg/min or higher are considered to represent abnormal microalbuminuria. Subsequent renal failure can be predicted by urinary albumin excretion rates exceeding 30 ľg/min. In an early morning spot urine, a ratio of albumin (ľg/L) to creatinine (mg/L) of < 30 is normal, and a ratio of 30–300 indicates microalbuminuria. At least two of three overnight timed urine specimens or early morning spot urines over a period of 3–6 months should be elevated before a diagnosis of abnormal microalbuminuria can be justified.

Increased microalbuminuria correlates with increased levels of blood pressure, and this may explain why increased proteinuria in diabetic patients is associated with an increase in cardiovascular deaths even in the absence of renal failure. Careful glycemic control as well as a low-protein diet (0.8 g/kg/d) may reduce both the hyperfiltration and the elevated microalbuminuria in patients in the early stages of diabetes and those with incipient diabetic nephropathy. Antihypertensive therapy also decreases microalbuminuria, and clinical trials with inhibitors of angiotensin I converting enzyme (eg, enalapril, 20 mg/d) show a reduction of microalbuminuria in diabetic patients even in the absence of hypertension. Microalbuminuria has recently been shown to correlate with slightly elevated nocturnal systolic blood pressure in “normotensive” diabetic patients, and antihypertensive therapy corrected this rise in blood pressure during sleep. This action, in addition to a reduction in mean arterial blood pressure, may contribute to the reported efficacy of ACE-inhibitors in reducing microalbuminuria in“normotensive” diabetic patients. However, the main action of these agents in reducing microalbuminuria is believed to be from a specific dilation of the glomerular efferent arteriole, thereby further reducing glomerular filtration pressure.

  1. Progressive diabetic nephropathy—Progressive diabetic nephropathy consists of proteinuria of varying severity, occasionally leading to nephrotic syndrome with hypoalbuminemia, edema, and an increase in circulating LDL cholesterol as well as progressive azotemia. In contrast to all other renal disorders, the proteinuria associated with diabetic nephropathy does not diminish with progressive renal failure (patients continue to excrete 10–11 g daily as creatinine clearance diminishes). As renal failure progresses, there is an elevation in the renal threshold at which glycosuria appears.

Hypertension develops with progressive renal involvement, and coronary and cerebral atherosclerosis seems to be accelerated. Once diabetic nephropathy has progressed to the stage of hypertension, proteinuria, or early renal failure, glycemic control is not beneficial in influencing its course. In this circumstance, antihypertensive medications, including ACE inhibitors, and restriction of dietary protein to 0.8 g/kg body weight per day are recommended.

When the serum creatinine reaches 3 mg/dL, consultation with a nephrologist is recommended. When the serum creatinine reaches 5 mg/dL, consultation with personnel at a center where renal transplantation is performed is indicated.

  1. TREATMENT

Hemodialysis has been of limited success in the treatment of renal failure due to diabetic nephropathy, primarily because of progression of large-vessel disease with resultant death and disability from stroke and myocardial infarction. Growing experience with chronic ambulatory peritoneal dialysis suggests that it may be a

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more convenient method of providing adequate dialysis with a lower incidence of complications.

Renal transplantation, especially from related donors, is often successful. For patients with compatible donors and no contraindications (such as severe cardiovascular disease), it is the treatment of choice.

Necrotizing Papillitis

This unusual complication of pyelonephritis occurs primarily in diabetic patients. It is characterized by fever, flank pain, pyuria, and sloughing of renal papillae in the urine. It is treated by intravenous administration of appropriate antibiotics.

Renal Decompensation After Radiographic Dyes

The use of radiographic contrast agents in diabetic patients with reduced creatinine clearance has been associated with the development of acute renal failure. Diabetic patients with normal renal function do not appear to be at increased risk for contrast nephropathy. If a contrast study is considered essential, patients with a serum creatinine of 1.5–2.5 mg/dL should be adequately hydrated before the procedure to produce a gentle diuresis of about 75 mL or so per hour. Other nephrotoxic agents such as nonsteroidal anti-inflammatory agents should be avoided. Although it was once believed that newer nonionic contrast agents were less likely to cause acute renal failure in diabetic patients, more recent prospective trials show no difference between these agents and conventional and much less costly ionic radiographic dyes. After the procedure, serum creatinine should be followed closely. Radiographic contrast material should not be given to a patient with a serum creatinine greater than 3 mg/dL unless the potential benefit outweighs the high risk of acute renal failure.

  1. Neurologic Complications (Diabetic Neuropathy)

Peripheral and autonomic neuropathy are the two most common complications of both types of diabetes. Their pathogenesis is poorly understood. Some lesions, such as the acute cranial nerve palsies and diabetic amyotrophy, have been attributed to ischemic infarction of the involved peripheral nerve. The much more common symmetric sensory and motor peripheral neuropathies and autonomic neuropathy are felt to be due to metabolic or osmotic toxicity somehow related to hyperglycemia.

Unfortunately, there is no consistently effective treatment for any of the neuropathies. However, several long-term clinical trials have definitively shown that normalization of blood glucose levels can prevent development and progression of this devastating complication.

Peripheral Sensory Neuropathy

  1. PATHOGENESIS AND CLINICAL FEATURES

Sensory loss is commonly preceded by months or years of paresthesias such as tingling, itching, and increasing pain. The pains can vary from mild paresthesias to severe shooting pains and may be more severe at night. Discomfort of the lower extremities can be incapacitating at times. Radicular pains in the chest and the abdominal area may be extremely difficult to distinguish from pain due to an intrathoracic or intra-abdominal source. Eventually, patients develop numbness, and tactile sensations decrease. The sensory loss is generally bilateral, symmetric, and associated with dulled perception of vibration, pain, and temperature, particularly in the lower extremities, but also evident in the hands. Sensory nerve conduction is delayed in peripheral nerves, and ankle jerks may be absent. Highly sensitive neurothesiometer devices are being utilized to characterize the threshold levels for pain and touch, so that signs of sensory defects can be detected earlier and patients with higher risk for neuropathic foot ulcers can be identified. Because all of these sensory disturbances are made worse by pressure applied to the involved nerves, symptoms may appear first in nerves that are entrapped, such as the median nerve in carpal tunnel syndrome or the nerves around the ankle.

Characteristic syndromes that develop in diabetic patients with sensory neuropathy and are related to their failure to perceive trauma include osteopathy of the foot with deformity of the ankle (so-called Charcot joint) and neuropathic ulceration of the foot.

  1. TREATMENT

Amitriptyline (50–75 mg at bedtime) has produced remarkable improvement in the lower extremity pain in some patients with sensory neuropathy. Dramatic relief has often occurred within 48–72 hours. This rapid response is in contrast to the 2 or 3 weeks required for an antidepressive effect. Patients often attribute benefit to their having a full night's sleep after amitriptyline in contrast to many prior sleepless nights occasioned by neuropathic pain. Mild to moderate morning drowsiness is a side effect that generally improves with time or can be lessened by giving the medication several hours before bedtime. This drug should be discontinued if there is no improvement after 4–5 days. Desipramine in doses of 25–150 mg per day has been reported to have the same efficacy for neuropathic leg pains as amitriptyline. These tricyclic drugs probably act by directly modulating nociceptive C fibers and their receptors.

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Gabapentin has also been shown to be effective in the treatment of painful neuropathy and should be tried if the tricyclic drugs prove ineffective. Other drugs have been used, including carbamazepine and phenytoin, but these are of questionable benefit for leg pain. Capsaicin, a topical irritant, has relieved local nerve pain in some studies; it is dispensed as a cream to be rubbed into the skin over the painful region.

It is essential that diabetic patients with peripheral neuropathy receive detailed instructions in foot care (see p 626). Special custom-made shoes are usually required to redistribute weight evenly over an insensitive foot, particularly when it has been deformed by surgery, by asymptomatic fractures, or by a Charcot joint.

Motor Neuropathy

Symmetric motor neuropathy occurs much less frequently than sensory neuropathy and is associated with delayed motor nerve conduction and muscle weakness and atrophy. Its pathogenesis is presumed to be similar to that of sensory loss. Mononeuropathy develops when there is vascular occlusion of a specific nerve trunk; if more than one nerve trunk is involved, the syndrome of mononeuritis multiplex occurs. Motor neuropathy is manifested by an abrupt onset of weakness in a distri-bution that reflects the nerve involved (eg, peroneal nerve involvement produces foot drop). A surprising number of these motor neuropathies improve after 6–8 weeks. Reversible cranial nerve palsies can occur and may present as lid ptosis and diplopia (cranial nerve III), lateral deviation of the eye (IV), inability to move the eye laterally (VI), or facial paralysis (Bell's palsy) (VII). Acute pain and weakness of thigh muscles bilaterally can occur with progressive wasting and weight loss. This has been termed diabetic amyotrophy and is more common in elderly men. Again, the prognosis is good, with recovery of motor function over several months in many cases. In more severe cases with extensive atrophy of limb musculature, this disorder has been termed “malignant cachexia” and mimics the end stages of advanced neoplasia, particularly when depression produces anorexia and weight loss. With this more severe manifestation of diabetic amyotrophy, recovery of muscle function may only be partial.

Autonomic Neuropathy

Neuropathy of the autonomic nervous system is common in patients with diabetes of long duration and can be a very disconcerting clinical problem. It can affect many diverse visceral functions. With autonomic neuropathy, there may be postural hypotension, resting fixed tachycardia, decreased cardiovascular responses to the Valsalva maneuver, gastroparesis, alternating bouts of diarrhea (often nocturnal) and constipation, difficulty in emptying the bladder, and impotence.

Erectile dysfunction due to neuropathy differs from the psychogenic variety in that the latter may be intermittent (erections occur under special circumstances), whereas diabetic erectile dysfunction is usually persistent. To distinguish neuropathic or psychogenic erectile dysfunction from the erectile dysfunction caused by aortoiliac occlusive disease or vasculopathy, papaverine is injected into the corpus cavernosum penis. If the blood supply is competent, a penile erection will occur (Chapter 12). Urinary incontinence, with large volumes of residual urine, and retrograde ejaculation can also result from pelvic neuropathy.

