Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 43 Insulin and Drugs Used in the Therapy of Diabetes Mellitus

MAJOR DRUG CLASSES

Insulin

Agents that promote insulin release

Sulfonylureas

Meglitinides

Incretin analogs

Dipeptidyl peptidase-IV inhibitors

Other antihyperglycemic agents

Biguanides

Thiazolidinediones

α-Glucosidase inhibitors

Amylin analogs

Therapeutic Overview

The two broad problems associated with diabetes mellitus are elevated blood glucose related to defects in the pancreatic secretion of insulin and decreased responsiveness of tissues to circulating insulin. Understanding and treating diabetes mellitus is complicated by its potentially heterogeneous etiology affecting both the amount and rate of decline of insulin secretion and variations in insulin responsiveness. These differences among individuals can be related to genomic alterations and physiological, pathological, and environmental conditions. The incidence of diabetes mellitus in the general population is estimated conservatively at 4% to 5%, although a higher incidence is suspected. According to the National Institutes of Health, complications of diabetes mellitus are the leading cause for new cases of blindness in adults, renal failure, and nontraumatic amputations. Further, diabetes mellitus is a major risk factor for reduced length of life, neuropathy, heart disease, and stroke. Numerous epidemiological studies reveal that these outcomes are positively affected by strict control of blood glucose levels. New classes of drugs that address the major causes of diabetes mellitus and insightful therapeutic concepts have vastly improved the consistency of blood sugar control and ultimately have reduced and delayed the pathological sequelae of this disease.

Normally, blood glucose is maintained within a relatively narrow range (80 to 100 mg/dL, or 0.44 to 0.55 mM). Regulation involves a complex interaction of the effects of hormones on tissue storage and use of glucose and other nutrients such as amino acids and fatty acids. When circulating levels of glucose increase, insulin is secreted by the pancreas and promotes the uptake and storage of glucose, amino acids, and fatty acids into insulin-responsive tissue including skeletal muscle and adipose tissue. Insulin also inhibits hepatic glucose output and promotes hepatic glycogen formation. The consequence of provocation of insulin secretion is rapid storage of

Abbreviations

ADP

Adenosine diphosphate

ATP

Adenosine triphosphate

cAMP

Cyclic adenosine monophosphate

DPP-IV

Dipeptidyl peptidase-IV

Epi

Epinephrine

GI

Gastrointestinal

GIP

Glucose-dependent insulinotropic polypeptide

GLP-1

Glucagon-like peptide-1

GLUT

Glucose transporter

GS

Glycogen synthase

HbA1c

Glycosylated hemoglobin

IRS

Insulin receptor substrate

IV

Intravenous

Kir6.2

Inward rectifying K+ channel 6.2 subunit of the ATP-sensitive K+ channel

PI 3-kinase

Phosphatidylinositol 3-kinase

PKA

cAMP-dependent protein kinase A

PKC

Protein kinase C

PPAR

Peroxisome proliferator-activated receptor

SC

Subcutaneous

SUR1

Sulfonylurea subunit of the ATP-sensitive K+ channel

nutrients from the blood into tissues to be used to meet energy and metabolic demands of the body.

If insulin levels or responsiveness of tissues to insulin action are inadequate, hyperglycemia ensues. According to guidelines established by the American Diabetes Association, a diagnosis of diabetes mellitus is established by a random plasma glucose equal to or exceeding 200 mg/dL (11 mM) with polyuria, polydipsia or other signs of diabetes; a fasting plasma glucose equal to or exceeding 126 mg/dL (7 mM); or a glucose level equal to or greater than 200 mg/dL at 2 hours after an oral glucose challenge of 75 gm. These values must be reproducible on at least two occasions.

In addition to overt diabetes mellitus, humans can exhibit impaired glucose tolerance, characterized by an elevated fasting blood glucose (110 to 126 mg/dL) and a 2-hour postprandial blood glucose of 140 to 200 mg/dL. Because patients exhibiting impaired glucose tolerance can either return to normal or develop sustained diabetes mellitus, these laboratory results must be repeated to confirm a diagnosis.

To determine how well blood glucose has been managed over a 2- to 3-month period, glycosylated hemoglobin (HbA1c) can be measured. Glycosylated hemoglobin is a molecule in red blood cells that attaches to glucose. HbA1c is normally 5%. An HbA1c of greater than 7% means that blood glucose levels have been poorly controlled, and the individual is at risk for developing problems such as kidney or nerve damage, heart disease, or stroke. The closer that HbA1c is to normal, the less risk for developing complications. It is important to recognize that it is not desirable to reduce glycosylated HbA1c values to the normal range if doing so results in hypoglycemic episodes.

The management of diabetes is highly individualized and must consider the patient’s health, frequency of episodes of diabetic ketoacidosis, hypoglycemia (insulin-induced) and hyperglycemia, need for insulin, and relationship between circulating insulin levels and tissue responsiveness to insulin. There are two primary types of diabetes mellitus, and the pharmacological strategies for treating these differ in several important ways. Plasma glucose and insulin levels after an oral glucose tolerance test in normal individuals, in individuals with both types of diabetes mellitus, and in individuals with impaired glucose tolerance are depicted in Figure 43-1.

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FIGURE 43–1 Plasma glucose and insulin levels after an oral aqueous glucose (75 gm) challenge after an 8-hour fast. Subjects were grouped based on a diagnosis of normal, (A); type 1 diabetes mellitus, (B); type 2 diabetes mellitus, (C); and impaired glucose tolerance, (D). (A), Nondiabetic individuals display a peak glucose concentration of 10 to 15 mM by 30 minutes and normoglycemia (5 mM) in 90 to 120 minutes; the insulin concentration follows a similar response. (B), At all time points, patients with type 1 diabetes mellitus exhibit greatly elevated plasma glucose levels compared with normal, and plasma insulin levels were essentially undetectable. In clinical practice patients with suspected type 1 diabetes mellitus are not usually subjected to oral glucose tolerance tests. Diagnosis of insulinopenia, which is accompanied by elevated blood glucose levels, is adequate information to initiate insulin treatment. (C), Hyperglycemia at all time points is also characteristic of type 2 diabetes mellitus. However, plasma insulin levels exhibit an extended delay, although nearly normal levels can be observed. In type 2 diabetes mellitus with insulin resistance, plasma glucose concentrations can remain elevated in spite of nearly normal levels of insulin. (D), For patients with impaired glucose tolerance, blood glucose at 30 to 60 minutes is higher than normal and may remain elevated at 120 minutes. Because of β cell compensation for impaired glucose, the plasma insulin concentrations are higher than normal, both in the fasting state and after glucose is administered. For many patients this is a temporary situation, and depending on the cause, the outcome can return to normal, remain unchanged, or mimic type 2 diabetes mellitus.

Type 1 diabetes mellitus is caused primarily by a T-cell mediated autoimmune response leading to destruction of the pancreatic β cells that produce insulin. Type 1 diabetes has an estimated frequency of 5% to 10% of total cases of diabetes mellitus and occurs predominantly before sexual maturation. Because the incidence of type 1 diabetes in homozygous twins is approximately 50%, factors other than genetic predisposition must be involved. The stimulus that prompts the immune system to attack β cells is still under investigation. The temporal nature of pancreatic β cell destruction can occur over a number of years, but after significant destruction (~90%), the onset of symptoms (polyuria, polydipsia, and polyphagia) can be abrupt. The increased urine volume is caused by osmotic diuresis resulting from increased concentrations of urinary glucose and ultimately ketone bodies. Thirst and hunger are compensatory responses. The development of diabetes mellitus is characterized by weight loss in the untreated disease and premature cessation of growth in children.

At the onset of symptoms, insulin levels are lower than normal and eventually become negligible (Fig. 43-1B), requiring replacement to prevent metabolic acidosis (ketosis), followed by diabetic coma and premature death. The goal of insulin replacement is the carefully controlled maintenance of blood glucose to prevent or delay the onset of long-term diabetic complications.

