Ganong’s Review of Medical Physiology, 24th Edition

CHAPTER 24 Endocrine Functions of the Pancreas & Regulation of Carbohydrate Metabolism


After reading this chapter, you should be able to:

image List the hormones that affect the plasma glucose concentration and briefly describe the action of each.

image Describe the structure of the pancreatic islets and name the hormones secreted by each of the cell types in the islets.

image Describe the structure of insulin and outline the steps involved in its biosynthesis and release into the bloodstream.

image List the consequences of insulin deficiency and explain how each of these abnormalities is produced.

image Describe insulin receptors, the way they mediate the effects of insulin, and the way they are regulated.

image Describe the types of glucose transporters found in the body and the function of each.

image List the major factors that affect the secretion of insulin.

image Describe the structure of glucagon and other physiologically active peptides produced from its precursor.

image List the physiologically significant effects of glucagon and the factors that regulate glucagon secretion.

image Describe the physiologic effects of somatostatin in the pancreas.

image Outline the mechanisms by which thyroid hormones, adrenal glucocorticoids, catecholamines, and growth hormone affect carbohydrate metabolism.

image Understand the major differences between type 1 and type 2 diabetes.


At least four polypeptides with regulatory activity are secreted by the islets of Langerhans in the pancreas. Two of these, insulin and glucagon, are hormones and have important functions in the regulation of the intermediary metabolism of carbohydrates, proteins, and fats. The third polypeptide, somatostatin, plays a role in the regulation of islet cell secretion, and the fourth, pancreatic polypeptide, is probably concerned primarily with the regulation of ion transport in the intestine. Glucagon, somatostatin, and possibly pancreatic polypeptide are also secreted by cells in the mucosa of the gastrointestinal tract.

Insulin is anabolic, increasing the storage of glucose, fatty acids, and amino acids. Glucagon is catabolic, mobilizing glucose, fatty acids, and the amino acids from stores into the bloodstream. The two hormones are thus reciprocal in their overall action and are reciprocally secreted in most circumstances. Insulin excess causes hypoglycemia, which leads to convulsions and coma. Insulin deficiency, either absolute or relative, causes diabetes mellitus (chronic elevated blood glucose), a complex and debilitating disease that if untreated is eventually fatal. Glucagon deficiency can cause hypoglycemia, and glucagon excess makes diabetes worse. Excess pancreatic production of somatostatin causes hyperglycemia and other manifestations of diabetes.

A variety of other hormones also have important roles in the regulation of carbohydrate metabolism.


The islets of Langerhans (Figure 24–1) are ovoid, 76- × 175-μm collections of cells. The islets are scattered throughout the pancreas, although they are more plentiful in the tail than in the body and head. β-islets make up about 2% of the volume of the gland, whereas the exocrine portion of the pancreas (see Chapter 25) makes up 80%, and ducts and blood vessels make up the remainder. Humans have 1 to 2 million islets. Each has a copious blood supply; blood from the islets, like that from the gastrointestinal tract (but unlike that from any other endocrine organs) drains into the hepatic portal vein.


FIGURE 24–1 Islet of Langerhans in the rat pancreas. Darkly stained cells are B cells. Surrounding pancreatic acinar tissue is light-colored (× 400). (Courtesy of LL Bennett.)

The cells in the islets can be divided into types on the basis of their staining properties and morphology. Humans have at least four distinct cell types: A, B, D, and F cells. A, B, and D cells are also called α, β, and δ cells. However, this leads to confusion in view of the use of Greek letters to refer to other structures in the body, particularly adrenergic receptors (see Chapter 7). The A cells secrete glucagon, the B cells secrete insulin, the D cells secrete somatostatin, and the F cells secrete pancreatic polypeptide. The B cells, which are the most common and account for 60–75% of the cells in the islets, are generally located in the center of each islet. They tend to be surrounded by the A cells, which make up 20% of the total, and the less common D and F cells. The islets in the tail, the body, and the anterior and superior part of the head of the human pancreas have many A cells and few if any F cells in the outer rim, whereas in rats and probably in humans, the islets in the posterior part of the head of the pancreas have a relatively large number of F cells and few A cells. The A-cell-rich (glucagon-rich) islets arise embryologically from the dorsal pancreatic bud, and the F-cell-rich (pancreatic polypeptide-rich) islets arise from the ventral pancreatic bud. These buds arise separately from the duodenum.

The B cell granules are packets of insulin in the cell cytoplasm. The shape of the packets varies from species to species; in humans, some are round whereas others are rectangular (Figure 24–2). In the B cells, the insulin molecule forms polymers and also complexes with zinc. The differences in the shape of the packets are probably due to differences in the size of polymers or zinc aggregates of insulin. The A granules, which contain glucagon, are relatively uniform from species to species (Figure 24–3). The D cells also contain large numbers of relatively homogeneous granules.


FIGURE 24–2 Electronmicrograph of two adjoining B cells in a human pancreatic islet. The B granules are the crystals in the membrane-lined vesicles. They vary in shape from rhombic to round (× 26,000). (Courtesy of A Like. Reproduced, with permission, from Fawcett DW: Bloom and Fawcett, A Textbook of Histology, 11th ed. Saunders, 1986.)


FIGURE 24–3 A and B cells, showing their relation to a blood vessel. RER, rough endoplasmic reticulum. Insulin from the B cell and glucagon from the A cell are secreted by exocytosis and cross the basal lamina of the cell and the basal lamina of the capillary before entering the lumen of the fenestrated capillary. (Reproduced with permission from Junqueira IC, Carneiro J: Basic Histology: Text and Atlas, 10th ed. McGraw-Hill, 2003.)