Gastroparesis should be a diagnostic consideration in type 1 diabetic patients who develop unexpected fluctuations and variability in their blood glucose levels after meals. Radiographic studies of the stomach and radioisotopic examination of gastric emptying after liquid and solid meals are of diagnostic value in these patients. Involvement of the gastrointestinal system may be manifested by nausea, vomiting, and postprandial fullness (from gastric atony); symptoms of reflux or dysphagia (from esophageal involvement); constipation and recurrent diarrhea, especially at night (from involvement of the small bowel and colon); and fecal incontinence (from anal sphincter dysfunction). Gallbladder function is altered, and this enhances stone formation.

Therapy is difficult and must be directed specifically at each abnormality. Use of Jobst fitted stockings, tilting the head of the bed, and arising slowly from the supine position are useful in minimizing symptoms of orthostatic hypotension. Some patients may require the addition of a mineralocorticoid such as fludrocortisone acetate (0.1–0.2 mg twice daily). Metoclopramide has been of some help in treating diabetic gastroparesis over the short term, but its effectiveness seems to diminish over time. It is a dopamine antagonist with central antiemetic effects as well as cholinergic action to facilitate gastric emptying. It can be given intravenously (10–20 mg) or orally (20 mg of liquid metoclopramide) before breakfast and supper. Drowsiness is its major adverse effect. Erythromycin is a motilin agonist and can be used to treat gastroparesis. Bethanechol has also been used for gastroparesis (as well as for an atonic urinary bladder) because of its cholinergic effect.

Diabetic diarrhea is occasionally aggravated by bacterial overgrowth from stasis in the small intestine, and a trial of broad-spectrum antibiotics may give relief. If this does not help, symptomatic relief can sometimes be achieved with antidiarrheal agents such as diphenoxylate with atropine or loperamide. Clonidine has been reported to lessen diabetic diarrhea, but its tendency to lower blood pressure in those patients who already have

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some degree of orthostatic hypotension often limits its usefulness. Metamucil and other bulk-providing agents may relieve either the diarrhea or the constipation phases, which often alternate. Beta-lactulose is useful in managing severe constipation. Bethanechol has occasionally improved emptying of the atonic urinary bladder. There are medical, mechanical, and surgical treatments available for treatment of erectile dysfunction. Penile erection depends on relaxation of the smooth muscle in the arteries of the corpus cavernosum penis, and this is mediated by nitric oxide-induced cyclic 3′, 5′-guanosine monophosphate (cGMP) formation. Sildenafil (Viagra) is a selective inhibitor of cGMP-specific phosphodiesterase type 5. In response to sexual stimulation, there is local release of nitric oxide and cGMP production, and sildenafil, by inhibiting the breakdown of cGMP, improves the ability to achieve and maintain an erection. In a randomized study of patients with diabetes and erectile dysfunction, 56% taking sildenafil reported improved erections compared with 10% on placebo. The reason for lack of response in the other 44% is not known. Phosphodiesterase type 5 is also present in vascular smooth muscle, and sildenafil can lower systolic and diastolic pressure by 7% and 10%, respectively. Patients with cardiovascular disease may be adversely affected by this blood pressure decline, especially at the time of sexual activity. Sildenafil also potentiates the hypotensive effects of nitrates, and its use in patients taking those agents is contraindicated.

Intracorporeal injection of vasoactive drugs causes penile engorgement and erection. Drugs most commonly used include papaverine alone, papaverine with phentolamine, and alprostadil (prostaglandin E1). Alprostadil injections are relatively painless, but careful instruction is essential to prevent local trauma, priapism, and fibrosis. Intraurethral pellets of alprostadil avoid the problem of injection of the drug.

External vacuum therapy (Erec-Aid System) is a nonsurgical treatment that consists of a suction chamber operated by a hand pump that creates a vacuum around the penis. This draws blood into the corpus cavernosum penis to produce an erection which is maintained by a specifically designed tension ring inserted around the base of the penis and which can be kept in place for up to 20–30 minutes.

Surgical implantation of a penile prosthesis should be considered for motivated patients when medical therapies prove to be unsatisfactory. (See Chapter 12.)

Aldose reductase inhibitors have been generally disappointing, with only marginal therapeutic results in either autonomic or peripheral diabetic neuropathy and a relatively high incidence of toxic side effects such as skin rash and neutropenia.

  1. Cardiovascular Complications

Heart Disease

Microangiopathy has recently been recognized to occur in the heart and may explain the existence of congestive cardiomyopathies found in diabetic patients without demonstrable coronary artery disease. Much more commonly, however, heart failure in the diabetic is a consequence of coronary atherosclerosis. Myocardial infarction is three to five times more common in diabetic patients than in age-matched controls and is the leading cause of death in patients with type 2 diabetes. A loss of the protection against myocardial infarction usually present in women during the childbearing years is particularly evident in diabetic women. The exact reason for the increased incidence of myocardial infarction in diabetics is not clear. It may reflect the combination of hyperlipidemia, abnormalities of platelet adhesiveness, coagulation factors, hypertension, and oxidative stress and inflammation.

The American Diabetes Association also recommends lowering blood pressure to 130/80 mm Hg or less. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized 33,357 subjects (age 55 years or older) with hypertension and at least one other coronary artery disease risk factor to receive treatment with chlorthalidone, amlodipine, or lisinopril. Chlorthalidone appeared to be superior to amlodipine and lisinopril in lowering blood pressure, in reducing the incidence of cardiovascular events, in tolerability, and in cost. The study included 12,063 individuals with type 2 diabetes. The Heart Outcomes Prevention Evaluation (HOPE) study randomized 9297 high-risk patients who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor to receive ramipril or placebo for a mean period of 5 years. Treatment with ramipril resulted in a 25% reduction of the risk of myocardial infarction, stroke, or death from cardiovascular disease. The mean difference in blood pressure between the placebo and ramipril groups was 2.2 mm Hg systolic and 1.4 mm diastolic, and the reduction in cardiovascular event rate remained significant after adjustment for this small difference in blood pressure. The mechanism underlying this protective effect of ramipril is unknown. Patients with type 2 diabetes who already have cardiovascular disease or microalbuminuria should therefore be considered for treatment with an ACE inhibitor. More clinical studies are needed to address the question of whether patients with type 2 diabetes who do not have cardiovascular disease or microalbuminuria would specifically benefit from ACE inhibitor treatment.

The American Diabetes Association also recommends aspirin, 81–325 mg/d, for primary prevention in

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patients with one or more cardiovascular risk factors who are over 30 years of age and for secondary prevention in patients with macrovascular disease. Contraindications to aspirin use include age less than 21 years (because of risk of Reye's syndrome), hepatic disease, and anticoagulant therapy.

Peripheral Vascular Disease

Atherosclerosis is markedly accelerated in the larger arteries. It is often diffuse, with localized enhancement in certain areas of turbulent blood flow, such as at the bifurcation of the aorta or other large vessels. Clinical manifestations of peripheral vascular disease include ischemia of the lower extremities, impotence, and intestinal angina.

The incidence of gangrene of the feet in diabetics is 30 times that in age-matched controls. The factors responsible for its development, in addition to peripheral vascular disease, are small vessel disease, peripheral neuropathy with loss of both pain sensation and neurogenic inflammatory responses and secondary infection. In two-thirds of patients with ischemic gangrene, pedal pulses are not palpable. In the remaining one-third who have palpable pulses, reduced blood flow through these vessels can be demonstrated by plethysmographic or Doppler ultrasound examination. Prevention of foot injury is imperative. Agents that reduce peripheral blood flow such as tobacco and propranolol should be avoided. Control of other risk factors such as hypertension is essential. Cholesterol-lowering agents are useful as adjunctive therapy when early ischemic signs are detected and when dyslipidemia is present. Patients should be advised to seek immediate medical care if a diabetic foot ulcer develops. Improvement in peripheral blood flow with endarterectomy and bypass operations is possible in certain patients.

  1. Skin Changes

Diabetic dermopathy is characterized by atrophic brown spots on the skin, usually in the pretibial area (“shin spots”). These changes may be a consequence of increased glycosylation of tissue proteins or vasculopathy. Eruptive xanthomas may develop in some poorly controlled diabetics who have marked hypertriglyceridemia. A rare skin complication, necrobiosis lipoidica diabeticorum, occurs predominantly on the shins and is characterized by marked thinning of the skin which allows the subcutaneous vessels to be seen as though through tissue paper. An element of vascular occlusion is generally present.

  1. Bone & Joint Complications

Bone and joint complications are generally attributed to metabolic or vascular sequelae of diabetes of long standing.

Juvenile Diabetic Cheirarthropathy

This is a syndrome of chronic progressive stiffness of the hand secondary to contracture and tightening of the skin over the joints. It is characterized by inability to flatten the palms against a flat surface. It usually occurs within 5–6 years after onset of type 1 diabetes. It is believed to be due to glycosylation of collagen and perhaps other proteins in connective tissue.

Dupuytren's Contracture

This consists of nodular thickening of the palmar fascia of the hand, producing a claw-like deformity. Although not specific to diabetes, when it occurs in a diabetic patient it may be the result of ischemic necrosis and secondary scarring of connective tissue as a consequence of diabetic microangiopathy.

Bone Demineralization

Bone demineralization has been reported to occur with increased frequency in diabetic patients. Bone density, as measured by photon absorption in the forearms, is 10–20% below normal in diabetics as compared to appropriately matched controls. Diabetes mellitus, however, does not seem to be associated with clinically important osteopenia, since there is no increase in the occurrence of skeletal fractures.

Joint Abnormalities

Bursitis, particularly of the shoulders and hips, occurs more frequently than expected in patients with diabetes. Gout also has a higher than expected incidence, especially in obese diabetics.

  1. Infection

Candidal infections occur more frequently in diabetic patients than in nondiabetic matched controls. Candidal infection can produce erythema and edema of intertriginous areas below the breasts, in the axillas, and between the fingers. It causes vulvovaginitis in most chronically uncontrolled diabetic women with persistent glucosuria and is a frequent cause of pruritus.