Type 2 diabetes mellitus is commonly diagnosed during middle-age but can occur at any age. Recent epidemiological studies suggest a disturbing increase in the incidence of obesity and type 2 diabetes mellitus in children. As with type 1 diabetes mellitus, there is a genetic predisposition, but the risk of developing the disease is strongly influenced by other risk factors including obesity and sedentary life style.

Metabolic abnormalities associated with type 2 diabetes mellitus precede the appearance of overt symptoms. The progression of symptoms may evolve from impaired glucose tolerance, to insulin-independent type 2 diabetes mellitus, to insulin-requiring type 2 diabetes mellitus. Detection of impaired glucose tolerance is difficult, because fasting blood glucose and insulin levels can be nearly normal. However, 2 hours after a glucose challenge, above-normal levels of blood sugar and insulin are observed (see Figs. 43-1, C and D). These results are related to insulin resistance at the cellular level leading to diminished glucose transport and metabolism, which promotes hyperglycemia and provokes pancreatic β cell insulin release. Although adequate insulin secretion can occur initially, the amount of insulin release diminishes eventually and is insufficient to reduce hyperglycemia and consequently overcome the effects of insulin resistance. Chronic stimulation of the pancreatic β cell is thought to increase metabolic activity, which can induce cell death and ultimately decreased ability to secrete insulin, leading to the symptoms associated with type 2 diabetes mellitus. The diagnosis of type 2 diabetes mellitus is based on the appearance of hyperglycemia as it meets the criteria discussed. Because the pharmacological agents that are used to manage type 2 diabetes mellitus require insulin, if insulin is lost at this stage, the patient will become a candidate for insulin supplementation.

Pharmacological management of hyperglycemia for patients with minimal insulin resistance can involve stimulation of endogenous insulin secretion, although exogenous supplementation may eventually become necessary. For the type 2 diabetic patient who exhibits primarily insulin resistance, management includes reducing glucose challenges through diet, weight loss, easing insulin resistance with drugs, and as becomes necessary, insulin supplementation. For the patient who exhibits both reduced insulin secretion and resistance to exogenous insulin, combination therapy involving drugs that affect insulin levels and resistance and diet, weight loss, and exercise offer the best management of blood glucose levels.

In type 2 diabetics the insulin levels remain adequate to prevent ketone body formation; thus ketosis and diabetic coma rarely develop. However, hyperosmolar coma can occur if insulin levels are insufficient to prevent glucosuria, and vomiting and diarrhea compound fluid loss. During periods of physical or emotional stress, insulin requirements, particularly for elderly patients, increase, and temporary supplementation may be necessary to avoid a diabetic or hyperosmolar coma, which is a potentially life-threatening situation.

Because hyperglycemia and its associated pathology gradually develop and little discomfort is noted, the type 2 diabetic may not appreciate the need to treat the disease to prevent long-term effects. Consequently, it is important to convince the patient that the quality of his or her health depends directly on committing to a long-term treatment strategy. Maintaining blood glucose concentrations near the normal range in type 2 diabetics by using insulin or pharmacological agents has been proven to significantly delay the development of long-term complications.

The management plan for type 2 diabetics must be tailored to meet individual patient needs and stage of development. Nonpharmacological strategies include dietary modifications (large proportion of complex carbohydrates/high fiber/low glycemic index/low fat), weight loss (as needed), and increased physical activity (as tolerated). Pharmacological approaches include supplementation or promotion of endogenous insulin secretion, antagonism of carbohydrate metabolism/absorption from the gastrointestinal (GI) tract, and/or reduction of insulin resistance. The long-term treatment plan of most type 2 diabetics will include pharmacologic therapy, and approximately half will need insulin supplementation.

A summary of the types of diabetes and their management is presented in the Therapeutic Overview Box.

Therapeutic Overview

Type 1 Diabetes Mellitus

Diabetic diet and exercise

Human insulin combination therapy

Addition of thiazolidinedione to manage concurrent insulin resistance

Management of Diabetic Ketoacidosis

Proper replacement of fluid, insulin, Na+, K+ and bicarbonate

Type 2 Diabetes Mellitus

Obesity management:

Diet, increased exercise, and weight reduction

Promoters of insulin secretion:

Sulfonylureas

Meglitinides

Incretin analogs

Dipeptidyl peptidase-IV inhibitors

Insulin supplementation

Management of insulin resistance:

Metformin

Thiazolidinediones

Pramlintide

α-Glucosidase inhibition to reduce postprandial carbohydrate challenge:

Metformin and miglitol

Combination therapy with multiple agents

Mechanisms of Action

Insulin

Insulin is a small acidic protein formed from the larger proinsulin precursor. Proinsulin is synthesized and packaged for secretion with trypsin-like proteases in the β cells of the islets of Langerhans. The precursor protein is proteolyzed within the secretory granule to form insulin via cleavage of a sequence of amino acids referred to as the C (connecting) peptide. Insulin is complexed with Zn++ within the granule. The active insulin protein is composed of an A peptide (21 amino acids), which has an intramolecular disulfide bond, and a B peptide (30 amino acids) that are covalently joined by two disulfide bonds (Fig. 43-2). Approximately equimolar amounts of insulin and C peptide are stored in and released from the granule, along with a much smaller amount of proinsulin.

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FIGURE 43–2 Primary structures of insulin and glucagon. The amino acid sequences of the 21-amino acid A chain and the 30-amino acid B chain of human insulin, and the 29 amino acids in human glucagon are shown. The single letter code for the amino acids is consistent with accepted nomenclature. The two interchain disulfide bridges and the intrachain disulfide in the A chain of insulin are indicated. Residues in beef or pork insulin that differ from those in human insulin are shown above or below the A and B chain sequences. Also depicted are the amino acids in glargine insulin, lispro insulin, and aspart insulin that differ from those in unmodified insulin.

Insulin release is modulated by many factors (Box 43-1) but is controlled primarily by glucose. When blood glucose levels increase, glucose is taken up and metabolized by the pancreatic β cell, generating adenosine triphosphate (ATP) (Fig. 43-3). The increase in the ATP/ADP ratio promotes closure of the inward rectifying potassium channel 6.2 subunit (Kir6.2) of the ATP-sensitive potassium channel (also referred to as the SUR1/Kir6.2 channel). The decreased permeability of potassium ions partially depolarizes the cell membrane, promoting calcium uptake via activation of its voltage-gated channels. The elevated intracellular calcium stimulates exocytosis of the granules, releasing insulin and other components into the circulation.

BOX 43–1 Some Factors that Control the Release of Endogenous Insulin

Stimulate

Nutrients

Glucose

Amino acids

Fatty acids

Ketone bodies

Hormones

Secretin

Glucagon

Pancreozymin

Gastrin

Vasoactive intestinal peptide

Gastric inhibitory polypeptide

Drugs

β Adrenergic agonists

Cholinergic agonists

Inhibit Zn++

Somatostatin

α Adrenergic agonists

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FIGURE 43–3 Stimulation of insulin secretion by glucose and oral hypoglycemic agents involves partial depolarization of the β cell plasma membrane. After an increase in blood glucose (Glc), more Glc enters the β cell via the glucose transporter, GLUT2. The Glc is phosphorylated by glucokinase to glucose 6-phosphate (G6P), which is subsequently metabolized via glycolysis and the TCA cycle, increasing intracellular ATP and decreasing ADP. The resulting increase in the ATP/ADP ratio results in inhibition of the inwardly rectifying K+channel, Kir6.2, resulting in partial membrane depolarization, triggering activation of voltage-gated Ca++ channels. The rise in intracellular Ca++ stimulates exocytosis of secretory granules containing insulin. The sulfonylureas and meglitinides bind to sites on the ATP-sensitive K+ channel to inhibit channel conductance, resulting in membrane depolarization, and Ca++ entry, promoting insulin release.