Insulin is a polypeptide containing two chains of amino acids linked by disulfide bridges Minor differences occur in the amino acid composition of the molecule from species to species. The differences are generally not sufficient to affect the biologic activity of a particular insulin in heterologous species but are sufficient to make the insulin antigenic. If insulin of one species is injected for a prolonged period into another species, the anti-insulin antibodies formed inhibit the injected insulin. Almost all humans who have received commercial bovine insulin for more than 2 months have antibodies against bovine insulin, but the titer is usually low. Porcine insulin differs from human insulin by only one amino acid residue and has low antigenicity. Human insulin produced in bacteria by recombinant DNA technology is now widely used to avoid antibody formation.


Insulin is synthesized in the rough endoplasmic reticulum of the B cells (Figure 24–3). It is then transported to the Golgi apparatus, where it is packaged into membrane-bound granules. These granules move to the plasma membrane by a process involving microtubules, and their contents are expelled by exocytosis (see Chapters 2 and 16). The insulin then crosses the basal lamina of the B cell and a neighboring capillary and the fenestrated endothelium of the capillary to reach the bloodstream. The fenestrations are discussed in detail in Chapter 31.

Like other polypeptide hormones and related proteins that enter the endoplasmic reticulum, insulin is synthesized as part of a larger preprohormone (see Chapter 1). The gene for insulin is located on the short arm of chromosome 11 in humans. It has two introns and three exons. Preproinsulin originates from the endoplasmic reticulum. The remainder of the molecule is then folded, and the disulfide bonds are formed to make proinsulin. The peptide segment connecting the A and B chains, the connecting peptide (C peptide), facilitates the folding and then is detached in the granules before secretion. Two proteases are involved in processing the proinsulin. Normally, 90–97% of the product released from the B cells is insulin along with equimolar amounts of C peptide. The rest is mostly proinsulin. C peptide can be measured by radioimmunoassay, and its level in blood provides an index of B cell function in patients receiving exogenous insulin.



Plasma contains a number of substances with insulin-like activity in addition to insulin. The activity that is not suppressed by anti-insulin antibodies has been called non-suppressible insulin-like activity (NSILA). Most, if not all, of this activity persists after pancreatectomy and is due to the insulin-like growth factors IGF-I and IGF-II (see Chapter 18). These IGFs are polypeptides. Small amounts are free in the plasma (low-molecular-weight fraction), but large amounts are bound to proteins (high-molecular-weight fraction).

One may well ask why pancreatectomy causes diabetes mellitus when NSILA persists in the plasma. However, the insulin-like activities of IGF-I and IGF-II are weak compared to that of insulin and likely subserve other specific functions.


The half-life of insulin in the circulation in humans is about 5 min. Insulin binds to insulin receptors, and some is internalized. It is destroyed by proteases in the endosomes formed by the endocytotic process.


The physiologic effects of insulin are far-reaching and complex. They are conveniently divided into rapid, intermediate, and delayed actions, as listed in Table 24–1. The best known is the hypoglycemic effect, but there are additional effects on amino acid and electrolyte transport, many enzymes, and growth. The net effect of the hormone is storage of carbohydrate, protein, and fat. Therefore, insulin is appropriately called the “hormone of abundance.”


TABLE 24–1 Principal actions of insulin.

The actions of insulin on adipose tissue; skeletal, cardiac, and smooth muscle; and the liver are summarized in Table 24–2.


TABLE 24–2 Effects of insulin on various tissues.


Glucose enters cells by facilitated diffusion (see Chapter 1) or, in the intestine and kidneys, by secondary active transport with Na+. In muscle, adipose, and some other tissues, insulin stimulates glucose entry into cells by increasing the number of glucose transporters (GLUTs) in the cell membranes.

The GLUTs that are responsible for facilitated diffusion of glucose across cell membranes are a family of closely related proteins that span the cell membrane 12 times and have their amino and carboxyl terminals inside the cell. They differ from and have no homology with the sodium-dependent glucose transporters, SGLT 1 and SGLT 2, responsible for the secondary active transport of glucose in the intestine (see Chapter 26) and renal tubules (see Chapter 38), although the SGLTs also have 12 transmembrane domains.

Seven different GLUTs, named GLUT 1–7 in order of discovery, have been characterized (Table 24–3). They contain 492–524 amino acid residues and their affinity for glucose varies. Each transporter appears to have evolved for special tasks. GLUT 4 is the transporter in muscle and adipose tissue that is stimulated by insulin. A pool of GLUT 4 molecules is maintained within vesicles in the cytoplasm of insulin-sensitive cells. When the insulin receptors of these cells are activated, the vesicles move rapidly to the cell membrane and fuse with it, inserting the transporters into the cell membrane (Figure 24–4). When insulin action ceases, the transporter-containing patches of membrane are endocytosed and the vesicles are ready for the next exposure to insulin. Activation of the insulin receptor brings about the movement of the vesicles to the cell membrane by activating phosphatidylinositol 3-kinase (Figure 24–4). Most of the other GLUT transporters that are not insulin-sensitive appear to be constitutively expressed in the cell membrane.


TABLE 24–3 Glucose transporters in mammals.


FIGURE 24–4 Cycling of GLUT 4 transporters through endosomes in insulin-sensitive tissues. Activation of the insulin receptor causes activation of phosphatidylinositol 3-kinase, which speeds translocation of the GLUT 4-containing endosomes into the cell membrane. The GLUT 4 transporters then mediate glucose transport into the cell.

In the tissues in which insulin increases the number of GLUTs in cell membranes, the rate of phosphorylation of the glucose, once it has entered the cells, is regulated by other hormones. Growth hormone and cortisol both inhibit phosphorylation in certain tissues. Transport is normally so rapid that it is not a rate-limiting step in glucose metabolism. However, it is rate-limiting in B cells.