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While antifungal creams containing miconazole or clotrimazole offer immediate relief of vulvovaginitis, recurrence is frequent unless glucosuria is reduced.

There are also several unusual infections that occur almost exclusively in diabetics (eg, emphysematous cholecystitis, mucormycosis, malignant otitis externa and necrotizing papillitis). As noted above, atherosclerosis with peripheral vascular disease is very common in the diabetic population, and the resultant ischemia undoubtedly plays a role in the frequent and severe lower extremity infections seen in these patients.

SURGERY IN THE DIABETIC PATIENT

Surgery represents a stress situation during which most of the insulin antagonists (catecholamines, GH, corticosteroids) are mobilized. In the diabetic patient, this can lead to a worsening of hyperglycemia and perhaps even ketoacidosis. The aim of medical management of diabetics during the perioperative period is to minimize these stress-induced changes. Recommendations for management depend both on the patient's usual diabetic regimen and on the type of surgery (major or minor) to be done.

DIABETICS REGULATED BY DIET ALONE

No special precautions must be taken unless diabetic control is markedly disturbed by the procedure. If this occurs, small amounts of regular insulin as needed will correct the hyperglycemia.

DIABETICS TAKING ORAL HYPOGLYCEMIC AGENTS

The oral medications are omitted on the day of surgery, and a dextrose infusion is started. Frequent bedside monitoring of blood glucose will detect any hypoglycemia or extremes of hyperglycemia. If the latter occurs, small amounts of regular insulin are given as needed. If this approach does not provide adequate control, an insulin-dextrose infusion should be started in the manner indicated below. The oral agents can be restarted once the patient is eating normally after the operation. It is important to order a postoperative serum creatinine level to ensure normal renal function prior to restarting metformin therapy.

DIABETICS TAKING INSULIN

Patients taking insulin represent the only serious challenge to management of diabetes when surgery is necessary. However, with careful attention to changes in the clinical or laboratory picture, most diabetic patients can be managed successfully.

Minor Surgery

For minor surgery requiring only local or spinal anesthesia or intravenous administration of a very transient anesthetic, half of the usual dose of insulin should be given in the morning. The patient should be placed early on the operating room schedule. A constant drip of 5% dextrose in water (at a rate of approximately 5 g of glucose per hour) should be infused, and blood glucose levels should be checked at regular intervals.

Major Surgery

The night before major surgery, a 9 PM bedtime snack is given. Thereafter, the patient should receive nothing by mouth. On the morning of surgery, the usual morning subcutaneous insulin dose is omitted; instead, 10 units of regular insulin is added to 1 L of 5% dextrose in half-normal saline, and this is infused intravenously at a rate of 100–180 mL/h. This will give the patient 1–1.8 units of insulin per hour, which, except in the most severe cases, will generally keep the blood glucose within the range of 100–250 mg/dL (5.5–13.9 mmol/L). The infusion may be continued for several days if necessary. Plasma glucose or blood glucose should be determined every 2–4 hours to be sure metabolic control is adequate. If it is not, adjustments in the ratio of insulin to dextrose in the intravenous solution can be made.

An alternative method which is gaining in popularity consists of separate infusions of insulin and glucose delivered by pumps to permit independent adjustments of each infusion rate depending on hourly variation of blood glucose values. Table 17-21 provides guidelines for management with an insulin drip, and the algorithms are designed to achieve glycemic control in the range of 120–180 mg/dL blood glucose.

Table 17-21. Guidelines for perioperative diabetes management with an intravenous insulin infusion.1

·         Insulin: Regular (human) 25 units in 250 mL of normal saline (1 unit/10 mL).

·         Intravenous infusions of insulin: Flush 50 mL through line before connecting to patient. Piggyback insulin line to the perioperative maintenance fluid line.

·         Perioperative maintenance fluid: Fluids must contain 5% dextrose (rate 100 mL/h).

·         Blood glucose: Monitor hourly intraoperatively.2

Blood Glucose (mg/dL)

Insulin

(units/h)

(mL/h)

< 80

0.0

0.0

81–100

0.5

5.0

101–140

1.0

10

141–180

1.5

15

181–220

2.0

20

221–260

2.5

25

261–300

3.0

30

301–340

4.0

40

> 341

5.0

50

·         Blood glucose < 80 mg/dL: Stop insulin and administer intravenous bolus of 50% dextrose in water (25 mL). Once blood glucose > 80 mg/dL, restart insulin infusion. It may be necessary to modify the algorithm.

·         Decreased insulin needs: Patients treated with diet or oral agents or < 50 units insulin per day, endocrinologic deficiencies.

·         Increased insulin needs: Obesity, sepsis, steroid therapy, renal transplant, coronary artery bypass.

1Reproduced, with permission, from Gavin LA: Perioperative management of the diabetic patient. Endocrinol Metab Clin North Am 1992;21:457.

2Blood glucose value ÷ 100 gives a reasonable estimate of infusion dosage (units/h).

After surgery, when the patient has resumed an adequate oral intake, subcutaneous administration of insulin can be resumed and intravenous administration

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of insulin and dextrose can be stopped half an hour after the first subcutaneous dose. Insulin needs may vary in the first several days after surgery because of continuing postoperative stresses and because of variable caloric intake. In this situation, multiple doses of regular insulin guided by blood glucose determinations can keep the patient in acceptable metabolic control.

DIABETES MELLITUS & PREGNANCY

John L. Kitzmiller MD

Hormone & Fuel Balance During Pregnancy

Pregnancy is characterized by major changes in the balance of metabolic fuels and hormones which significantly affect the management of diabetes. Basal hepatic glucose production increases as pregnancy progresses in spite of increased basal insulin secretion, demonstrating insulin resistance of the hepatic cells. However, plasma concentrations of glucose in the fasting state decline slightly, associated with increasing fetal-placental utilization of glucose. Although fat deposition is accentuated in early pregnancy, lipolysis is enhanced by human placental lactogen (hPL) later in gestation, and more glycerol and free fatty acids (FFA) are released in the postabsorptive state (distant from meals). The increased FFA contribute to the impaired glucose utilization by skeletal muscle characteristic of advancing pregnancy. Ketogenesis is also accentuated in the postabsorptive state during pregnancy, secondary to hormonal effects on the maternal liver cells and increased provision of substrate FFA.

The balance of metabolic fuels is also different in the fed state during pregnancy. Despite increased insulin secretion after a carbohydrate or amino acid load (or both) in normal pregnancy, there is a striking reduction in insulin-mediated glucose disposal by peripheral tissue (muscle) by the third trimester. The result is somewhat higher maternal blood glucose levels in nondiabetic subjects and severe hyperglycemia in insufficiently treated pregnant diabetic women. This insulin resistance has been related to hPL, progesterone, cortisol, prolactin, and FFA, with defects at the post-insulin receptor level in hepatic and muscle cells. Glucagon is well suppressed by glucose during pregnancy, and secretory responses of glucagon to amino acids are not increased above nonpregnant levels. After meals, more glucose is converted to triglyceride in pregnant compared with nonpregnant subjects, which would tend to conserve calories and enhance fat deposition.

Overview of Diabetes During Pregnancy

In the past, diabetic pregnant women were classified on the basis of duration and severity of diabetes (Table 17-22). The classification system of Priscilla White was

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originally used to indicate prognosis of perinatal outcome and to determine obstetric management. Because the perinatal mortality rate has declined dramatically for many reasons in women in all classes, the system is now used mainly to describe and compare populations of diabetic pregnant women. However, certain characteristics of patients are still pertinent. The risk of complications is minimal if gestational diabetes is well controlled by diet alone, and these patients may be otherwise managed as normal pregnant women. Class B patients, mainly women with type 2 diabetes with onset less than 10 years previously, will probably have residual islet B cell function, and control of hyperglycemia may be easier than in class C or D patients, who have brittle type 1 diabetes. Finally, the most compli-cated and difficult pregnancies occur in women with renal, retinal, or cardiovascular disease (classes F, H, and R).

The hormonal and metabolic effects of pregnancy are associated with increased risks of both hypoglycemic insulin reactions and ketoacidosis. Increasing amounts of insulin are usually required to control hyperglycemia throughout gestation.

Table 17-22. Classification of diabetes during pregnancy (Priscilla White).

Class

Characteristics

Implications

Gestational diabetes

Abnormal glucose tolerance during pregnancy; postprandial hyperglycemia during pregnancy.

Diagnosis before 30 weeks' gestation important to prevent macrosomia. Treat with diet adequate in calories to prevent maternal weight loss. Goal is postprandial blood glucose < 130 mg/dL (7.2 mmol/L) at 1 hour or < 105 mg/dL (5.8 mmol/L) at 2 hours. If insulin is necessary, manage as in classes B, C, and D.

A

Chemical diabetes diagnosed before pregnancy; managed by diet alone; any age at onset.

Management as for gestational diabetes.

B

Insulin treatment or oral hypoglycemic agent used before pregnancy; onset at age 20 or older; duration < 10 years.

Some endogenous insulin secretion may persist. Fetal and neonatal risks same as in classes C and D, as is management; can be type 1 or 2.

C

Onset at age 10–20, or duration 10–20 years.

Insulin-deficient diabetes of juvenile onset; type 1.

D

Onset before age 10, or duration > 20 years, or chronic hypertension (not pre- eclampsia), or background retinopathy (tiny hemorrhages).

Fetal macrosomia or intrauterine growth retardation possible. Retinal microaneurysms, dot hemorrhages, and exudates may progress during pregnancy, then regress after delivery.

F

Diabetic nephropathy with proteinuria.

Anemia and hypertension common; proteinuria increases in third trimester, declines after delivery. Fetal intrauterine growth retardation common; perinatal survival about 90% under optimal conditions; bed rest necessary.

H

Coronary artery disease.

Serious maternal risk.

R

Proliferative retinopathy.

Neovascularization, with risk of vitreous hemorrhage or retinal detachment; laser photocoagulation useful; abortion usually not necessary. With active process of neovascularization, prevent bearing-down efforts.