Measurement of the C peptide can be used clinically to estimate insulin secretion. If circulating insulin levels are appropriate, hepatic glucose output is suppressed, and glucose uptake by skeletal muscle and adipocytes is stimulated, resulting in only a transient increase in blood glucose levels. When administered as a drug, insulin lowers blood glucose by mimicking the effects of the endogenous hormone. The disappearance of insulin is regulated by proteolytic systems or insulinase activity in a variety of tissues, with the liver being the most prominent. Almost half of the insulin released by the pancreas into the portal vein is destroyed by hepatic degradation.

The cellular effects of insulin are initiated after insulin binds to a plasma membrane receptor (Fig. 43-4). The insulin receptor is composed of two α-subunits and two β-subunits. The interaction of insulin with the α-subunit results in changes in the β-subunit configuration, leading to activation of the tyrosine protein kinase that resides in the β-subunit. The phosphorylation of peptide substrates by the insulin receptor tyrosine kinase leads to activation of various anabolic pathways, inhibition of catabolic processes, and subsequently modulation of gene expression. The major peptide substrates for the insulin receptor are insulin receptor substrate (IRS)-1 and IRS-2. Phosphotyrosine residues in the IRS proteins serve as binding sites for intermediaries that trigger signal transduction pathways. The best defined of these pathways involves the small guanosine triphosphate (GTP)-binding protein Ras and leads to cell growth, differentiation, or both. However, the most important acute metabolic effects of insulin are mediated by phosphatidylinositol 3-kinase (PI 3-kinase), which is activated upon binding to phosphorylated IRS proteins. The phospholipid products generated by PI 3-kinase promote activation of several protein kinases including protein kinase B(Akt) and protein kinase C (PKC). These kinases phosphorylate effectors that activate glucose transporters (GLUT) and glycogen synthase (GS) and increase the synthesis of triglyceride and protein. Phosphotyrosine phosphatases are also activated that limit the duration of effects promoted by phosphotyrosines.

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FIGURE 43–4 Major signal transduction pathways that mediate insulin action. Insulin (I) binding to its receptor results in increased tyrosine (Y) phosphorylation of the adapter proteins, with src humology sequences (Shc) and insulin receptor substrate (IRS) proteins 1 and 2. This creates docking sites for downstream effectors, which bind to phosphotyrosine-containing sites. One such effector is the Grb-2/mSOS complex, which is activated when it binds to either Shc or IRS proteins. Grb-2/mSOS activates Ras, which triggers the sequential phosphorylation and activation of the following kinases: Raf, MEK, mitogen-activated protein kinase (MAPK), and Rsk. This pathway is involved in the proliferative response of cells to insulin and several growth factors. The MAPK pathway is also activated by the protein tyrosine phosphatase SHP-2, which is recruited to IRS proteins in response to insulin. PI 3-kinase uses two SH domains in its p85 regulatory subunit to bind phosphorylated IRS proteins. Binding activates the p110 catalytic subunit of PI 3-kinase, generating phospholipid products that activate several downstream protein kinases, including Akt and isoforms of protein kinase C (PKC). These downstream kinases phosphorylate regulatory proteins in the cell, leading to the activation of glucose transport and to increases in the rates of synthesis of glycogen, lipid, and protein.

Stimulation of glycogen synthesis is very important in the action of insulin to lower blood glucose concentrations. Glucose taken up in response to insulin is deposited as glycogen in liver and skeletal muscle. Activation of glucose transport and GS contributes to the overall effects of insulin on glycogen synthesis. Increasing glucose transport allows more glucose to enter the muscle fiber, and activation of GS converts the glucose into glycogen. The control of GS activity is very important in this process and involves phosphorylation/dephosphorylation mechanisms (Fig. 43-5). GS is inactivated upon phosphorylation by the kinase GSK-3 and activated upon dephosphorylation by the protein phosphatase PP1G. In addition, phosphorylation of GSK-3 by Akt inactivates the kinase. Thus activation of Akt by insulin (see Fig. 43-4) leads to the inactivation of GSK-3, thereby tipping the balance to favor activation of GS by PP1G. In addition, by stimulating glucose transport via GLUT4, insulin increases the concentration of intracellular glucose 6-phosphate, an allosteric activator of GS. Insulin stimulates glucose transport in skeletal muscle and adipocytes by causing GLUT4 to translocate from intracellular vesicular compartments to the plasma membrane, an action promoted by signals from arising from Akt, PKC, or both (see Fig. 43-5). Increasing the number of glucose transporters at the cell surface increases glucose uptake into the cell. Interruption of any of these processes can be associated with genomic-associated insulin resistance.

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FIGURE 43–5 Stimulation of glycogen (Gly) synthesis by insulin involves activation of both glucose transport and glycogen synthase (GS). Insulin stimulates glucose transport by promoting movement of glucose transporter (GLUT4)-containing vesicles (GTV) to the plasma membrane. Translocation occurs in response to activation of Akt, PKC, or both. After vesicle fusion, the number of GLUT4 molecules at the cell surface is increased. Glucose (Glc) is then able to cross the membrane more rapidly and is phosphorylated in the cell to glucose 6-phosphate. A portion of the glucose 6-phosphate is metabolized by the hexose monophosphate pathway (HMP). This pathway, which is stimulated by insulin, generates pentoses for nucleotide synthesis and reducing equivalents for fatty acid synthesis. Another portion of glucose 6-phosphate enters the glycolytic pathway. Pyruvate generated from glycolysis enters the tricarboxylic acid (TCA) cycle and is metabolized to CO2, resulting in the generation of ATP. The bulk of the glucose that enters a muscle fiber in response to insulin is converted to glycogen (Gly). The glucose 6-phosphate is isomerized to glucose 1-phosphate, which is converted to uridine diphosphoglucose (UDPG), the substrate for glycogen synthase (GS), the enzyme that synthesizes glycogen. Insulin activates GS by increasing the activity of Akt, which phosphorylates and inactivates GSK-3. This allows the protein phosphatase, PP1G, to predominate, thereby increasing the fraction of GS that is in the dephosphorylated, active form.

Glucagon

Glucagon is a single-chain polypeptide with a molecular weight of approximately 3500 (see Fig. 43-2). It is synthesized in the α cells of the pancreatic islets through processes involving enzymatic cleavage of specific bonds in proglucagon, a large precursor. In the stomach and GI tract, a related molecule, glycentin, is formed from proglucagon. Glucagon is sometimes referred to as a counterregulatory hormone, because its action to increase blood glucose is counter to that of insulin. Glucagon levels may be inappropriately elevated in both type 1 and type 2 diabetics, contributing to the hyperglycemia in these diseases.

The major physiological role of glucagon is to maintain blood glucose during times of fasting. Glucagon secretion is inhibited by hyperglycemia and is stimulated in response to hypoglycemia or an increase in certain amino acids. Glucagon interacts with a specific receptor on the outer surface of sensitive cells, leading to activation of adenylyl cyclase and phospholipase C, resulting in increased intracellular cyclic adenosine monophosphate (cAMP) and inositol 1,4,5-trisphosphate. In the liver these second messengers increase glucose output by increasing glycogenolysis and gluconeogenesis.

Glucagon is sometimes used as a drug to increase blood glucose concentrations in seriously hypoglycemic patients unable to take glucose orally. Its chief use, however, is in radiology. When administered with a radiopaque substance, glucagon relaxes GI smooth muscles, allowing better visualization of tumors and other GI disorders. Glucagon also stimulates lipolysis in adipocytes and has both chronotropic and inotropic effects in the heart. It is occasionally used to stimulate cardiac function after overdose of a β adrenergic receptor antagonist.