Insulin also increases the entry of glucose into liver cells, but it does not exert this effect by increasing the number of GLUT 4 transporters in the cell membranes. Instead, it induces glucokinase, and this increases the phosphorylation of glucose, so that the intracellular free glucose concentration stays low, facilitating the entry of glucose into the cell.

Insulin-sensitive tissues also contain a population of GLUT 4 vesicles that move into the cell membrane in response to exercise, a process that occurs independent of the action of insulin. This is why exercise lowers blood sugar. A 5’-AMP-activated kinase may tigger the insertion of these vesicles into the cell membrane.


The maximal decline in plasma glucose occurs 30 min after intravenous injection of insulin. After subcutaneous administration, the maximal fall occurs in 2–3 h. A wide variety of insulin preparations are now available commercially. These include insulins that have been complexed with protamine and other polypeptides to delay absorption and degradation, and synthetic insulins in which there have been changes in amino acid residues. In general, they fall into three categories: rapid, intermediate-acting, and long-acting (24–36 h).


Insulin causes K+ to enter cells, with a resultant lowering of the extracellular K+ concentration. Infusions of insulin and glucose significantly lower the plasma K+ level in normal individuals and are very effective for the temporary relief of hyperkalemia in patients with renal failure. Hypokalemia often develops when patients with diabetic acidosis are treated with insulin. The reason for the intracellular migration of K+ is still uncertain. However, insulin increases the activity of Na, K ATPase in cell membranes, so that more K+ is pumped into cells.


The hypoglycemic and other effects of insulin are summarized in temporal terms in Table 24–1, and the net effects on various tissues are summarized in Table 24–2. The action on glycogen synthase fosters glycogen storage, and the actions on glycolytic enzymes favor glucose metabolism to two carbon fragments (see Chapter 1), with resulting promotion of lipogenesis. Stimulation of protein synthesis from amino acids entering the cells and inhibition of protein degradation foster growth.

The anabolic effect of insulin is aided by the protein-sparing action of adequate intracellular glucose supplies. Failure to grow is a symptom of diabetes in children, and insulin stimulates the growth of immature hypophysectomized rats to almost the same degree as growth hormone.



Insulin receptors are found on many different cells in the body, including cells in which insulin does not increase glucose uptake.

The insulin receptor, which has a molecular weight of approximately 340,000, is a tetramer made up of two α and two β glycoprotein subunits (Figure 24–5). All these are synthesized on a single mRNA and then proteolytically separated and bound to each other by disulfide bonds. The gene for the insulin receptor has 22 exons and in humans is located on chromosome 19. The α subunits bind insulin and are extracellular, whereas the β subunits span the membrane. The intracellular portions of the β subunits have tyrosine kinase activity. The α and β subunits are both glycosylated, with sugar residues extending into the interstitial fluid.


FIGURE 24–5 Insulin, IGF-I, and IGF-II receptors. Each hormone binds primarily to its own receptor, but insulin also binds to the IGF-I receptor, and IGF-I and IGF-II bind to all three. The purple boxes are intracellular tyrosine kinase domains. Note the marked similarity between the insulin receptor and the IGF-I receptor; also note the 15 repeat sequences in the extracellular portion of the IGF-II receptor. ISF, interstitial fluid.

Binding of insulin triggers the tyrosine kinase activity of the β subunits, producing autophosphorylation of the β subunits on tyrosine residues. The autophosphorylation, which is necessary for insulin to exert its biologic effects, triggers phosphorylation of some cytoplasmic proteins and dephosphorylation of others, mostly on serine and threonine residues. Insulin receptor substrate (IRS-1) mediates some of the effects in humans but there are other effector systems as well (Figure 24–6). For example, mice in which the insulin receptor gene is knocked out show marked growth retardation in utero, have abnormalities of the central nervous system (CNS) and skin, and die at birth of respiratory failure, whereas IRS-1 knockouts show only moderate growth retardation in utero, survive, and are insulin-resistant but otherwise nearly normal.


FIGURE 24–6 Intracellular responses triggered by insulin binding to the insulin receptor. Red circles and circles labeled P represent phosphate groups. IRS-1, insulin receptor substrate-1.

The growth-promoting protein anabolic effects of insulin are mediated via phosphatidylinositol 3-kinase (PI3K), and evidence indicates that in invertebrates, this pathway is involved in the growth of nerve cells and axon guidance in the visual system.

It is interesting to compare the insulin receptor with other related receptors. The insulin receptor is very similar to the receptor for IGF-I but different from the receptor for IGF-II (Figure 24–5). Other receptors for growth factors and receptors for various oncogenes also are tyrosine kinases. However, the amino acid composition of these receptors is quite different.

When insulin binds to its receptors, they aggregate in patches and are taken up into the cell by receptor-mediated endocytosis (see Chapter 2). Eventually, the insulin–receptor complexes enter lysosomes, where the receptors are broken down or recycled. The half-life of the insulin receptor is about 7 h.


The far-reaching physiologic effects of insulin are highlighted by a consideration of the extensive and serious consequences of insulin deficiency (Clinical Box 24–1).


Diabetes Mellitus

The constellation of abnormalities caused by insulin deficiency is called diabetes mellitus. Greek and Roman physicians used the term “diabetes” to refer to conditions in which the cardinal finding was a large urine volume, and two types were distinguished: “diabetes mellitus,” in which the urine tasted sweet; and “diabetes insipidus,” in which the urine had little taste. Today, the term “diabetes insipidus” is reserved for conditions in which there is a deficiency of the production or action of vasopressin (see Chapter 38), and the unmodified word “diabetes” is generally used as a synonym for diabetes mellitus.