If diabetes is poorly controlled in the first weeks of pregnancy, the risks of spontaneous abortion and congenital malformation of the infant are increased. Later in pregnancy, polyhydramnios is also common in women with poorly controlled diabetes and may lead to preterm delivery. Fetal hypoxia may develop in the third trimester if blood glucose levels frequently exceed 180 mg/dL (10 mmol/L). In poorly controlled patients, careful fetal monitoring must be used to prevent stillbirth. The high incidence of fetal macrosomia (birth weight > 90th percentile for gestational age) associated with maternal hyperglycemia and fetal hyperinsulinemia increases the potential for traumatic vaginal delivery;

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cesarean deliveries are more common in these cases. Fetal intrauterine growth restriction may occur in diabetic women with vascular disease or those with relative hypoglycemia induced by overzealous treatment.

Neonatal risks linked to maternal glycemic control include respiratory distress syndrome, hypoglycemia, hyperbilirubinemia, hypocalcemia, and poor feeding. Although these problems are usually limited to the first days of life, excess maternal glucose and β-hydroxybutyrate levels with the fetus in utero have been related to diminished performance on intelligence and psychomotor testing during subsequent childhood development. However, if diabetic women adhere to a program of careful management and surveillance, they have greater than 95% chance of delivering a healthy child.

In the following sections, the convention used for designating the number of weeks of gestation is the number of weeks from the last menstrual period, confirmed by ultrasound measurements.

Gestational Diabetes

Impaired glucose tolerance develops in 2–8% of pregnant women, usually during the second half of gestation. The frequency depends on ethnic group (highest in Asian-American, Latina, Native American, Polynesian), and is increased in those with central obesity or a family history of diabetes. The mechanism of glucose intolerance in lean women results from sluggish first-phase insulin release coupled with excessive insulin resistance. In overweight women with gestational diabetes, insulin resistance increases more than in overweight controls, despite increased circulating insulin levels, so that insulin secretion is actually inadequate in relation to the hyperglycemia.

Strategies for diagnosis are outlined in Table 17-23. After diagnosis, the patient should be placed on a diabetic meal plan modified for pregnancy: 25–35 kcal/kg ideal weight, 40–55% carbohydrate, 20% protein, and 25–40% fat. Calories are distributed over three meals and three snacks (Table 17-24). Most patients can be taught to count their carbohydrates and to read food labels. The goal of therapy is not weight reduction but prevention of fasting and postprandial hyperglycemia. If fasting capillary blood glucose levels exceed 90–100 mg/dL (5–5.6 mmol/L) or if 1-hour or 2-hour postprandial glucose values are consistently greater (respectively) than 130 or 105 mg/dL (7.2 or 5.8 mmol/L), therapy is begun with human insulin. As an alternative, consider the sulfonylurea glyburide, which crosses the human placenta poorly. Current research is evaluating its efficacy and safety when dietary therapy fails to produce normoglycemia.

Table 17-23. Screening and diagnosis of gestational diabetes.1

Risk for gestational diabetes mellitus should be ascertained at the first prenatal visit
Low risk:
   Universal versus selective screening remains controversial; most diabetes organizations state that blood glucose testing is not normally required if all of the following characteristics are present:
      Member of an ethnic group with a low prevalence of gestational diabetes mellitus
      No known diabetes in first-degree relatives
      Age < 25 years
      Weight normal before pregnancy
      No history of abnormal glucose metabolism or poor pregnancy outcome
Average risk:
   Perform blood glucose testing at 24–28 weeks using one of the following
      One-step protocol: 75 g, 2-hour oral glucose tolerance test on all women:
         Fasting: < 95 mg/dL (5.3 mmol/L)
         1 hour: < 180 mg/dL (< 10 mmol/L)
         2 hours: < 155 mg/dL (< 8.6 mmol/L)
      Two-step protocol: 50 g, 1-hour plasma glucose on all women: if test done in fasting state, threshold is > 130 mg/dL (> 7.2 mmol/L); if test done in fed state, threshold is 140 mg/dL (> 7.8 mmol/L). Then test with 100 g, 3 hours, in fasting state:
         Fasting: < 95 mg/dL (< 5.3 mmol/L)
         1 hour: < 180 mg/dL (< 10 mmol/L)
         2 hours: < 155 mg/dL (< 8.6 mmol/L)
         3 hours: < 140 mg/dL (< 7.8 mmol/L)
         If one value is abnormal, repeat test in 4 weeks
High risk:
   Perform testing as soon as feasible. If negative, repeat at 24–28 weeks

1Adapted from Summary and Recommendations, Fourth International Workshop-Conference on Gestational Diabetes Mellitus: Diabetes Care 1998;21(Suppl 2):B162.

Progression to type 2 diabetes later in life will occur in 5–50% of women with gestational diabetes. The wide range in incidence is influenced by body weight, family history, glucose levels, and the need for insulin treatment during pregnancy—and the choice of contraception and lifestyle after pregnancy. All patients with gestational diabetes should undergo a 75 g 2-hour glucose tolerance test at 6–10 weeks after delivery to guide future medical management. Follow-up protocols after pregnancy and criteria for the diagnosis of diabetes mellitus in the nonpregnant state are presented in Table 17-25.

Table 17-24. Management of diet for patients with gestational diabetes.

1. Assess present pattern of food consumption.

2. Balance calories with optimal weight gain.

1. Caloric intake: 25–35 kcal/kg ideal weight.

2. Weight gain: 0.45 kg (1 lb) per month during the first trimester; 0.2–0.35 kg (0.5–0.75 lb) per week during the second and third trimesters.

3. Distribute calories and carbohydrates over 3 meals and 3 snacks; evening snack to include complex carbohydrate and at least one meat exchange.

4. Use food exchanges to assess the amount of carbohydrate, protein, and fat:

1. Carbohydrate: 40–55% of calories or ≥ 150 g/d.

2. Protein: 20% of calories or ≥ 74 g/d.

3. Fat: 25–40% of calories.

5. Emphasize high-fiber, complex carbohydrate foods.

6. Identify individual glycemic responses to certain foods.

7. Tailor eating plans to personal needs.

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Glucose Monitoring & Insulin Management

The goal of insulin therapy during pregnancy is to prevent both preprandial and postprandial hyperglycemia, but in type 1 diabetic patients, caution must be used to avoid debilitating hypoglycemic reactions. Perinatal outcome will be optimal if patients aim for fasting plasma glucose levels below 100 mg/dL (5.6 mmol/L) and postprandial levels below 130 mg/dL (7.2 mmol/L). In type 1 patients with hypoglycemia unawareness, somewhat higher blood glucose targets should be selected. Self-monitoring of capillary blood glucose should be done at home and in the workplace several times daily using glucose oxidase strips and portable reflectance colorimeters with memory capacity. Confirmation of long-term control is provided by sequential measurement of glycosylated hemoglobin and fructosamine.

Most pregnant diabetic patients will require at least two daily injections of a mixture of regular and intermediate insulin in order to prevent fasting and postprandial hyperglycemia. Common insulin regimens are outlined in Table 17-26. The usual practice for initiation of insulin therapy in pregnant women with gestational diabetes mellitus or type 2 diabetes is to give two-thirds of the insulin before breakfast and one-third before supper. More stringent regimens of administering short-acting subcutaneous insulin three times a day before meals and intermediate insulin at bedtime to control overnight and fasting glucose—or of continuous subcutaneous insulin infusion with a portable pump—may be necessary to achieve normoglycemia in many women, especially those with type 1 diabetes. These women will also benefit from learning to self-adjust their doses of short-acting insulin based on planned carbohydrate load or premeal blood glucose levels. (See previous section: Insulin.)

Table 17-25. Follow-up (after pregnancy) of patient with gestational diabetes mellitus.

Encourage breast feeding.
Montitor postprandial blood glucose occasionally to be sure it is < 180 mg/dL (< 10 mmol/L).
Perform 75-g 2-hour oral glucose test at 6–12 weeks postpartum.

Diagnosis

Fasting Blood Glucose mg/dL (mmol/L)

Two-Hour Value mg/dL (mmol/L)

Normal

< 100 (< 6.1)

< 140 (< 7.8)

Impaired glucose tolerance

110–125 (6.1–6.9)

140–199 (7.8–11.1)

Diabetes mellitus

> 125 (7.0)

> 199 (> 11.1)

Contraception: Barrier methods, Cu 7 IUD, low-dose birth control pills such as Ovcon 35, Triphasil (which do not affect glucose tolerance or lipid profiles).
Use diet and exercise for women with impaired glucose tolerance and those with central body obesity. Impaired glucose tolerance implies a high risk of development of type 2 diabetes.
Obtain annual blood glucose test of some kind and especially before the next pregnancy.

Hypoglycemic reactions are more frequent and sometimes more severe in early gestation but are a risk at any time during pregnancy. Therefore, insulin-treated patients must use timely between-meal and bedtime snacks to prevent hypoglycemia—and type 1 diabetic patients must keep glucagon on hand, and a member of the household must be instructed in the technique of injection. Hypoglycemic reactions have not been associated with fetal death or congenital anomalies, but they pose a risk to maternal health.

Diabetic Complications & Pregnancy

  1. VOMITING OF PREGNANCY

In early gestation, diabetic gastroparesis or gastropathy can severely exacerbate the nausea and vomiting of pregnancy (hyperemesis gravidarum), which sometimes will continue into the third trimester. Drugs stimulating gastric motility such as erythromycin and cisapride may be useful, but many patients with this complication will require hyperalimentation to achieve nutritional intake adequate for fetal development.

Table 17-26. Illustration of use of home blood glucose monitoring to determine insulin dosage during pregnancy.

Self-Monitored Capillary Blood Glucose

Insulin Doses

Fasting blood glucose

148 mg/dL (8.2 mmol/L)

14 units regular, 28 units intermediate

1 h after breakfast

206 mg/dL (11.4 mmol/L)

 

1 h after lunch

152 mg/dL (8.4 mmol/L)

1 h after supper

198 mg/dL (11.0 mmol/L)

9 units regular, 10 units intermediate

2–4 AM

142 mg/dL (7.9 mmol/L)

 

Suggested changes based on pattern of blood glucose values over 2–3 days: slight increases in presupper intermediate insulin to control fasting blood glucose next day, in morning regular insulin to control postbreakfast glucose, and in presupper regular insulin to control postsupper hyperglycemia. Dose of morning intermediate insulin is adequate to control early afternoon blood glucose. When dose of presupper intermediate insulin is increased, patient should test to detect and prevent nocturnal hypoglycemia. One-hour postprandial testing is advised to detect the probable peaks of glycemic excursions. Patient should also test when symptoms of hypoglycemia appear.