Incretins

The incretins are a group of hormones that have been shown recently to play an important role in the regulation of glucose homeostasis and represent a relatively new target for drug action. The incretins are produced by cells in the GI tract in response to the absorption of food and are believed to increase the function of pancreatic islets. Incretins stimulate the β cells to produce insulin and impair the ability of the α cells to secrete glucagon, particularly when circulating levels of glucose are high. Incretins have also been shown to increase the growth and mass of β cells, delay gastric emptying, and promote the feeling of satiety through central mechanisms. The two best characterized incretins are glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory peptide) and glucagon-like peptide-1 (GLP-1). Although increased levels of these incretins decrease blood glucose, they have very short half-lives (approximately 2 minutes) as they undergo rapid proteolysis by the enzymedipeptidyl peptidase-IV (DPP-IV). Individuals with type 2 diabetes appear to have decreased GIP activity and decreased levels of GLP-1. Restoring incretin function, which promotes the health and function of the islets, is a major focus of current drug development. Indeed, incretin analogs and DPP-IV inhibitors both represent new classes of drugs for the treatment of type 2 diabetes.

Agents that Promote Insulin Release

On the basis of mechanism of action, four classes of drugs promote insulin secretion, the sulfonylureas, meglitinides, incretin analogs, and DPP-IV inhibitors (Fig. 43-6). The effectiveness of these agents is dependent on functioning pancreatic β cells, and these agents are not beneficial if the patient exhibits severe insulin deficiency.

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FIGURE 43–6 Structures of representative agents that promote insulin release.

Sulfonylureas

Tolbutamide, tolazamide, acetohexamide, and chlorpropamide are the first-generation sulfonylureas; glyburide, glipizide, and glimepiride are second-generation agents, which are effective at 10 to 100 times lower concentrations. All of the sulfonylureas promote insulin release by binding to the sulfonylurea subunit (SUR1) of the SUR1/Kir6.2 ATP-sensitive K+ channel (see Fig. 43-3). Binding inhibits channel conductance, resulting in partial depolarization of the membrane and activation of voltage-sensitive Ca++ channels. The resulting increase in cytosolic Ca++ promotes exocytosis of the secretory granules containing insulin. Insulin release is essential for the hypoglycemic actions of the sulfonylureas. However, after long-term treatment with sulfonylureas, the concentrations of insulin return to pretreatment values, even though the hypoglycemic effect persists. Thus it is assumed that sulfonylureas increase insulin sensitivity by enhancing the effect of insulin to stimulate glucose uptake into muscle and adipose cells.

Meglitinides

Two members of this class have been approved for use in the United States: repaglinide and nateglinide. These agents have a mechanism of action similar to the sulfonylureas to inhibit K+ conductance by the Kir6.2 ATP-sensitive K+ channel. Although the meglitinides bind to a site distinct from that of the sulfonylureas, stimulation of insulin secretion occurs by the same membrane depolarization mechanism (see Fig. 43-3).

Incretin Analogs

Exenatide is a synthetic peptide with an amino acid sequence that partially overlaps that of human GLP-1 (see Fig. 43-6). Exenatide binds to and activates the GLP-1 receptor on the pancreatic β cell to increase levels of cAMP and the density of membrane-associated GLUT2 transporters. The consequence of the increased glucose uptake and ATP formation is closure of the Kir6.2 ATP-sensitive K+channel, analogous to the natural process stimulated by sulfonylureas. As a consequence, exenatide promotes the release of insulin from pancreatic β cells in the presence of elevated glucose levels.

Dipeptidyl Peptidase-IV Inhibitors

Sitagliptin is a DPP-IV inhibitor that decreases the inactivation of endogenous incretin hormones, thereby increasing their concentrations and prolonging their action. As a consequence, insulin release increases and glucagon levels decrease in a glucose-dependent manner. Sitagliptin exhibits selectivity for DPP-IV and does not inhibit other peptidases at therapeutic concentrations.

Other Antihyperglycemic Agents

Other agents that are used for the treatment of diabetes include drugs that reduce insulin resistance including the biguanides and the thiazolidinediones, α-glucosidase inhibitors, and a modified amylin peptide (Fig. 43-7).

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FIGURE 43–7 Structures of other representative antihyperglycemic agents.

Biguanides

Metformin is a biguanide that decreases hepatic glucose output, inhibits absorption of glucose from the GI tract, and increases glucose uptake by muscle cells and adipocytes. Although not fully understood, the mechanism of action involves activation of cAMP-dependent protein kinase (PKA). Activation of this kinase in skeletal muscle and adipocytes leads to increased glucose transport by promoting translocation of GLUT4 to the cell surface (see Fig. 43-5).

At therapeutic doses, metformin is comparable in efficacy to sulfonylureas in maintaining lower levels of blood glucose in the type 2 diabetic. However, the acute effect of a single dose of metformin on blood glucose is less pronounced than a meglitinide such as repaglinide. Nevertheless, metformin, unlike sulfonylureas and meglitinides, has very little potential to cause hypoglycemia. Moreover, unlike insulin, agents that promote insulin release, or the thiazolidinediones, metformin does not cause weight gain and is often a preferred drug in the treatment of obese type 2 diabetics.

Thiazolidinediones

The thiazolidinediones lower blood glucose by improving insulin sensitivity, leading to the use of the term insulin sensitizer. Two drugs in this class, rosiglitazone and pioglitazone, are currently approved for use in the United States. A related agent, troglitazone, was withdrawn from the market when its use was connected with hepatotoxicity. Thiazolidinediones are activating ligands for the peroxisome proliferator-activated receptor (PPAR) type γ (PPAR-γ). Activation of PPAR-γ leads to dissociation of transcription repressors, attraction of transcription activators, and activation of insulin-responsive genes. By artificially promoting the action of insulin, these agents facilitate insulin-induced decreased blood glucose. Because thiazolidinediones increase insulin sensitivity, they seem to be ideal for the management of insulin resistance. When used alone, however, they are less effective than sulfonylureas in lowering blood glucose levels. On the other hand, rosiglitazone and pioglitazone synergize with sulfonylureas and insulin in decreasing blood glucose in type 2 diabetics. Consequently, thiazolidinediones are commonly used in combination therapy. Thiazolidinediones are completely ineffective if used without insulin for the treatment of type 1 diabetes and are useful in combination therapy with insulin to treat type 1 diabetes with insulin resistance.

α-Glucosidase Inhibitors

Acarbose and miglitol inhibit α-glucosidases, which are enzymes in the GI tract involved in the degradation of complex carbohydrates. By preventing the generation of monosaccharides, which are more readily absorbed than complex carbohydrates, these inhibitors blunt the rise in blood glucose concentrations after a meal. The reduction of blood glucose produced by these inhibitors is small and has only small effects on hyperglycemia associated with diabetes. However, these agents can be included in combination therapy regimens.

Amylin Analogs

Pramlintide is a synthetic analog of human amylin, a peptide hormone synthesized by pancreatic β cells that is co-secreted with insulin in response to elevated blood glucose and functions as a synergistic partner. Pramlinitide, like amylin, complements the actions of insulin through several mechanisms including inhibition of glucagon secretion from pancreatic α cells, which improves hepatic insulin sensitivity by increasing glucose use and decreasing gluconeogenesis. Pramlinitide also delays gastric emptying without altering nutrient absorption and suppresses appetite through a centrally mediated mechanism. Levels of HbA1c and total cholesterol are also reduced. Pramlintide is used as adjunctive treatment of patients with both type 1 and 2 diabetes mellitus who fail to achieve full glycemic control with insulin and other agents.

Pharmacokinetics

Insulin

Insulin cannot be administered orally because it is degraded by GI tract proteases. There are several routes available for dispensing insulin, intravenous (IV) administration for the emergency treatment of diabetic coma, inhaled insulin formulations for supplementation, and subcutaneous (SC) injection, the most common route for maintenance. Insulin preparations were developed to address several functions of insulin, including maintenance of relatively constant and low levels to meet cellular requirements and a rapid increase and decline to fulfill the role for insulin in managing nutritional intake and storage. Thus insulin preparations were developed with different pharmacokinetic properties, for example, different times of onset, peak activities, and durations of action. The success of this ongoing process can be seen in Table 43-1.