The cause of clinical diabetes is always a deficiency of the effects of insulin at the tissue level. Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), is due to insulin deficiency caused by autoimmune destruction of the B cells in the pancreatic islets, and it accounts for 3–5% of cases and usually presents in children. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), is characterized by the dysregulation of insulin release from the B cells, along with insulin resistance in peripheral tissues such as skeletal muscle, brain, and liver. Type 2 diabetes historically presented in overweight or obese adults, although it is increasingly being diagnosed in children as childhood obesity increases.

Diabetes is characterized by polyuria (passage of large volumes of urine), polydipsia (excessive drinking), weight loss in spite of polyphagia (increased appetite), hyperglycemia, glycosuria, ketosis, acidosis, and coma. Widespread biochemical abnormalities are present, but the fundamental defects to which most of the abnormalities can be traced are (1) reduced entry of glucose into various “peripheral” tissues and (2) increased liberation of glucose into the circulation from the liver. Therefore there is an extracellular glucose excess and, in many cells, an intracellular glucose deficiency—a situation that has been called “starvation in the midst of plenty.” Also, the entry of amino acids into muscle is decreased and lipolysis is increased.


In type 1 diabetes, the mainstay of therapy is provision of exogenous insulin, carefully titrated to dietary intake of glucose. In type 2 diabetes, lifestyle changes such as alterations in the diet or increased exercise can often delay symptoms in early disease, but these are difficult to secure. Insulin-sensitizing drugs represent second-line agents (see Chapter 16).

In humans, insulin deficiency is a common pathologic condition. In animals, it can be produced by pancreatectomy; by administration of alloxan, streptozocin, or other toxins that in appropriate doses cause selective destruction of the B cells of the pancreatic islets; by administration of drugs that inhibit insulin secretion; and by administration of anti-insulin antibodies. Strains of mice, rats, hamsters, guinea pigs, miniature swine, and monkeys that have a high incidence of spontaneous diabetes mellitus have also been described.


In diabetes, glucose piles up in the bloodstream, especially after meals. If a glucose load is given to a diabetic, the plasma glucose rises higher and returns to the baseline more slowly than it does in normal individuals. The response to a standard oral test dose of glucose, the oral glucose tolerance test, is used in the clinical diagnosis of diabetes (Figure 24–7).


FIGURE 24–7 Oral glucose tolerance test. Adults are given 75 g of glucose in 300 mL of water. In normal individuals, the fasting venous plasma glucose is less than 115 mg/dL, the 2-hour value is less than 140 mg/dL, and no value is greater than 200 mg/dL. Diabetes mellitus is present if the 2-hour value and one other value are greater than 200 mg/dL. Impaired glucose tolerance is diagnosed when the values are above the upper limits of normal but below the values diagnostic of diabetes.

Impaired glucose tolerance in diabetes is due in part to reduced entry of glucose into cells (decreased peripheral utilization). In the absence of insulin, the entry of glucose into skeletal, cardiac, and smooth muscle and other tissues is decreased (Figure 24–8). Glucose uptake by the liver is also reduced, but the effect is indirect. Intestinal absorption of glucose is unaffected, as is its reabsorption from the urine by the cells of the proximal tubules of the kidneys. Glucose uptake by most of the brain and the red blood cells is also normal.


FIGURE 24–8 Disordered plasma glucose homeostasis in insulin deficiency. The heavy arrows indicate reactions that are accentuated. The rectangles across arrows indicate reactions that are blocked.

The second and the major cause of hyperglycemia in diabetes is derangement of the glucostatic function of the liver (see Chapter 28). The liver takes up glucose from the bloodstream and stores it as glycogen, but because the liver contains glucose 6-phosphatase it also discharges glucose into the bloodstream. Insulin facilitates glycogen synthesis and inhibits hepatic glucose output. When the plasma glucose is high, insulin secretion is normally increased and hepatic glucogenesis is decreased. This response does not occur in type 1 diabetes (as insulin is absent) and in type 2 diabetes (as tissues are insulin-resistant). Glucagon can contribute to hyperglycemia as it stimulates gluconeogenesis. Glucose output by the liver can be stimulated by catecholamines, cortisol, and growth hormone (ie, during a stress response).


Hyperglycemia by itself can cause symptoms resulting from the hyperosmolality of the blood. In addition, there is glycosuria because the renal capacity for glucose reabsorption is exceeded. Excretion of the osmotically active glucose molecules entails the loss of large amounts of water (osmotic diuresis; see Chapter 38). The resultant dehydration activates the mechanisms regulating water intake, leading to polydipsia. There is an appreciable urinary loss of Na+ and K+ as well. For every gram of glucose excreted, 4.1 kcal is lost from the body. Increasing the oral caloric intake to cover this loss simply raises the plasma glucose further and increases the glycosuria, so mobilization of endogenous protein and fat stores and weight loss are not prevented.

When plasma glucose is episodically elevated over time, small amounts of hemoglobin A are nonenzymatically glycated to form HbAIc (see Chapter 31). Careful control of the diabetes with insulin reduces the amount formed and consequently HbAIc concentration is measured clinically as an integrated index of diabetic control for the 4- to 6-weeks period before the measurement.

The role of chronic hyperglycemia in production of the long-term complications of diabetes is discussed below.


The abundance of glucose outside the cells in diabetes contrasts with the intracellular deficit. Glucose catabolism is normally a major source of energy for cellular processes, and in diabetes energy requirements can be met only by drawing on protein and fat reserves. Mechanisms are activated that greatly increase the catabolism of protein and fat, and one of the consequences of increased fat catabolism is ketosis.