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  1. DIABETIC RETINOPATHY

Pregnancy also affects diabetic retinopathy. Background diabetic retinopathy may develop or progress during pregnancy, but it usually regresses postpartum. If background retinopathy is already present in early pregnancy, the rate of progression to neovascularization (proliferative diabetic retinopathy) will be 6% → 18% → 38%, depending on the extent of background retinopathy from mild to moderate to severe preproliferative changes. The risk factors for progression to proliferative retinopathy include poor glycemic control before and during early pregnancy, rapid improvement in glycemic control during pregnancy, hypertension, and perhaps the many growth factors derived from placental tissue. These risks are an important reason to institute intensified preconception management of diabetes. During pregnancy, sequential ophthalmologic examinations are essential in women with type 1 or type 2 diabetes, and laser photocoagulation treatment of the retina may be necessary.

  1. DIABETIC NEPHROPATHY

The risk of worsening of diabetic nephropathy during pregnancy depends on baseline renal function and the degree of hypertension. Total urinary albumin excretion does not increase much in normal pregnancy, but total urinary protein collections, which obstetricians have used to define preeclampsia, may show a twofold increase in uncomplicated gestation. Diabetic women with microalbuminuria (30–299 mg/24 h) may have worsening of the albuminuria during pregnancy with regression postpartum, and 15–45% will develop the preeclamptic syndrome. Based on pooled data from several studies of pregnant diabetic women with a clinical level of proteinuria (24-hour urinary albumin > 300 mg) at the beginning of pregnancy, if initial renal function is preserved (serum creatinine < 1.2 mg/dL [> 106 ľmol/L]; creatinine clearance < 80 mL/min with complete collection), then 15–20% are expected to show moderate decline during gestation, and 6% will have renal failure at follow-up several years after pregnancy. The latter figure may not be different from the course of diabetic nephropathy in nonpregnant women with this level of initial renal function. If initial renal function in pregnancy is impaired (serum creatinine > 1.2 mg/dL [> 106 ľmol/L]; creatinine clearance < 80 mL/min with complete collection), then 35–40% are expected to show further decline during pregnancy and 45–50% will have renal failure at follow-up. Thus, careful preconception counseling is important for these patients and their family members.

  1. DIABETIC NEUROPATHY

The course of diabetic neuropathy is uncertain during pregnancy, and treatment may be relatively ineffective. The agents commonly used (amitriptyline, desip-ramine) may produce neonatal withdrawal symptoms.

Fetal Development & Growth

  1. CONGENITAL ANOMALIES

Major congenital anomalies are those that may affect the life of the individual or require major surgery for correction. The incidence in infants of poorly controlled diabetic mothers is 6–12%, compared with about 2% in infants born to diabetic women who begin pregnancy with normal glycohemoglobin or infants of a nondiabetic population. Since perinatal deaths due to stillbirth and respiratory distress syndrome have declined

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in pregnancies complicated by diabetes, the proportion of fetal and neonatal deaths ascribed to congenital anomalies has risen to over 50%. The types of anomalies most common in infants of diabetic mothers and their presumed time of occurrence during embryonic development are listed in Table 17-27. It is apparent that any intervention to reduce the incidence of major congenital anomalies must be applied very early in pregnancy. The finding that the excess risk of anomalies is associated with the group of diabetic women with elevated glycosylated hemoglobin early in pregnancy suggests that poor diabetic control is related to the risk of major congenital anomalies in their infants. Protocols of intensive diabetic management instituted prior to conception and continued through early pregnancy have resulted in significant reduction in the frequency of anomalies. Primary care physicians treating diabetic women of reproductive age should counsel them about the possibility and risks of pregnancy and help them achieve good glycemic control if pregnancy is desired.

Table 17-27. Congenital malformations in infants of diabetic mothers.1

 

Ratio of Incidences Diabetic vs Control Group

Latest Gestational Age for Occurrence (Weeks After Menstruation)

Caudal regression

252

5

Anencephaly

3

6

Spina bifida, hydrocephalus, or other central nervous system defects

2

6

Cardiac anomalies

4

 

   Transposition of great vessels

 

7

   Ventricular septal defect

8

   Atrial septal defect

8

Anal/rectal atresia

3

8

Renal anomalies

5

 

   Agenesis

6

7

   Cystic kidney

4

7

   Ureter duplex

23

7

Situs inversus

84

6

1 Modified and reproduced, with permission, from Kucera J: Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 1971;7:61; and Mills JL, Baker L, Goldman AS: Malformations in infants of diabetic mothers occur before the seventh gestational week: Implications for treatment. Diabetes 1979;28:292.

  1. NEURAL TUBE DEFECTS

Ultrasonography in the first half of pregnancy confirms the dating of gestation and may detect neural tube defects (anencephaly, meningomyelocele) that occur with a higher incidence in infants of poorly controlled diabetic mothers. The physician should also screen all insulin-dependent pregnant women at 14–16 weeks of gestation for elevated serum alpha-fetoprotein levels that may suggest less severe cases of neural tube defects, eg, spina bifida. Later in pregnancy, at 18–22 weeks, sophisticated ultrasonographic examinations are used to detect congenital heart defects or other severe anomalies. Subsequent examinations at 26 and 36 weeks measure fetal growth and well-being.

  1. MACROSOMIA

Many fetuses of poorly controlled diabetic mothers are macrosomic (large for dates), with increased fat stores, increased length, and increased abdomen-to-head or thorax-to-head ratios. The hypothesis that fetal macrosomia results from the causal chain of maternal hyperglycemia → fetal hyperglycemia → fetal hyperinsulinemia → fetal macrosomia has been confirmed by clinical and experimental studies. Macrosomic infants of diabetic mothers have significantly higher concentrations of C peptide in their cord sera or amniotic fluid (representing endogenous insulin secretion) than do those with birth weights appropriate for gestational age. Monkey fetuses with insulin-releasing pellets implanted in utero become macrosomic. In human pregnancies, the determinants of fetal hyperinsulinemia may be not only maternal hyperglycemia, however. Other metabolic substrates that cross the placenta, such as branched-chain amino acids, are insulinogenic and may play a role in fetal macrosomia, and transplacental lipids could contribute to fat deposition.

The level of maternal glycemia is related to birth weight adjusted for gestational age, and prevention of maternal hyperglycemia throughout pregnancy can reduce the incidence of macrosomia and birth trauma. The glycemic threshold for fetal macrosomia seems to be postprandialpeak values above 130 mg/dL (7.2 mmol/L). On the other hand, too tight glycemic control (average peak postprandial blood glucose levels below 110 mg/dL [6.1 mmol/L]) can be associated with insufficient fetal growth and small-for-dates infants,

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which may also induce complications in the neonatal period.

  1. POLYHYDRAMNIOS

Polyhydramnios is an excess volume of amniotic fluid (> 1000 mL, often > 3000 mL). It may cause severe discomfort or premature labor and is most often associated with fetal macrosomia. The excess volume of amniotic fluid is not related simply to the concentration of glucose or other solutes in amniotic fluid or to excess fetal urine output as measured by change in bladder size by means of ultrasonography. Other possible factors include decreased fetal swallowing, decidual and amniotic fluid prolactin, and as yet unknown determinants of the complicated multicompartmental intrauterine transfer of water. Polyhydramnios is rare in women with well-controlled diabetes.

  1. GROWTH RETARDATION

In contrast to fetal macrosomia, the fetus of a woman with diabetes of long duration and vascular disease may suffer intrauterine fetal growth restriction related to inadequate uteroplacental perfusion. All body diameters may be below normal on ultrasonographic measurements, but the abdominal circumference is especially affected, and oligohydramnios and abnormal doppler flow measurements of the umbilical cord are common. In these patients provision of adequate rest, meticulous control of hypertension (target < 135/85 mm Hg), maintenance of normal blood glucose levels, and intensive fetal surveillance are all essential for success.

  1. INTRAUTERINE DEATH

Prior to the 1970s, the incidence of apparently sudden intrauterine fetal demise in the third trimester of diabetic pregnancies was at least 5%. Since the risk increased as pregnancies approached term, iatrogenic preterm delivery was instituted but the incidence of neonatal deaths from respiratory distress syndrome increased. Except for congenital malformations, the cause of stillbirth is often not obvious. The risk is greater with poor diabetic control, and the incidence of fetal death exceeds 50% if ketoacidosis develops in the mother. Some instances of fetal demise are associated with preeclampsia-eclampsia, which is a common complication in diabetic pregnant women. Fetal death has been associated also with pyelonephritis, which is now largely prevented by screening for and treating asymptomatic bacteriuria. Other than these known risk factors, one can presume—based on experimental studies—that the combination of fetal hyperglycemia and hypoxia leads to acidosis and myocardial dysfunction. Good glycemic control in diabetic women greatly reduces the risk of stillbirth.

Obstetric Management

  1. MONITORING

(Table 17-28.) Technologic advances have led to techniques for detecting fetal hypoxia and preventing stillbirth. Most simply, the infrequency of fetal movement as noted in regular fetal kick counts (few than four per hour) may indicate fetal jeopardy. More rigorous analysis of fetal activity patterns using ultrasonography is known as the “fetal biophysical profile,” which assesses gross body movements, the tone of the limbs, and chest wall motions as well as reactivity of the fetal heart rate and the volume of amniotic fluid. The measurement of maternal estriol levels for fetal evaluation is now of only historical interest. This assay was based on the knowledge that placental production of estriol is dependent on precursors from the fetal adrenals and correlates with the mass and well-being of the fetal-placental unit, but application of the assay was imprecise and was supplanted by antepartum fetal heart rate (FHR) monitoring. The presence of fetal heart rate accelerations and long-range

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variability on the nonstress test (NST) and the absence of late decelerations (lower FHR persists after the contraction subsides) on the contraction stress test (CST) indicates that the fetus is well oxygenated. However, the predictive value of a normal result is only valid for a short duration in diabetic women with unstable metabolic control or hypertension. These patients may have to be hospitalized for daily fetal testing. Generally, the NST and CST are sensitive screening tests, and abnormal results of FHR monitoring in these tests will overestimate the diagnosis of fetal distress. Therefore, it is wise to obtain additional evidence of fetal jeopardy (by biophysical ultrasonographic assessment) before cesarean delivery is recommended in preterm pregnancies. In term gestation with abnormal fetal testing, there is little to be gained by continuing the pregnancy.