TABLE 43–1 Pharmacokinetic Parameters of Selected Human Insulin Preparations*

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Insulin Preparations

Before 1982, insulin preparations were extracted from the pancreases of slaughterhouse animals. Presently recombinant human insulin preparations are commonly used. Insulin preparations with differing pharmacokinetics can be divided into four categories: rapid-acting, short-acting, intermediate-acting, and long-acting. However, this nomenclature does not do justice to current treatment concepts using combinations of forms of genetically altered human insulin. Rapid-acting preparations with short durations are commonly used with meals to maximize storage of nutrients, and longer acting forms that have a flat activity peak are used to maintain baseline levels. The pharmacokinetic properties of these preparations allow them to be coadministered and minimize their overlapping activities. Specifically, combination therapy with these two types of altered recombinant human insulin improves control of blood sugar by reducing the incidences of hypoglycemia and hyperglycemia. Several premixed formulations of such preparations are available (see Trade Names Box).

Regular insulin is classified as a short-acting preparation. Insulin has a strong tendency to dimerize, and dimeric insulin is absorbed less rapidly than monomeric insulin. Two rapid-acting preparations, lispro insulin and aspart insulin, have been developed by modifying the insulin protein to prevent dimerization. In lispro insulin, the lysine and proline residues at positions 28 and 29 in the B chain are interchanged (see Fig. 43-2), whereas in aspart insulin, proline 28 is replaced with arginine.

NPH insulin is an intermediate-acting preparation containing the modifier protein protamine. When insulin is mixed with protamine, the two proteins form an insoluble complex, delaying absorption and onset and extending the duration of action. NPH insulin has a neutral (N) pH, contains protamine (P), and was developed by Hagedorn (H). Lente insulin is another intermediate-acting preparation that is a mixture of precipitated forms that occurs when insulin is mixed with Zn++. Lente insulin has an onset and duration of action comparable to NPH insulin.

Long-acting insulin preparations are not readily soluble and are absorbed only after dissolving in the interstitial fluid. The delayed solubility prolongs the duration of insulin action. The extended-action preparations are injected SC and must not be injected IV. There are two long-acting insulin preparations. Ultralente insulin is a suspension of large insulin-Zn++ crystals that dissolve slowly at the site of injection. Glargine insulin was developed by engineering two additional arginines at the COOH terminus of the B chain and a glycine in place of the aspargine at position 21 in the A chain (see Fig. 43-2). The additional arginines increase the charge and decrease the solubility of the protein at neutral pH. Arginine 21 was replaced with glycine to prevent desamidation, a process accelerated by acidic pH. Glargine insulin also precipitates at the site of injection, creating a depot that dissolves slowly and produces a stable baseline level of circulating drug.

Agents that Promote Insulin Release

The sulfonylureas are rapidly and completely absorbed from the GI tract and highly bound to plasma proteins. The first-generation drugs typically bind by ionic interactions and may be displaced by other drugs using such interactions. Second-generation sulfonylureas interact with albumin through nonionic binding, which makes them relatively more difficult to displace and increases their duration of action. Most sulfonylureas are metabolized in the liver, and the metabolites are excreted by the kidney. Pharmacokinetic parameters of sulfonylureas are summarized in Table 43-2. The duration of action of these drugs enables them to be administered as a single daily dose. The drugs are metabolized to inactive or weakly active products primarily by the liver.

TABLE 43–2 Pharmacokinetic Properties of Current Commonly Used Agents that Promote Insulin Release

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The meglitinides, repaglinide and nateglinide, have more rapid onsets and shorter durations of action than the sulfonylureas. Hypoglycemic actions with the meglitinides may occur as early as 20 minutes after an oral dose. Consequently, these drugs are generally taken immediately before meals to ensure that the effect on enhancing insulin release coincides with the increase in blood glucose. The meglitinides are highly bound to plasma proteins but not readily displaced by other drugs. Repaglinide is metabolized by oxidation and conjugation with glucuronic acid to products eliminated in the feces. Nateglinide is metabolized in the liver to products excreted in the urine.

The incretin analog exenatide is administered SC. Median peak plasma levels are reached in 2 hours. Exenatide is eliminated predominantly by glomerular filtration followed by proteolytic degradation.

Sitagliptin, a DPP-4 inhibitor, is rapidly absorbed after oral administration. Peak plasma levels are achieved in 1 to 4 hours. Sitagliptin is reversibly bound to plasma proteins (38%), and nearly 80% of an administered dose is excreted unchanged in the urine. Hepatic metabolism represents a minor pathway and involves CYP3A4 and CYP2C8.

Other Antihyperglycemic Agents

Pharmacokinetic properties of other agents used for the treatment of diabetes mellitus are summarized in Table 43-3.

TABLE 43–3 Pharmacokinetic Properties of Other Agents to Treat Diabetes Mellitus

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The thiazolidinediones are rapidly and completely absorbed after oral administration and highly bound to serum proteins. Rosiglitazone is metabolized to inactive products in the liver, followed by glucuronidation and sulfation. Pioglitazone is also extensively metabolized to several active metabolites, which accumulate in the blood to higher levels than the unmodified drug, thus increasing the duration of action. Pioglitazone and its metabolites are conjugated with glucuronic acid or sulfate and are excreted in the bile.

The amount of acarbose absorbed systemically is negligible. Miglitol is absorbed, although there is no evidence that the circulating drug contributes to its actions. The half-life of circulating miglitol is 2 hours, and almost all the drug is eliminated unchanged in the urine.

Pramlintide is administered SC, and peak serum levels are reached within 30 minutes. Pramlintide is metabolized primarily to the biologically active des-lys derivative by the kidneys.

Relationship of Mechanisms of Action to Clinical Response

Sustained elevation of blood glucose, as occurs in both type 1 and type 2 diabetes mellitus, is damaging to the microvasculature. This is believed to be the result of nonenzymatic glycation of proteins in the vessel wall and generation of other reactive products, as a result of the abnormal metabolism of glucose and lipids. Measurements of blood glucose and HbA1c provide an indication of the risk of developing long-term complications. An increase in the incidence of retinopathy is first detected when fasting blood glucose reaches a sustained level of 126 mg/dL, a primary reason this value was selected as the critical point for diagnosing diabetes mellitus. Therapy with insulin or agents that reduce blood glucose to near-normal levels clearly reduces the vessel damage that underlies diabetic retinopathy, nephropathy, and neuropathy.

Insulin

The actions of insulin that contribute to the uptake and storage of glucose are summarized in Box 43-2. Insulin stimulates glucose transport by facilitated diffusion into muscle cells and adipocytes by promoting translocation of GLUT4 to the cell surface. Hepatic glucose transport is mediated by GLUT2, and its membrane density is insulin-independent. The hepatic effects of insulin are metabolic, for example, insulin inhibits glycogenolysis and gluconeogenesis. Although the effects of insulin on gluconeogenesis are restricted to the liver, the hormone affects activity of many intracellular enzymes involved in energy storage in all major insulin-sensitive tissues. As a result, glucose is efficiently converted to glycogen, triglyceride, and protein.