Deficient glucose utilization and deficient hormone sensing (insulin, leptin, CCK) in the cells of the hypothalamus that regulate satiety are the probable causes of hyperphagia in diabetes. The feeding area of the hypothalamus is not inhibited and thus satiety is not sensed so food intake is increased.

Glycogen depletion is a common consequence of intracellular glucose deficit, and the glycogen content of liver and skeletal muscle in diabetic animals is usually reduced.


In diabetes, the rate at which amino acids are catabolized to CO2 and H2O is increased. In addition, more amino acids are converted to glucose in the liver. The increased gluconeogenesis has many causes. Glucagon stimulates gluconeogenesis, and hyperglucagonemia is generally present in diabetes. Adrenal glucocorticoids also contribute to increased gluconeogenesis when they are elevated in severely ill diabetics. The supply of amino acids is increased for gluconeogenesis because, in the absence of insulin, less protein synthesis occurs in muscle and hence blood amino acid levels rise. Alanine is particularly easily converted to glucose. In addition, the activity of the enzymes that catalyze the conversion of pyruvate and other two-carbon metabolic fragments to glucose is increased. These include phosphoenolpyruvate carboxykinase, which facilitates the conversion of oxaloacetate to phosphoenolpyruvate (see Chapter 1). They also include fructose 1,6-diphosphatase, which catalyzes the conversion of fructose diphosphate to fructose 6-phosphate, and glucose 6-phosphatase, which controls the entry of glucose into the circulation from the liver. Increased acetyl-CoA increases pyruvate carboxylase activity, and insulin deficiency increases the supply of acetyl-CoA because lipogenesis is decreased. Pyruvate carboxylase catalyzes the conversion of pyruvate to oxaloacetate (see Figure 1–22).

In diabetes, the net effect of accelerated protein conversion to CO2, H2O, and glucose, plus diminished protein synthesis, is protein depletion and wasting. Protein depletion from any cause is associated with poor “resistance” to infections.


The principal abnormalities of fat metabolism in diabetes are acceleration of lipid catabolism, with increased formation of ketone bodies, and decreased synthesis of fatty acids and triglycerides. The manifestations of the disordered lipid metabolism are so prominent that diabetes has been called “more a disease of lipid than of carbohydrate metabolism.”

Fifty per cent of an ingested glucose load is normally burned to CO2 and H2O; 5% is converted to glycogen; and 30–40% is converted to fat in the fat depots. In diabetes, less than 5% of ingested glucose is converted to fat, despite a decrease in the amount burned to CO2 and H2O, and no change in the amount converted to glycogen. Therefore, glucose accumulates in the bloodstream and spills over into the urine.

The role of lipoprotein lipase and hormone-sensitive lipase in the regulation of the metabolism of fat depots is discussed in Chapter 1. In diabetes, conversion of glucose to fatty acids in the depots is decreased because of the intracellular glucose deficiency. Insulin inhibits the hormone-sensitive lipase in adipose tissue, and, in the absence of this hormone, the plasma level of free fatty acids (NEFA, UFA, FFA) is more than doubled. The increased glucagon also contributes to the mobilization of FFA. Thus, the FFA level parallels the plasma glucose level in diabetes and in some ways is a better indicator of the severity of the diabetic state. In the liver and other tissues, the fatty acids are catabolized to acetyl-CoA. Some of the acetyl-CoA is burned along with amino acid residues to yield CO2 and H2O in the citric acid cycle. However, the supply exceeds the capacity of the tissues to catabolize the acetyl-CoA.

In addition to the previously mentioned increase in gluconeogenesis and marked outpouring of glucose into the circulation, the conversion of acetyl-CoA to malonyl-CoA and thence to fatty acids is markedly impaired. This is due to a deficiency of acetyl-CoA carboxylase, the enzyme that catalyzes the conversion. The excess acetyl-CoA is converted to ketone bodies (Clinical Box 24–2).



When excess acetyl-CoA is present in the body, some of it is converted to acetoacetyl-CoA and then, in the liver, to acetoacetate. Acetoacetate and its derivatives, acetone and β–hydroxybutyrate, enter the circulation in large quantities (see Chapter 1).

These circulating ketone bodies are an important source of energy in fasting. Half of the metabolic rate in fasted normal dogs is said to be due to metabolism of ketones. The rate of ketone utilization in diabetics is also appreciable. It has been calculated that the maximal rate at which fat can be catabolized without significant ketosis is 2.5 g/kg body weight/d in diabetic humans. In untreated diabetes, production is much greater than this, and ketone bodies pile up in the bloodstream.

In uncontrolled diabetes, the plasma concentration of triglycerides and chylomicrons as well as FFA is increased, and the plasma is often lipemic. The rise in these constituents is mainly due to decreased removal of triglycerides into the fat depots. The decreased activity of lipoprotein lipase contributes to this decreased removal.


As noted in Chapter 1, acetoacetate and β-hydroxybutyrate are anions of the fairly strong acids acetoacetic acid and β-hydroxybutyric acids. The hydrogen ions from these acids are buffered, but the buffering capacity is soon exceeded if production is increased. The resulting acidosis stimulates respiration, producing the rapid, deep respiration described by Kussmaul as “air hunger” and named (for him) Kussmaul breathing. The urine becomes acidic. However, when the ability of the kidneys to replace the plasma cations accompanying the organic anions with H+ and NH4+ is exceeded, Na+ and K+ are lost in the urine. The electrolyte and water losses lead to dehydration, hypovolemia, and hypotension. Finally, the acidosis and dehydration depress consciousness to the point of coma. Diabetic acidosis is a medical emergency. Now that the infections that used to complicate the disease can be controlled with antibiotics, acidosis is the most common cause of early death in clinical diabetes.