Table 17-28. Schedule of obstetric tests and procedures.

Procedure

Risk Based on Glycemic Control, Presence of Vascular Disease

Low Risk

High Risk

Ultrasound to date gestation

8–12 weeks

8–12 weeks

Prenatal genetic diagnosis

As needed

As needed

Targeted perinatal ultrasound; fetal echocardiography

18–22 weeks

18–22 weeks

Fetal kick counts

28 weeks

28 weeks

Ultrasound for fetal growth

28 and 37 weeks1

Every 3–8 weeks

Antepartum FHR monitoring, backup with biophysical profile

36 weeks, weekly

27 weeks, 1–3 per week

Amniocentesis for lung

35–38 weeks

Induction of labor

41 weeks2

35–38 weeks

1Not needed in normoglycemic, diet-treated women with gestational diabetes mellitus.

2Earlier for obstetric reasons or for impending fetal macrosomia.

  1. TIMING OF DELIVERY

Unless maternal or fetal complications arise, the goal for delivery in diabetic women should be 38–41 weeks in order to reduce neonatal morbidity from preterm deliveries. On the other hand, the obstetrician may wish to induce labor before 39 weeks if there is concern about increasing fetal weight. Before a preterm delivery decision (less than 37 weeks) is made—or at 37–38 weeks in women with poor glycemic control—fetal pulmonary maturity should be determined. Tests for maturity using amniocentesis predict a low risk of neonatal respiratory distress syndrome and include the leci-thin/sphingomyelin (L/S) ratio, phosphatidylglycerol, and other biochemical or physical assays of surfactant activity. In pregnancies complicated by hyperglycemia, fetal hyperinsulinemia can lead to low pulmonary surfactant apoprotein production. The lowest risk for respiratory distress syndrome is attained by delaying delivery (if possible) until 38–41 weeks and minimizing the need for cesarean sections.

  1. ROUTE OF DELIVERY

Once fetal lung maturity is likely, the route of delivery must be selected based on the usual obstetric indications. If the fetus seems large (> 4200 g) on clinical and ultrasonographic examination of diabetic women, cesarean section probably should be performed because of the possibility of shoulder dystocia and birth trauma. Otherwise, induction of labor is reasonable, because maternal and peripartum risks are fewer following vaginal delivery. Once labor is under way, continuous fetal heart rate monitoring is essential. Maternal blood glucose levels > 150 mg/dL (8.3 mmol/L) can be associated with intrapartum fetal hypoxia.

Insulin Management for Labor & Delivery

The diabetic parturient may be unusually sensitive to insulin during active labor and delivery, and severe maternal hypoglycemia is possible if delivery occurs sooner than anticipated and a high dose of subcutaneous intermediate-acting insulin was previously administered. Protocols for continuous low-dose intravenous insulin administration during labor or prior to cesarean delivery are used to achieve stringent control of blood glucose in order to reduce the incidence of intrapartum fetal distress and neonatal metabolic problems (Table 17-29). A cord blood glucose level at delivery correlates positively with the higher maternal levels, and there is no upper limit on placental transfer of glucose. During labor, maternal plasma glucose can usually be kept below 110 mg/dL (6.1 mmol/L) with 1–2 units of regular insulin and 7.5 g of dextrose given intravenously

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every hour. If cesarean section is necessary, insulin management is similar, and infants do equally well with general, spinal, or epidural anesthesia as long as the diabetic parturient does not receive rapid high-volume loads of glucose-containing intravenous solutions.

Table 17-29. Protocol for intrapartum insulin infusion.1

Intravenous fluids
   If blood glucose is > 130 mg/dL (> 7.2 mmol/L), infuse mainline Ringer's lactate at a rate of 125 mL/h.
   If blood glucose is < 130 mg/dL (< 7.2 mmol/L), infuse mainline Ringer's lactate to keep vein open and begin Ringer's lactate and 5% dextrose at a rate of 125 mL/h controlled by infusion pump.
Insulin infusion
   Mix 25 units of regular human insulin (U100) in 250 mL NaCl 0.9% and piggyback to mainline. The concentration is 1 unit/10 mL. Adjust intravenous insulin hourly according to the following table when the blood glucose is > 70 mg/dL (> 3.9 mmol/L).

Blood glucose mg/dL (mmol/L)

Insulin (units/h)

Infusion (mL/h)

< 70 (< 3.9)

None

None

71–90 (3.9–5)

0.5

5

91–110 (5.1–6.1)

1

10

111–130 (6.2–7.2)

2

20

131–150 (7.3–8.3)

3

30

151–170 (8.4–9.4)

4

40

171–190 (9.5–10.6)

5

50

> 190 (> 10.6)

Call MD and check urine ketones

1Protocol useful also for diabetic pregnant women who are “NPO” or being treated with beta-adrenergic tocolysis or corticosteroids. The scale dosages may need to be doubled for the latter. Boluses of short-acting insulin must be used to cover meals.

Neonatal Morbidity

Planning for the care of the infant should be started prior to delivery, with participation by the pediatrician or neonatologist in decisions about timing and management of delivery. In complicated cases, the pediatrician must be in attendance to learn about antenatal problems, to assess the need for resuscitation, to identify major congenital anomalies, and to plan initial therapy for the sick infant if required.

  1. RESPIRATORY DISTRESS SYNDROME

Infants of poorly controlled diabetic mothers have an increased risk of respiratory distress syndrome. Possible reasons include abnormal production of pulmonary surfactant or connective tissue changes leading to decreased pulmonary compliance. However, in recent years, the incidence of respiratory distress syndrome has declined from 24% to 5%, probably related to better maternal glycemic control, selected use of amniotic fluid tests, and delivery of most infants at term (see above). The diagnosis of respiratory distress syndrome is based on clinical signs (grunting, retraction, respiratory rate > 60/min), typical findings on chest x-ray (diffuse reticulogranular pattern and air bronchogram), and an increased oxygen requirement (to maintain the PaO2 at 50–70 mm Hg) for more than 48 hours with no other identified cause of respiratory difficulty (heart disease, infection). Survival of infants with respiratory distress syndrome has dramatically improved as a result of advances in ventilation therapy and intrapulmonary administration of surfactant.

  1. HYPOGLYCEMIA

Hypoglycemia is common in the first 48 hours after delivery of previously hyperglycemic mothers and is defined as blood glucose below 30 mg/dL (1.7 mmol/L) regardless of gestational age. The symptomatic infant may be lethargic rather than jittery, and hypoglycemia may be associated with apnea, tachypnea, cyanosis, or seizures. Hypoglycemia has been related to elevated fetal insulin levels during and after delivery. Infants of diabetic mothers may also have deficient catecholamine and glucagon secretion, and the hypoglycemia may be related to diminished hepatic glucose production and oxidation of free fatty acids. The pediatrician attempts to prevent hypoglycemia in “well” infants with early feedings of 10% dextrose in water by bottle or gavage by 1 hour of age. If this is not successful, treatment with intravenous dextrose solutions is indicated. There are usually no long-term sequelae of episodes of neonatal hypoglycemia.

Other possible problems in infants of diabetic mothers include hypocalcemia < 7 mg/dL [1.75 mmol/L], hyperbilirubinemia > 15 mg/dL [256 ľmol/L], polycythemia (central hematocrit > 70%), and poor feeding. These complications are also somehow related to fetal hyperglycemia and hyperinsulinemia and probably to intermittent low-level fetal hypoxia. Improved control of the maternal diabetic state has reduced their incidence.

PROGNOSIS FOR PATIENTS WITH DIABETES MELLITUS

In patients with type 1 diabetes, the results of the Diabetes Control and Complications Trial have established the benefit of near-normalization of glycemia in preventing or delaying the progression of diabetic microangiopathy. Similar trials of intensive therapy of hypertension as well as control of blood glucose in the United Kingdom indicate that a similar benefit occurs in type 2 diabetes, particularly with regard to macrovascular disease and microangiopathy. Currently, the prospect for retarding the progression of diabetic eye complications in both types of diabetes is good because of benefits derived from laser photocoagulation. Education as to proper foot care has been immensely valuable in reducing morbidity from diabetic foot problems. Management of hypertension, dyslipidemia, and cessation of cigarette smoking have been of great benefit in preventing or reducing the progression of retinopathy, nephropathy, and atherosclerosis. Newer methods for delivering purified insulins and for self-monitoring blood glucose have improved the overall outlook for patients with diabetes mellitus. However, present methods of subcutaneous insulin delivery need much improvement before physiologic insulin secretion is reproduced. Hypoglycemia remains a serious risk in all regimens of intensive insulin therapy attempting normalization of blood glucose. It is clear that the diabetic patient's intelligence, motivation, and awareness of potential complications of the disease are major factors contributing to a successful outcome. In addition, appropriate education of diabetic patients to provide the knowledge, the guidelines, and the tools to help them take charge of their own day-to-day diabetes management is essential to improve the long-term prognosis.

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REFERENCES

The Endocrine Pancreas

Aguilar-Bryan L et al: Cloning of the beta cell high-affinity sulfo-nylurea receptor: a regulator of insulin secretion. Science 1995;268:423.

Atria TE et al: Secretion of pancreatic polypeptide in patients with pancreatic endocrine tumors. N Engl J Med 1986;315:287.

Daniel S et al: Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. Diabetes 1999;48:1686.

Duckworth WC, Bennett RG, Hamel FG: Insulin degradation: progress and potential. Endocr Rev 1998;19:608.

Edwards CMB et al: Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9–39. Diabetes 1999;48:86.