BOX 43–2 Actions of Insulin

Carbohydrate Metabolism

Increases glucose transport

Increases glycogen synthesis

Increases glucose oxidation

Decreases gluconeogenesis

Lipid Metabolism

Increases fatty acid transport

Increases triglyceride synthesis (includes fatty acid synthesis and esterification)

Decreases lipolysis

Protein Metabolism

Increases amino acid transport

Increases protein synthesis (including messenger ribonucleic acid transcription and translation)

Decreases protein degradation

Elevated blood lipids increase the risk of atherosclerosis, and insulin has several actions that decrease serum lipid concentrations (Box 43-2). Lipids are transported in blood primarily as particles containing cholesterol esters complexed with proteins (see Chapter 25). Before the fatty acids can be taken up into cells, the cholesterol esters must be hydrolyzed by lipoprotein lipase, which is stimulated by insulin. Insulin also stimulates fatty acid synthesis, although the concentration of free fatty acids in the circulation decreases because insulin decreases lipolysis and accelerates fatty acid esterification. Stimulation of glucose transport into fat cells increases the supply of glycerol phosphate used in esterification.

Type 2 diabetes is frequently associated with hypercholesterolemia and hypertension, and the coexistence of these disorders is referred to as metabolic syndrome. The significance of this association with respect to the underlying causes of type 2 diabetes, hypercholesterolemia, and hypertension is unclear. However, it is important to recognize that type 2 diabetics often have other disorders that place them at risk of developing atherosclerosis. Aggressively treating hypertension and hyperlipidemia in such individuals is important to decrease the risk of cardiovascular disease (see Chapter 25).

Effects of insulin on lipid metabolism are also critical in preventing ketoacidosis. Ketone bodies are synthesized from acetyl coenzyme A, and production of ketone bodies during fasting is a normal activity in the liver, which releases ketones into the circulation for transport to heart, skeletal muscle, and other tissues for use as an energy source. The term ketone body, used to describe the compounds that produce ketosis, is a misnomer, because the major ketone body produced during diabetes or fasting in humans, β-hydroxybutyrate, is not a ketone. Except for acetone, all ketone bodies are organic acids, explaining why decreased blood pH is associated with their production. Because acetone is volatile, it is excreted to some extent by the lungs, accounting for the “fruity” acetone breath of people with severe ketosis. When insulin concentrations are decreased, as occurs in diabetes or fasting, production of ketone bodies is favored. Severe ketosis does not develop in nondiabetic individuals, however, because only a small amount of insulin is needed to reduce lipolysis in adipocytes. This reduces the supply of fatty acids, which are a major source of acetyl coenzyme A in the liver.

The later stages of diabetic ketoacidosis are associated with severe fluid depletion, partly because of the osmotic diuresis caused by increased glucose and ketone bodies in the urine; fluid loss also occurs with vomiting. Unconsciousness, referred to as diabetic coma, followed by cardiovascular collapse and death, occurs if appropriate therapy is not instituted. Treatment involves administration of insulin and rehydration, with careful monitoring to establish and maintain electrolyte balance and to prevent hypoglycemia.

Muscle wasting is a consequence of untreated type 1 diabetes that is corrected by insulin treatment. Insulin increases protein synthesis in various cells by stimulating several steps in the synthetic pathway, including transcription, rate of amino acid transport, and translation of messenger ribonucleic acid into protein. Insulin also potently slows proteolysis.

Agents that Promote Insulin Release

The sulfonylureas and meglitinides lower blood glucose by promoting insulin release from pancreatic β cells; these drugs can also enhance insulin action in target tissues. The clinical response to these agents is due to increased insulin secretion.

The incretin analog exenatide is indicated as adjunctive therapy in patients with type 2 diabetes who are taking a sulfonylurea, metformin, or a thiazolidinedione, alone or in combination, but fail to achieve adequate glycemic control. Similarly, sitagliptin is indicated for patients with type 2 diabetes who do not achieve glycemic control with metformin or a thiazolidinedione alone.

Other Antihyperglycemic Agents

Metformin acts in part by enhancing insulin sensitivity but also has direct effects on inhibiting hepatic glucose output and increasing glucose transport that are insulin-independent. Metformin decreases elevated blood glucose in type 2 diabetics and has been proven to decrease the incidence of long-term diabetic complications.

Rosiglitazone and pioglitazone increase insulin sensitivity in muscle, liver, and adipose tissue, enhancing the action of insulin on glucose, lipid, and protein metabolism. By decreasing the amount of insulin that needs to be released to control blood glucose, the thiazolidinediones may also exert protective effects on β cells.

Miglitol delays glucose absorption, which blunts postprandial blood glucose levels; fasting blood glucose is unaffected.

Pramlitide inhibits glucagon secretion, which promotes hepatic insulin sensitivity by increasing glucose use. It also decreases gastric emptying and appetite. Several long-term randomized, double-blind, placebo-controlled trials indicate decreased HbA1c levels without concomitant weight gain, which is a major complaint and reason for terminating therapy with thiazolidinediones.

Pharmacovigilance: Clinical Problems, Side Effects, and Toxicity

Controlling Blood Glucose

A major problem in treating diabetes mellitus is that control of blood glucose cannot be achieved with a fixed concentration of insulin. Insulin release is subject to complex regulation by many factors (Box 43-1), and circulating concentrations can change dramatically in nondiabetic subjects to maintain glucose levels within the normal range. Correlating insulin concentrations with the glucose load is a major challenge in insulin therapy, particularly because insulin sensitivity may vary greatly among individuals. Too little insulin results in hyperglycemia, whereas too much causes hypoglycemia and potentially insulin shock. As mentioned, the general strategy is to inject a short-acting insulin preparation to produce a peak in insulin that coincides with the rise in blood glucose that follows a meal and to use an extended-action preparation to establish a baseline concentration to prevent hyperglycemia between meals and during the overnight period. Administering insulin with variable-rate infusion pumps provides a more flexible means to control circulating insulin. There is evidence that tighter control of the blood glucose concentration is possible with these devices, although hypoglycemic episodes are also more frequent. Careful monitoring of blood glucose levels is essential.

Any of several factors can cause insulin sensitivity to change, foiling even conscientious attempts at control. A change in dietary pattern is frequently the cause of episodes of hyperglycemia or hypoglycemia. Exercise or ethanol intake can greatly increase insulin sensitivity, decreasing the hormonal requirement. Stress, pregnancy, or drugs, including thiazide diuretics and β adrenergic antagonists, decrease insulin sensitivity and exacerbate signs and symptoms of diabetes mellitus.

Insulin

Hypoglycemia is the most serious complication of insulin therapy. Among its causes are mistakes made in calculating doses or the timing of injections, changes in eating patterns, increased energy expenditure, or an increase in sensitivity. The brain has an absolute requirement for glucose, and severe hypoglycemia can cause unconsciousness, convulsions, brain damage, and death. Symptoms of hypoglycemia are often caused by increases in epinephrine (Epi) secretion, abnormal functioning of the central nervous system, or both. When the blood glucose concentration declines rapidly, Epi is released as a compensatory mechanism to stimulate hepatic glucose production and mobilize energy reserves. Rapid heart rate, headache, cold sweat, weakness, and trembling are characteristic responses to Epi (see Chapter 11). The extent to which these symptoms are observed varies considerably, depending on the individual and the rate of fall of the blood glucose concentration. Impaired neural function leads to blurred vision, an incoherent speech pattern, and mental confusion. At this point an experienced diabetic may be able to recognize his or her hypoglycemic state and take corrective action. However, the disoriented person is likely to need assistance. A glucose tablet or other source of rapidly absorbed glucose may be given to a conscious person Use of a medical identification bracelet can be life-saving.

The unconscious hypoglycemic state induced by an insulin overdose is referred to as insulin coma. Because of the risk of choking, one should never attempt to administer food or drink to an unconscious person. Insulin coma is sometimes confused with diabetic coma, but the two have opposite causes and different therapeutic interventions. Diabetic coma results from an insulin deficit and involves ketoacidosis, electrolyte imbalance, and dehydration that usually develops over hours or days. In contrast, the onset of an insulin coma may be very rapid. Thus a rapid onset and recent insulin administration implicates insulin coma. Management of an insulin coma requires rapid restoration of blood glucose by intravenous administration of concentrated (50%) dextrose solutions using large central veins and careful management.