In severe acidosis, total body Na+ is markedly depleted, and when Na+ loss exceeds water loss, plasma Na+ may also be low. Total body K+ is also low, but the plasma K+ is usually normal, partly because extracellular fluid (ECF) volume is reduced and partly because K+ moves from cells to ECF when the ECF H+ concentration is high. Another factor tending to maintain the plasma K+ is the lack of insulin-induced entry of K+ into cells.


Coma in diabetes can be due to acidosis and dehydration. However, the plasma glucose can be elevated to such a degree that independent of plasma pH, the hyperosmolarity of the plasma causes unconsciousness (hyperosmolar coma). Accumulation of lactate in the blood (lactic acidosis) may also complicate diabetic ketoacidosis if the tissues become hypoxic, and lactic acidosis may itself cause coma. Brain edema occurs in about 1% of children with ketoacidosis, and it can cause coma. Its cause is unsettled, but it is a serious complication, with a mortality rate of about 25%.


In diabetes, the plasma cholesterol level is usually elevated and this plays a role in the accelerated development of the atherosclerotic vascular disease that is a major long-term complication of diabetes in humans. The rise in plasma cholesterol level is due to an increase in the plasma concentration of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) (see Chapter 1). These in turn may be due to increased hepatic production of VLDL or decreased removal of VLDL and LDL from the circulation.


Because of the complexities of the metabolic abnormalities in diabetes, a summary is in order. One of the key features of insulin deficiency (Figure 24–9) is decreased entry of glucose into many tissues (decreased peripheral utilization). Also, the net release of glucose from the liver is increased (increased production), due in part to glucagon excess. The resultant hyperglycemia leads to glycosuria and a dehydrating osmotic diuresis. Dehydration leads to polydipsia. In the face of intracellular glucose deficiency, appetite is stimulated, glucose is formed from protein (gluconeogenesis), and energy supplies are maintained by metabolism of proteins and fats. Weight loss, debilitating protein deficiency, and inanition are the result.


FIGURE 24–9 Effects of insulin deficiency. (Courtesy of RJ Havel.)

Fat catabolism is increased and the system is flooded with triglycerides and FFA. Fat synthesis is inhibited and the overloaded catabolic pathways cannot handle the excess acetyl-CoA that is formed. In the liver, the acetyl-CoA is converted to ketone bodies. Two of these are organic acids, and metabolic acidosis develops as ketones accumulate. Na+ and K+ depletion is added to the acidosis because these plasma cations are excreted with the organic anions not covered by the image secreted by the kidneys. Finally, the acidotic, hypovolemic, hypotensive, depleted animal or patient becomes comatose because of the toxic effects of acidosis, dehydration, and hyperosmolarity on the nervous system and dies if treatment is not instituted.

All of these abnormalities are corrected by administration of insulin. Although emergency treatment of acidosis also includes administration of alkali to combat the acidosis and parenteral water, Na+, and K+ to replenish body stores, only insulin repairs the fundamental defects in a way that permits a return to normal.



All the known consequences of insulin excess are manifestations, directly or indirectly, of the effects of hypoglycemia on the nervous system. Except in individuals who have been fasting for some time, glucose is the only fuel used in appreciable quantities by the brain. The carbohydrate reserves in neural tissue are very limited and normal function depends on a continuous glucose supply. As the plasma glucose level falls, the first symptoms are palpitations, sweating, and nervousness due to autonomic discharge. These appear at plasma glucose values slightly lower than the value at which autonomic activation first begins, because the threshold for symptoms is slightly above the threshold for initial activation. At lower plasma glucose levels, so-called neuroglycopenic symptoms begin to appear. These include hunger as well as confusion and the other cognitive abnormalities. At even lower plasma glucose levels, lethargy, coma, convulsions, and eventually death occur. Obviously, the onset of hypoglycemic symptoms calls for prompt treatment with glucose or glucose-containing drinks such as orange juice. Although a dramatic disappearance of symptoms is the usual response, abnormalities ranging from intellectual dulling to coma may persist if the hypoglycemia was severe or prolonged.


One important compensation for hypoglycemia is cessation of the secretion of endogenous insulin. Inhibition of insulin secretion is complete at a plasma glucose level of about 80 mg/dL (Figure 24–10). In addition, hypoglycemia triggers increased secretion of at least four counter-regulatory hormones: glucagon, epinephrine, growth hormone, and cortisol. The epinephrine response is reduced during sleep. Glucagon and epinephrine increase the hepatic output of glucose by increasing glycogenolysis. Growth hormone decreases the utilization of glucose in various peripheral tissues, and cortisol has a similar action. The keys to counter-regulation appear to be epinephrine and glucagon: if the plasma concentration of either increases, the decline in the plasma glucose level is reversed; but if both fail to increase, there is little if any compensatory rise in the plasma glucose level. The actions of the other hormones are supplementary.


FIGURE 24–10 Plasma glucose levels at which various effects of hypoglycemia appear.

Note that the autonomic discharge and release of counter-regulatory hormones normally occurs at a higher plasma glucose level than the cognitive deficits and other more serious CNS changes (Figure 24–10). For diabetics treated with insulin, the symptoms caused by the autonomic discharge serve as a warning to seek glucose replacement. However, particularly in long-term diabetics who have been tightly regulated, the autonomic symptoms may not occur, and the resulting hypoglycemia unawareness can be a clinical problem of some magnitude.


The normal concentration of insulin measured by radioimmunoassay in the peripheral venous plasma of fasting normal humans is 0–70 μU/mL (0–502 pmol/L). The amount of insulin secreted in the basal state is about 1 U/h, with a fivefold to 10-fold increase following ingestion of food. Therefore, the average amount secreted per day in a normal human is about 40 U (287 nmol).