Eliasson L et al: PKC-dependent stimulation of exocytosis by sulfonylureas in pancreatic beta cells. Science 1996;271:813.

Fehman H-C, Goke R, Goke B: Cell and molecular biology of the incretin hormones glucagon-like peptide I and glucose-dependent insulin releasing polypeptide. Endocr Rev 1995; 16:390.

Galloway JA et al: Biosynthetic human proinsulin: Review of chemistry, in vitro and in vivo receptor binding, animal and human pharmacology studies, and clinical trial experience. Diabetes Care 1992;15:666.

Gribble FM et al: Tissue specificity of sulfonylureas: studies on cloned cardiac and beta cell K+ ATP channels. Diabetes 1998;47:1412.

Holst JJ: Glucagonlike peptide 1: A newly discovered hormone. Gastroenterology 1994;107:1848.

Kahn BB: Facilitative glucose transporters: Regulatory mechanisms and dysregulation in diabetes. J Clin Invest 1992;89:1367.

Kahn SE, Andrikopoulos S, Verchere CB: Islet amyloid: a long-recognized but unappreciated pathological feature of type 2 diabetes. Diabetes 1999;48:241.

Kumar U et al: Subtype-selective expression of the five somatostatin receptors (hSSTR 1–5) in human pancreatic islet cells. Diabetes 1999;48:77.

Lefebvre PJ: Glucagon and its family revisited. Diabetes Care 1995;18:715.

Philippe J: Structure and pancreatic expression of the insulin and glucagon genes. Endocr Rev 1991;12:252.

Polonsky KS: The beta-cell in diabetes: From molecular genetics to clinical research. Diabetes 1995;44:705.

Rehfeld JF: The new biology of gastrointestinal hormones. Physiol Rev 1998;78:1087.

Resine T, Bell GI: Molecular biology of somatostatin receptors. Endocr Rev 1995;16:427.

Stephens JM, Pilch PF: The metabolic regulation and vesicular transport of GLUT 4, the major insulin responsive glucose transporter. Endocr Rev 1995;16:529.

Swenne I: Pancreatic beta-cell growth and diabetes mellitus. Diabetologia 1992;35:193.

Westermark P et al: Islet amyloid polypeptide A novel controversy in diabetes research. Diabetologia 1992;35:297.

Diagnosis, Classification, & Pathophysiology of Diabetes Mellitus

Alberti KGMM et al: Definition, diagnosis and classification of diabetes mellitus and its complications. Diabet Med 1998;15: 539.

Atkinson MA, Eisenbarth GS: Type 1 diabetes; new perspectives on disease pathogenesis and treatment. Lancet 2001;358:221.

Bell GI: Molecular defects in diabetes mellitus. Diabetes 1991; 40:413.

Bjorntorp P: Metabolic implications of body fat distribution. Diabetes Care 1991;14:1132.

Cherrington AD: Control of glucose uptake and release by the liver in vivo. Diabetes 1999;48:1198.

Clare-Salzer MJ, Tobin AJ, Kaufman DL: Glutamate decarboxylase: An autoantigen in IDDM. Diabetes Care 1992;15:132.

Cox NJ et al: Loci on chromosome 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nat Genet 1999;21:213.

Davies JL et al: A genome-wide search for human type 1 diabetes susceptibility genes. Nature 1994;371:130.

DeFronzo RA, Ferrannini E: Insulin resistance: A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173.

Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002;346:1685.

Ferrannini E: Insulin resistance versus insulin deficiency in noninsulin-dependent diabetes mellitus: problems and prospects. Endocr Rev 1998;19:477.

Goodyear LJ, Kahn BB: Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 1998;49:235.

Gottlieb PA, Eisenbarth GS: Diagnosis and treatment of pre-insulin dependent diabetes. Annu Rev Med 1998;49:391.

Herold KC et al: ANTI-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 2002;346:1692.

Howard BV, Howard WJ: Dyslipidemia in noninsulin-dependent diabetes mellitus. Endocr Rev 1994;15:263.

Hunter SJ, Garvey WT: Insulin action and insulin resistance: Diseases involving defects in insulin receptors, signal transduction, and the glucose transport effector system. Am J Med 1998;105:331.

Jequier E, Tappy L: Regulation of body weight in humans. Physiol Rev 1999;79:451.

Kadowski T et al: A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 1994; 330:962.

Karam JH: Type II diabetes and syndrome X: Pathogenesis and glycemic management. Endocrinol Metab Clin North Am 1992;21:329.

Knowler WC et al: Preventing non-insulin-dependent diabetes. Diabetes 1995;44:483.

Knowler WC et al: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393.

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Leahy JL, Bonner-Weir S, Weir GC: Beta-cell dysfunction induced by chronic hyperglycemia: Current ideas on mechanism of impaired glucose-induced insulin secretion. Diabetes Care 1992;15:442.

Meyer C, Doston JM, Gerich JE: Role of the human kidney in glucose counterregulation. Diabetes 1999;48:943.

Miller SP et al: Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype. Diabetes 1999;48:1645.

O'Rahilly S, Moller DE: Mutant insulin receptors in syndromes of insulin resistance. Clin Endocrinol 1992;36:121.

Pugliese A et al: The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 1997;15:293.

Raz I et al: B-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomized, double-blind, phase II trial. Lancet 2001;358:1749.

Rossini AA et al: Immunopathogenesis of diabetes mellitus. Diabetes Reviews 1993;1:43.

Saltiel AR, Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001;414:799.

Shepherd PR, Kahn BB: Glucose transporters and insulin action: implications for insulin resistance and diabetes mellitus. N Engl J Med 1999;341:248.

Stumvoll M et al: Renal glucose production and utilization: new aspects in humans. Diabetologia 1997;40:749.

UK Prospective Diabetes Study (UKPDS) Group:

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854.

Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 39.) BMJ 1998;317:713.

Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999; 281:2005.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837.

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 1998;317:703.

Vafiadis P et al: Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997;15:289.

Virkamaki A, Ueki K, Kahn CR: Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 1999;103:931.

Zawalich WS, Kelley GG: The pathogenesis of NIDDM: The role of the pancreatic beta cell. Diabetologia 1995;38:986.

Treatment of Diabetes Mellitus

American Diabetes Association: Management of dyslipidemia in adults with diabetes. Diabetes Care 1998;21(Suppl 1):S36.

Bode BW, Tamborlane WV, Davidson PC: Insulin pump therapy in the 21st century. Strategies for successful use in adults, adolescents and children with diabetes. Postgrad Med 2002;111:69.

Bolli GB et al: Glucose counterregulation and waning of insulin in the Somogyi phenomenon (posthypoglycemic hyperglyce-mia). N Engl J Med 1984;311:1214.

Bolli GB: Physiological insulin replacement in type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes 2001;109(Suppl 2): 5317.

Boner G, Cao Z, Cooper ME: Combination antihypertensive therapy in the treatment of diabetic nephropathy. Diabetes Technol Ther 2002;4:313.

Brink SJ, Stewart C: Insulin pump treatment in insulin-dependent diabetes mellitus: Children, adolescents, and young adults. JAMA 1986;255:617]

Clarke WL et al: Multifactorial origin of hypoglycemic symptom unawareness in IDDM. Diabetes 1991;40:680.

Cryer PE: Hypoglycemia is the limiting factor in the management of diabetes. Diabetes Metab Res Rev 1999;15:42.

Cryer PE: Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM: A vicious cycle. Diabetes 1992;41:255.

Cusi K, DeFronzo RA: Metformin: a review of its metabolic effects. Diabetes Rev 1998;6:89.

DCCT Research Group: Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med 1991;90:450.

DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977.

De Lorgeril M et al: Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99:779.

DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281.

Dunn FL: Management of hyperlipidemia in diabetes mellitus. Endocrinol Metab Clin North Am 1992;21:395.

Franz MJ et al: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002;25:148.

Gavin LA: Perioperative management of the diabetic patient. Endocrinol Metab Clin North Am 1992;21:457.

Groop LC et al: Morning or bedtime insulin combined with sulfonylurea in treatment of NIDDM. Diabetes Care 1992; 15:831.

Heine RJ et al: Absorption kinetics and action profiles of mixtures of short- and intermediate-acting insulins. Diabetologia 1984;27:558.

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Kang S et al: Subcutaneous insulin absorption explained by insulin's physicochemical properties. Diabetes Care 1991;14: 942.

Karam JH: Type II diabetes and syndrome X: Pathogenesis and glycemic management. Endocrinol Metab Clin North Am 1992;21:329.

Kendall DM, Robertson RP: Pancreas and islet transplantation: challenges for the twenty first century. Endocrinol Metab Clin North Am 1997;26:611.

Khan M et al: A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care 2002;25:708.

Kirpichnikov D et al: Metformin—an update. Ann Intern Med 2002;137:25.

Lebovitz HE: Oral therapies for diabetic hyperglycemia. Endocrinol Metab Clin North Am 2001;30:909.

Little RR et al: Relationship of glycosylated hemoglobin to oral glucose tolerance: Implications for diabetes screening. Diabetes 1988;37:60.

Max MB et al: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992;326: 1250.

Nathan DM et al: The clinical information value of the glycosylated hemoglobin assay. N Engl J Med 1984;310:341.

Nolte MS: Insulin therapy in insulin-dependent (type I) dia-betes mellitus. Endocrinol Metab Clin North Am 1992;21:281.

Owens DR et al: Insulins today and beyond. Lancet 2001;358:739.

Perriello G, De Feo P, Bolli GB: The dawn phenomenon: Nocturnal blood glucose homeostasis in insulin-dependent diabetes mellitus. Diabetic Med 1988;5:13.

Robertson RP: Pancreas islet transplantation for diabetes: successes, limitations and challenges for the future. Mol Genet Metab 2001;74:200.

Robertson RP et al: Therapeutic controversy: Pancreas transplantation for type 1 diabetes. J Clin Endocrinol Metab 1998;83: 1868.

Rosskamp RH, Park G: Long acting insulin analogs. Diabetes Care 1999;22(Suppl 2):B109.

Stacher G: Diabetes mellitus and the stomach. Diabetologia 2001; 44:1080.