Insulin has relatively few other side effects. Temporary visual disturbances may result from changes in the refractile properties of the lens brought about by decreasing osmolarity as glucose is brought under control. Localized fat accumulation can occur if insulin is repeatedly administered at the same site. This is caused by the stimulation of triglyceride accumulation in adipocytes surrounding the injection site. Curiously, lipoatrophy may also occur at the injection site. Both of these problems are typically remedied by rotating injection sites, a practice highly encouraged. Injecting insulin preparations can cause localized allergic reactions leading to pain and itching. These reactions are usually not severe and may disappear with time. Systemic allergic reactions, which may trigger anaphylaxis, occur much less frequently.

Agents that Promote Insulin Release

The use of sulfonylureas in the treatment of type 2 diabetes was considered controversial for several years as a result of the University Group Diabetes Program, a large long-term clinical trial involving 12 university medical centers. The original goal was to determine whether insulin therapy or orally administered hypoglycemic agents were of any benefit in delaying the onset of diabetic complications. Several years into the study, some participants, notably elderly women treated with tolbutamide, appeared to be dying of cardiovascular disease at a higher rate than those in the control groups, and tolbutamide was withdrawn from the trial. This “newly” discovered risk reduced enthusiasm for these agents. Subsequently it was suggested that patients assigned to the tolbutamide group had more risk factors (e.g., high blood pressure or elevated serum cholesterol concentration). More recently the United Kingdom Prospective Diabetes Study reported no increase in the incidence of cardiovascular death, myocardial infarction, or sudden death with sulfonylurea (glimepiride or chlorpropamide) therapy. Currently, it is presumed that sulfonylureas may be used safely to treat type 2 diabetes mellitus. These studies did promote the development of the second-generation sulfonylureas.

Weight gain related to the increase in insulin action on triglyceride synthesis occurs in most diabetics treated with oral hypoglycemic agents. A more serious complication is hypoglycemia, which may be due to an overdose, increased insulin sensitivity, change in dietary pattern, or increased energy expenditure. If the response is mild, it can be corrected by decreasing the dose of drug. However, severe cases may persist for days and require infusion of glucose.

The action of the meglitinides may be complicated by drugs that induce or inhibit the hepatic P450 system. Drugs that induce cytochromes P450 such as rifampin, barbiturates, and carbamazepine decrease the concentration of repaglinide, whereas drugs that inhibit CYP3A4 such as erythromycin, ketoconazole, and miconazole enhance repaglinide accumulation. Gemfibrozil markedly enhances the effects of repaglinide and should not be coadministered.

Adverse effects associated with exenatide are generally dose-related and decrease over time. These side effects include mild to moderate nausea, asthenia, decreased appetite, and reactions at the injection site. The development of anti-exenatide antibodies has been noted in 38% of patients, because exenatide is a protein with potential immunogenic properties. In addition, because exenatide delays gastric emptying, the rate of absorption of orally administered drugs may be affected. Thus these drugs should be taken 1 hour before exenatide injection.

Allergic reactions to sitagliptin include rashes, hives, and facial and neck swelling. In addition, serious hypersensitivity reactions have been reported including anaphylaxis, angioedema, and exfoliative conditions, including Stevens-Johnson syndrome.

In general, GI disturbances, allergic reactions, dermatological problems, and transient leukopenia can be expected in a small percentage of patients taking oral hypoglycemic agents. A disulfiram type of response (i.e., flushing, nausea, headache) caused by inhibition of aldehyde dehydrogenase is sometimes a problem if sulfonylureas are taken with alcohol, particularly with chlorpropamide. Chlorpropamide also causes fluid retention, resulting from release of antidiuretic hormone.

Contraindications

Agents that act by promoting insulin release are contraindicated in patients who do not have a proven pancreatic reserve of insulin. In addition, attention must be given to the metabolism and route of excretion of the drugs before beginning sulfonylurea therapy in patients with impaired hepatic or renal function. In these cases treatment with insulin may be the best choice. Although no teratogenic effects have been reported, these drugs should not be administered to pregnant or lactating women.

Exenatide should not be administered to patients with renal impairment or end-stage renal disease and is not recommended for patients with severe GI disorders. Clinical problems are summarized in the Clinical Problems Box.

Other Antihyperglycemic Agents

These agents rarely produce hypoglycemia. However, each class of agents has different complications and side effects, which are described in the following text.

Metformin

Some form of GI distress occurs in more than half of individuals receiving metformin. These side effects are at least partly due to inhibition of nutrient absorption and may include diarrhea, nausea, vomiting, and flatulence. The severity usually diminishes with time, and only approximately 6% of individuals are ultimately unable to tolerate metformin. GI symptoms are less frequent with an extended-release preparation.

CLINICAL PROBLEMS

Insulin

Symptoms of hypoglycemia

Visual disturbances

Peripheral edema

Local or systemic allergic reactions

Sulfonylureas

Symptoms of hypoglycemia

Gastrointestinal disturbances

Hematological disturbances

Ethanol intolerance

Meglitinides

Blood levels markedly affected by drugs altering cytochromes P450

Incretin Analogs (Exenatide)

Nausea (~30%)

Hypoglycemia

Development of anti-exenatide antibodies

May affect rate of absorption of orally administered drugs

Dipeptidyl Peptidase-IV Inhibitors (Sitagliptin)

Nausea

Hypoglycemia

Rashes

Hypersensitivity reactions including anaphylaxis and Stevens-Johnson syndrome

Metformin

Lactic acidosis (in patients with impaired renal function)

Gastrointestinal problems

Thiazolidinediones

Potential increased incidence of cardiovascular events

Edema

Weight gain, abdominal fat

α-Glucosidase Inhibitors

Abdominal pain

Diarrhea

Flatulence

Malabsorption of carbohydrate, Ca++, iron, thyroid hormone, and some hydrophobic drugs and vitamins

Pramlintide

Nausea

Vomiting

Headache

Potentiation of insulin-induced hypoglycemia when coadministered

Phenformin, a biguanide related to metformin, was withdrawn from the market when it was demonstrated that the drug had serious side effects, including lactic acidosis, which resulted in death in approximately half of the cases. Metformin has also been linked to lactic acidosis, although the incidence is very low. Those at highest risk appear to be elderly diabetic patients with impaired renal function. Thus metformin is indicated for use only in patients having normal renal function, and renal function should be monitored frequently in elderly patients. Excessive consumption of ethanol is contraindicated, because ethanol potentiates effects of metformin on lactate metabolism.

Thiazolidinediones

The most serious effects that have been associated with both rosiglitazone and pioglitazone are those affecting the cardiovascular system. Although there are conflicting results on whether these compounds increase the risk of chest pain, heart attacks, and heart-related deaths, in mid-2007 the United States Food and Drug Administration added a “Black Box” warning for both these agents, indicating that they may worsen heart failure. Subsequently, an upgraded warning was issued for rosiglitazone, indicating that it may be “associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction.” However, results to date remain inconclusive on this issue.

Rosiglitazone and pioglitazone also lead to weight gain by most patients. As PPAR-γ agonists, thiazolidinediones increase adipocyte proliferation and insulin sensitivity, thereby enhancing accumulation of triglycerides. Thiazolidinediones also cause fluid retention, which contributes to the increase in body weight. Edema can complicate therapy with antihypertensives and diuretics. No evidence of hepatotoxicity has been obtained in clinical studies with rosiglitazone and pioglitazone. Nevertheless, troglitazone, a structurally related compound, has been associated with idiosyncratic hepatotoxicity. Therefore liver enzymes should be monitored before treatment and periodically during therapy.

α-Glucosidase Inhibitors

Acarbose and miglitol disrupt the normal metabolism of complex carbohydrates in the GI tract, and side effects relating to carbohydrate malabsorption may be as high as 70%. The incidence and severity of side effects, which include abdominal pain, diarrhea, and flatulence, generally diminish with continued treatment. Nevertheless, α-glucosidase inhibitors are contraindicated

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are many of the important compounds available in the United States.)