Factors that stimulate and inhibit insulin secretion are summarized in Table 24–4.


TABLE 24–4 Factors affecting insulin secretion.


It has been known for many years that glucose acts directly on pancreatic B cells to increase insulin secretion. The response to glucose is biphasic; there is a rapid but short-lived increase in secretion followed by a more slowly developing prolonged increase.

Glucose enters the B cells via GLUT 2 transporters and is phosphorylated by glucokinase then metabolized to pyruvate in the cytoplasm (Figure 24–11). The pyruvate enters the mitochondria and is metabolized to CO2 and H2O via the citric acid cycle with the formation of ATP by oxidative phosphorylation. The ATP enters the cytoplasm, where it inhibits ATP-sensitive K+ channels, reducing K+ efflux. This depolarizes the B cell, and Ca2+ enters the cell via voltage-gated Ca2+ channels. The Ca2+ influx causes exocytosis of a readily releasable pool of insulin-containing secretory granules, producing the initial spike of insulin secretion.


FIGURE 24–11 Insulin secretion. Glucose enters B cells by GLUT 2 transporters. It is phosphorylated and metabolized to pyruvate (Pyr) in the cytoplasm. The Pyr enters the mitochondria and is metabolized via the citric acid cycle. The ATP formed by oxidative phosphorylation inhibits ATP-sensitive K+ channels, reducing K+ efflux. This depolarizes the B cell, and Ca2+ influx is increased. The Ca2+ stimulates release of insulin by exocytosis. Glutamate (Glu) is also formed, and this primes secretory granules, preparing them for exocytosis.

Metabolism of pyruvate via the citric acid cycle also causes an increase in intracellular glutamate. The glutamate appears to act on a second pool of secretory granules, committing them to the releasable form. The action of glutamate may be to decrease the pH in the secretory granules, a necessary step in their maturation. The release of these granules then produces the prolonged second phase of the insulin response to glucose. Thus, glutamate appears to act as an intracellular second messenger that primes secretory granules for secretion.

The feedback control of plasma glucose on insulin secretion normally operates with great precision so that plasma glucose and insulin levels parallel each other with remarkable consistency.


Insulin stimulates the incorporation of amino acids into proteins and combats the fat catabolism that produces the β-keto acids. Therefore, it is not surprising that arginine, leucine, and certain other amino acids stimulate insulin secretion, as do β–keto acids such as acetoacetate. Like glucose, these compounds generate ATP when metabolized, and this closes ATP-sensitive K+ channels in the B cells. In addition, L-arginine is the precursor of NO, and NO stimulates insulin secretion.


Tolbutamide and other sulfonylurea derivatives such as acetohexamide, tolazamide, glipizide, and glyburide are orally active hypoglycemic agents that lower blood glucose by increasing the secretion of insulin. They only work in patients with some remaining B cells and are ineffective after pancreatectomy or in type 1 diabetes. They bind to the ATP-inhibited K+ channels in the B cell membranes and inhibit channel activity, depolarizing the B cell membrane and increasing Ca2+ influx and hence insulin release, independent of increases in plasma glucose.

Persistent hyperinsulinemic hypoglycemia of infancy is a condition in which plasma insulin is elevated despite the hypoglycemia. The condition is caused by mutations in the genes for various enzymes in B cells that decrease K+ efflux via the ATP-sensitive K+ channels. Treatment consists of administration of diazoxide, a drug that increases the activity of the K+ channels or, in more severe cases, subtotal pancreatectomy.

The biguanide metformin is an oral hypoglycemic agent that acts in the absence of insulin. Metformin acts primarily by reducing gluconeogenesis and therefore decreasing hepatic glucose output. It is sometimes combined with a sulfonylurea in the treatment of type 2 diabetes. Metformin can cause lactic acidosis, but the incidence is usually low.

Troglitazone (Rezulin) and related thiazolidinediones are also used in the treatment of diabetes because they increase insulin-mediated peripheral glucose disposal, thus reducing insulin resistance. They bind to and activate peroxisome proliferator-activated receptor γ (PPAR>γ) in the nucleus of cells. Activation of this receptor, which is a member of the superfamily of hormone-sensitive nuclear transcription factors, has a unique ability to normalize a variety of metabolic functions.


Stimuli that increase cAMP levels in B cells increase insulin secretion, including β-adrenergic agonists, glucagon, and phosphodiesterase inhibitors such as theophylline.

Catecholamines have a dual effect on insulin secretion; they inhibit insulin secretion via α2-adrenergic receptors and stimulate insulin secretion via β-adrenergic receptors. The net effect of epinephrine and norepinephrine is usually inhibition. However, if catecholamines are infused after administration of α-adrenergic blocking drugs, the inhibition is converted to stimulation.


Branches of the right vagus nerve innervate the pancreatic islets, and stimulation of this parasympathetic pathway causes increased insulin secretion via M4 receptors (see Table 7–2). Atropine blocks the response and acetylcholine stimulates insulin secretion. The effect of acetylcholine, like that of glucose, is due to increased cytoplasmic Ca2+, but acetylcholine activates phospholipase C, with the released IP3 releasing the Ca2+ from the endoplasmic reticulum.

Stimulation of the sympathetic nerves to the pancreas inhibits insulin secretion. The inhibition is produced by released norepinephrine acting on α2-adrenergic receptors. However, if α-adrenergic receptors are blocked, stimulation of the sympathetic nerves causes increased insulin secretion mediated by β2-adrenergic receptors. The polypeptide galanin is found in some of the autonomic nerves innervating the islets, and galanin inhibits insulin secretion by activating the K+ channels that are inhibited by ATP. Thus, although the denervated pancreas responds to glucose, the autonomic innervation of the pancreas is involved in the overall regulation of insulin secretion (Clinical Box 24–3).