Yusuf S et al: Effects of an angiotensin-converting enzyme inhibitor, ramipril, on death from cardiovascular causes, myocardial infarction and stroke in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145.

Acute Complications of Diabetes Mellitus

Bell DS, Alele J: Diabetic ketoacidosis. Why early detection and aggressive treatment are crucial. Postgrad Med 1997;101: 193,203.

Chan NN, Brain HP, Feher MD: Metformin-associated lactic acidosis: a rare or very rare clinical entity? Diabet Med 1999; 16:273.

Cohen RD: Lactic acidosis: New perspectives on origins and treatment. Diabetes Rev 1994;2:86.

Ennis ED, Stahl EJ, Kreisberg RA: The hyperosmolar hyperglycemic syndrome. Diabetes Rev 1994;2:115.

Genuth SM: Diabetic ketoacidosis and hyperglycemic, hyperosmolar coma. Curr Ther Endocrinol Metab 1997;6:438.

Gonzalez-Campoy JM, Robertson RP: Diabetic ketoacidosis and hyperosmolar nonketotic state: gaining control over extreme hyperglycemic complications. Postgrad Med 1996;99:143.

Henderson G: The psychosocial treatment of recurrent diabetic ketoacidosis: An interdisciplinary team approach. Diabetes Educator 1991;17:119.

Kitabchi AE et al: Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001;24:131.

Lorber D: Nonketotic hypertonicity in diabetes mellitus. Med Clin North Am 1995;70:39.

Okuda Y et al: Counterproductive effects of sodium bicarbonate in diabetic ketoacidosis. J Clin Endocrinol Metab 1996;81:314.

Singh RK, Perros P, Frier BM: Hospital management of diabetic ketoacidosis: are clinical guidelines implemented effectively? Diabet Med 1997;14:482.

Trence DL, Hirsch IB: Hyperglycemic crises in diabetes mellitus type 2. Endocrinol Metab Clin North Am 2001;30:817.

Wagner A et al: Therapy of severe diabetic ketoacidosis. Zero mortality under very-low-dose insulin application. Diabetes Care 1999;22:674.

Wiggam MI et al: Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study. Diabetes Care 1997;20:1347.

Wrenn KD et al: The syndrome of alcoholic ketoacidosis. Am J Med 1991;91:119.

Chronic Complications of Diabetes Mellitus

Aiello LP et al: Diabetic retinopathy. Diabetes Care 1998;21:143.

American Diabetes Association Position Statement: Diabetes nephropathy. Diabetes Care 2002;25(Suppl 1):S85.

Brownlee M: Glycation products and the pathogenesis of diabetic complications. Diabetes Care 1992;15:1835.

Caputo GM et al: Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994;331:854.

Clark CM, Lee DA: Drug Therapy: Prevention and treatment of the complications of diabetes mellitus. N Engl J Med 1995; 332:1210.

Cogan DG et al: Aldose reductase and complications of diabetes. Ann Intern Med 1984;101:82.

Deckert T et al: Microalbuminuria: Implications for micro- and macrovascular disease. Diabetes Care 1992;15:1181.

Donahue RP, Orchard TJ: Diabetes mellitus and macrovascular complications: An epidemiological perspective. Diabetes Care 1992;15:1141.

Feingold KR et al: Muscle capillary basement membrane width in patients with vacor-induced diabetes mellitus. J Clin Invest 1986;78:102.

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Ferris FL, Davis MD, Aiello LM: Treatment of diabetic retinopathy. N Engl J Med 1999;341:667.

Horowitz M et al: Gastric emptying in diabetes: clinical significance and treatment. Diabet Med 2002;19:177.

Ibrahim HN, Hostetter TH: Diabetic nephropathy. J Am Soc Nephrol 1997;8:487.

Klein R, Klein BEK, Moss SE: Epidemiology of proliferative diabetic retinopathy. Diabetes Care 1992;15:1875.

Knowles HC Jr: Long-term juvenile diabetes treated with unmeasured diet. Trans Assoc Am Physicians 1971;84:95.

Lipshultz LI, Kim ED: Treatment of erectile dysfunction in men with diabetes. JAMA 1999;281:465.

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;298:2981.

Markell MS, Friedman EA: Diabetic nephropathy: Management of the end stage patient. Diabetes Care 1992;15:1226.

Mauer SM et al: Long-term study of normal kidneys transplanted into patients with type I diabetes. Diabetes 1989;38:516.

Mogensen CE: The kidney in diabetes: how to control renal and related cardiovascular complications. Am J Kidney Dis 2001;37(1 Suppl 2):S2.

Parkhouse N, Le Quesne PM: Impaired neurogenic vascular response in patients with diabetes and neuropathic foot lesions. N Engl J Med 1988;318:1306.

Ramsay RC et al: Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 1988;318:208.

Raskin P et al: Capillary basement membrane width in diabetic children. Am J Med 1975;58:365.

Rosenbloom AL et al: Limited joint mobility in childhood diabetes: Family studies. Diabetes Care 1983;6:370.

Viberti G et al: Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA 1994;271:275.

Vinik AI et al: Diabetic neuropathies. Diabetologia 2000;43:957.

Diabetes Mellitus & Pregnancy

American Diabetes Association: Gestational Diabetes Mellitus. Definition, detection, and diagnosis. Diabetes Care 2002;25 (Suppl 1):S94.

Barbour LA et al: Human placental growth hormone causes severe insulin resistance in transgenic mice. Am J Obst Gynecol 2002;186:512.

Boden G: Fuel metabolism in pregnancy and in gestational diabetes mellitus. Obstet Gynecol Clin North Am 1996;23:1.

Buchanan TA et al: Preservation of pancreatic B-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796.

Chew EY et al: Metabolic control and progression of retinopathy. Diabetes Care 1995;18:631.

Combs CA et al: Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. Diabetes Care 1992;15:1251.

de Veciana M et al: Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995;333:1237.

Diabetes Control and Complications Trial Research Group: Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 2000;23: 1084.

Ekbom P et al: Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 2001;24:1739.

Fine EL et al: Evidence that elevated glucose causes altered gene expression, apoptosis, and neural tube defects in a mouse model of diabetic pregnancy. Diabetes 1999;48:2454.

Friedman JE et al: Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. Diabetes 1999;48:1807.

Garcia-Patterson A et al: In pregnancies with gestational diabetes mellitus and intensive therapy, perinatal outcome is worse in small-for-gestational-age newborns. Am J Obstet Gynecol 1998;179:481.

Hemachandra A et al: The influence of pregnancy on IDDM complications. Diabetes Care 1995;18:950.

Illsley NP: Placental glucose transport in diabetic pregnancy. Clinical Obstet Gynecol 2000;43:116.

Jovanovic-Peterson L et al: Maternal postprandial glucose levels and infant birth weight: The diabetes in early pregnancy study. Am J Obstet Gynecol 1991;164:103.

Kautzky-Willer A et al: Pronounced insulin resistance and inadequate beta-cell secretion characterize lean gestational diabetes during and after pregnacy. Diabetes Care 1997;20:1717.

Kirwan JP et al: TNF-alpha is a predictor of insulin resistance in human pregnancy. Diabetes 2002;51:2207.

Kitzmiller JL et al: Preconception management of diabetes continued through early pregnancy prevents the excess frequency of major congenital anomalies in infants of diabetic mothers. JAMA 1991;265:731.

Kitzmiller JL: Sweet success with diabetes: The development of insulin therapy and glycemic control for pregnancy. Diabetes Care 1993;16(Suppl 3):107.

Kitzmiller JL et al: Pre-conception care of diabetes, congenital malformations, and spontaneous abortions. Technical review. Diabetes Care 1996;19:514.

Kitzmiller JL, Combs CA: Diabetic nephropathy and pregnancy. Obstet Gynecol Clin North Am 1996;23:173.

Kjos SL et al: Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes. JAMA 1998;280:533.

Koren G: Glyburide and fetal safety; transplacental pharmacokinetic considerations. Reprod Toxicol 2001;15:227.

Landon MB, Gabbe SG: Fetal surveillance and timing of delivery in pregnancy complicated by diabetes mellitus. Obstet Gynecol Clin North Am 1996;23:109.

Langer O et al: Intensified versus conventional management of gestational diabetes. Am J Obstet Gynecol 1994;170:1036.

Langer O et al: A comparison of glyburide and insulin in women with gestational diabetes. N Engl J Med 2000;343:1134.

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Leunda-Casi A et al: Increased cell death in mouse blastocysts exposed to high D-glucose in vitro: implications of an oxidative stress and alterations in glucose metabolism. Diabetologia 2002;45:571.

McIntyre HD et al: Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth. J Clin Endocrinol Metab 2000;85:1143.

Metzger B, Coustan DR, and the Organizing Committee: Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes. Diabetes Care 1998;21(Suppl 2):B162.

Piper JM: Lung maturation in diabetes in pregnancy: If and when to test. Semin Perinatol 2002;26:206.

Sermer MS et al: Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3,637 women without gestational diabetes. Am J Obstet Gynecol 1995;173:145.

Sibai BM et al: Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes. Am J Obstet Gynecol 2000;182:364.

Silverman BL et al: Fetal hyperinsulinism and impaired glucose tolerance in adolescent offspring of diabetic mothers. Diabetes Care 1995;18:611.

Silverman BL, Purdy L, Metzger BE: The intrauterine environment: implications for the offspring of diabetic mothers. Diabetes Rev 1996;4:21.

Tomazic M et al: Comparison of alterations in insulin signaling pathway in adipocytes from type II diabetic pregnant women and women with gestational diabetes. Diabetologia 2002; 45:502.

Verma A et al: Insulin resistance syndrome in women with prior history of gestational diabetes mellitus. J Clin Endocrinol Metab 2002;87:3227.

White P: Diabetes mellitus in pregnancy. Clin Perinatol 1974;1: 331.

Winkler G et al: Tumor necrosis factor system in insulin resistance in gestational diabetes. Diab Res Clin Pract 2002;56:93.

Xiang AH et al: Multiple metabolic defects during late pregnancy in women at high risk for Type 2 diabetes. Diabetes 1999; 48:848.

*A convenient method for estimating serum osmolality is provided in the section on diabetic ketoacidosis.


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