Insulin

Rapid Acting

Lispro insulin (Humalog)

Aspart insulin (NovoLog)

Glulisine insulin (Apidra)

Short-Acting

Regular human insulin (Humulin R, Novolin R, Velosulin)

Regular porcine insulin (Iletin II regular)

Intermediate Acting

Human Lente insulin (Humulin-L, Novolin L)

NPH human insulin (Humulin NPH, Novolin N)

NPH porcine insulin (Iletin II NPH)

Long-acting

Ultralente human insulin (Humulin-U)

Glargine human insulin (Lantus)

Insulin Detemir (Levemir)

Combinations

Mixture 50% NPH insulin, 50% regular insulin (Humulin 50/50)

Mixture of 75% lispro insulin protamine suspension and 25% lispro insulin (Humalog Mix 75/25)

Mixture of 70% insulin aspart protamine suspension and 30% insulin aspart (NovoLog Mix 70/30)

Dipeptidyl Peptidase-IV Inhibitors

Sitagliptin (Januvia)

Incretin Analogs

Exenatide (Byetta)

Sulfonylureas

Chlorpropamide (Diabinese)

Acetohexamide (Dymelor)

Glimepiride (Amaryl)

Glipizide (Glucotrol)

Glyburide (Micronase, DiaBeta)

Tolazamide (Tolinase)

Tolbutamide (Orinase)

Meglitinides

Repaglinide (Prandin)

Nateglinide (Starlix)

Biguanides

Metformin (Glucophage)

Metformin extended-release (Glucophage XR)

Thiazolidinediones

Rosiglitazone (Avandia)

Pioglitazone (Actos)

α-Glucosidase Inhibitors

Acarbose (Precose)

Miglitol (Glyset)

Modified Amylin Peptide

Pramlintide (Symlin)

Drug Combinations Containing Metformin

Rosiglitazone plus metformin (Avandamet)

Glyburide plus metformin (Glucovance)

Glipizide plus metformin (Metaglip)

in inflammatory bowel disease, colonic ulceration, partial intestinal obstruction, or any other intestinal disease or condition that could be exacerbated by the increased formation of gas in the intestine.

Pramlintide

Adverse effects associated with pramlintide, when coadministered with insulin, involve primarily the GI system. In addition, although pramlintide alone does not decrease blood glucose levels, if it is coadministered with insulin, it can increase the incidence of hypoglycemic episodes, requiring a 50% reduction of the preprandial dose of short-acting insulin. Because pramlintide delays gastric emptying, it should not be used for patients who are taking other drugs that alter GI motility such as anticholinergics.

New Horizons

Recent advances in the management of diabetes mellitus have been remarkable, suggesting that future treatment will improve greatly. In the area of insulin replacement, the use of a solution of modified forms of human insulin having a rapid onset and short duration of action or possessing a delayed onset and long duration of action with a flat insulin activity peak has proven to be very effective. Specifically, combination therapy with these agents more closely mimics the rapid, short-duration insulin release, which normally occurs in response to a carbohydrate challenge, and a low constant sustained level. Further, this type of combination therapy reduces the incidence of treatment-induced hypoglycemia, which can occur during combination therapy when the hypoglycemic effects of the coadministered insulins overlap. In addition, successful attempts to transplant pancreatic islet cells suggest that this will become a viable treatment option once the side effects of immunosuppression can be minimized. Identification of markers to identify and prevent type 1 diabetes is being actively investigated.

The management of patients during the early onset of type 2 diabetes mellitus can be characterized by an initial period of elevated insulin secretion, which eventually wanes. Chronic stimulation of insulin secretion is provoked by hyperglycemia arising from insulin resistance, which causes insulin levels to accumulate ultimately leading to hypoglycemic incidents. Eventually, the stress of chronic stimulation of insulin secretion leads to a decreasing ability to secrete insulin resulting in sustained hyperglycemia that requires pharmacological treatment. Initially, the management of hypoglycemia would involve appropriate glucose supplementation and/or α-glucosidase inhibitors with meals to reduce dietary glucose challange. During the loss of insulin secretion, the patient can be managed by pharmacological stimulation of pancreatic insulin secretion and/or reduction of insulin resistance. Ultimately, insulin supplementation will be required to satisfactorily manage hyperglycemia.

Insulin resistance in type 2 diabetes is related chiefly (70% to 80%), but not exclusively, with defects in nonoxidative glucose disposal. Genetic links to subsets of type 2 diabetes include mutations of the insulin receptor, glucokinase, and mitochondrial genes, although these mutations account for a small percentage of the total cases of type 2 diabetes.

The mechanisms underlying the relationship between obesity and insulin resistance (metabolic syndrome) are complex. Obesity, increased appetite, and insulin sensitivity appear associated. Although not well appreciated, increased insulin receptors may be related to the balance of satiety signaling factors such as those released from the epithelial cells of the stomach lining (e.g., ghrelin), which increase feeding behaviors, and those released from adipose tissue (e.g., leptin and adiponectin).

FURTHER READING

Abramowicz M, Zuccotti G. Drugs for Type 2 Diabetes. Treat Guidel Med Lett. 2008;6:47-54.

Anonymous. Thiazolidinediones and cardiovascular disease. Med Lett. 2007;49:57-60.

Charpentier G. Oral combination therapy for type 2 diabetes. Diabetes Metab Res Rev. 2002;(Suppl 3):S70-S76.

McMahon GT, Arky RA. Inhaled insulin. N Engl J Med. 2007;356:497-502.

Nathan DM. New treatments for diabetes. N Engl J Med. 2007;356:437-440.

SELF-ASSESSMENT QUESTIONS

1. Which of the following BEST explains why the coadministration of ultrafast-acting and extended-acting human insulin reduces the incidence of insulin-induced hypoglycemia?

A. Extended-acting insulin does not exhibit a peak of biological activity, which reduces its ability to be additive with the hypoglycemic effect of the fast-acting forms.

B. Because the ultrafast insulin is much more rapidly absorbed than the extended-acting from the site of injection, there is little coincidence of their cellular effects that precipitates hypoglycemia.

C. The longer duration of activity of the extended-acting insulin allows the use of low dosages, which reduces its ability to increase the incidence of hypoglycemia.

D. The physiological effects produced by the low levels of the extended-acting insulin are inadequate to act synergistically with the ultrafast insulin.

E. The overlap of their maximum biological activities is minimal.

2. An unconscious patient wearing a diabetes alert bracelet is admitted to the ER. Blood sugar as measured with a glucometer was found to be very high, and the patient has skin tugor suggestive of dehydration. Before the receipt of stat laboratory results and in addition to intravenous administration of rapid-acting insulin, which of the following is most likely to be immediately administered?

A. Bicarbonate (HCO3) solution

B. Dextrose solution (5%)

C. Hypotonic saline

D. Isotonic saline

E. K+ solution

3. If the patient described in the previous question has the same presentation but his blood sugar is found to be low, which of the following is most likely to be immediately administered?

A. HCO3 solution

B. Dextrose solution (5%)

C. Hypotonic saline

D. Isotonic saline

E. K+ solution

4. A 55-year-old menopausal woman was recently diagnosed with type 2 diabetes based on her fasting blood glucose values. Her HbA1c levels average < 7% so that diet, exercise, and a single drug (monotherapy) may be sufficient to regulate her fasting glucose levels. Which of the following should be prescribed?

A. Acarbose

B. Tolbutamide

C. Short-acting insulin

D. Metformin

E. Glyburide

5. Which of the following medications, when taken prior to eating, is especially effective for correcting postprandial hyperglycemia after a high-carbohydrate meal, so that hypoglycemia postdosing is minimized?

A. Acarbose

B. Tolbutamide

C. Tolazamide

D. Glyburide

E. Glitazone