Effects of K+ Depletion

K+ depletion decreases insulin secretion, and K+-depleted patients, for example, patients with primary hyperaldosteronism (see Chapter 20), develop diabetic glucose tolerance curves. These curves are restored to normal by K+repletion.


The thiazide diuretics, which cause loss of K+ as well as Na+ in the urine (see Chapter 37), decrease glucose tolerance and make diabetes worse. They apparently exert this effect primarily because of their K+-depleting effects, although some of them also cause pancreatic islet cell damage. Potassium-sparing diuretics, such as amiloride, should be substituted in the diabetic patient who needs such treatment.


Orally administered glucose exerts a greater insulin-stimulating effect than intravenously administered glucose, and orally administered amino acids also produce a greater insulin response than intravenous amino acids. These observations led to exploration of the possibility that a substance secreted by the gastrointestinal mucosa stimulated insulin secretion. Glucagon, glucagon derivatives, secretin, cholecystokinin (CCK), gastrin, and gastric inhibitory peptide (GIP) all have such an action (see Chapter 25), and CCK potentiates the insulin-stimulating effects of amino acids. However, GIP is the only one of these peptides that produces stimulation when administered in doses that reflect blood GIP levels produced by an oral glucose load.

Recently, attention has focused on glucagon-like polypeptide 1 (7–36) (GLP-1 [7–36]) as an additional gut factor that stimulates insulin secretion. This polypeptide is a product of preproglucagon. B cells have GLP-1 (7–36) receptors as well as GIP receptors, and GLP-1 (7–36) is a more potent insulinotropic hormone than GIP. GIP and GLP-1 (7–36) both appear to act by increasing Ca2+ influx through voltage-gated Ca2+ channels.

The possible roles of pancreatic somatostatin and glucagon in the regulation of insulin secretion are discussed below.


The magnitude of the insulin response to a given stimulus is determined in part by the secretory history of the B cells. Individuals fed a high-carbohydrate diet for several weeks not only have higher fasting plasma insulin levels but also show a greater secretory response to a glucose load than individuals fed an isocaloric low-carbohydrate diet.

Although B cells respond to stimulation with hypertrophy like other endocrine cells, they become exhausted and stop secreting (B cell exhaustion) when the stimulation is marked or prolonged. The pancreatic reserve is large and it is difficult to produce B cell exhaustion in normal animals, but if the pancreatic reserve is reduced by partial pancreatectomy, exhaustion of the remaining B cells can be initiated by any procedure that chronically raises the plasma glucose level. For example, diabetes can be produced in animals with limited pancreatic reserves by anterior pituitary extracts, growth hormone, thyroid hormones, or the prolonged continuous infusion of glucose alone. The diabetes precipitated by hormones in animals is at first reversible, but with prolonged treatment it becomes permanent. The transient diabetes is usually named for the agent producing it, for example, “hypophysial diabetes” or “thyroid diabetes.” Permanent diabetes persisting after treatment has been discontinued is indicated by the prefix meta-, for example, “metahypophysial diabetes” or “metathyroid diabetes.” When insulin is administered along with the diabetogenic hormones, the B cells are protected, probably because the plasma glucose is lowered, and diabetes does not develop.

It is interesting in this regard that genetic factors may be involved in the control of B cell reserve. In mice in which the gene for IRS-1 has been knocked out (see above), a robust compensatory B cell response occurs. However, in IRS-2 knockouts, the compensation is reduced and a more severe diabetic phenotype is produced.



Human glucagon, a linear polypeptide with a molecular weight of 3485, is produced by the A cells of the pancreatic islets and the upper gastrointestinal tract. It contains 29 amino acid residues. All mammalian glucagons appear to have the same structure. Human preproglucagon (Figure 24–12) is a 179-amino-acid protein that is found in pancreatic A cells, in L cells in the lower gastrointestinal tract, and in the brain. It is the product of a single mRNA, but it is processed differently in different tissues. In A cells, it is processed primarily to glucagon and major proglucagon fragment (MPGF). In L cells, it is processed primarily to glicentin, a polypeptide that consists of glucagon extended by additional amino acid residues at either end, plus glucagon-like polypeptides 1 and 2 (GLP-1 and GLP-2). Some oxyntomodulin is also formed, and in both A and L cells, residual glicentin-related polypeptide (GRPP) is left. Glicentin has some glucagon activity. GLP-1 and GLP-2 have no definite biologic activity by themselves. However, GLP-1 is processed further by removal of its amino-terminal amino acid residues and the product, GLP-1 (7–36), is a potent stimulator of insulin secretion that also increases glucose utilization (see above). GLP-1 and GLP-2 are also produced in the brain. The function of GLP-1 in this location is uncertain, but GLP-2 appears to be the mediator in a pathway from the nucleus tractus solitarius (NTS) to the dorsomedial nuclei of the hypothalamus, and injection of GLP-2 lowers food intake. Oxyntomodulin inhibits gastric acid secretion, though its physiologic role is unsettled, and GRPP does not have any established physiologic effects.


FIGURE 24–12 Posttranslational processing of preproglucagon in A and L cells. S, signal peptide; GRPP, glicentin-related polypeptide; GLP, glucagon-like polypeptide; Oxy, oxyntomodulin; MPGF, major proglucagon fragment. (Modified from Drucker DJ: Glucagon and glucagon-like peptides. Pancreas 1990;5:484.)


Glucagon is glycogenolytic, gluconeogenic, lipolytic, and ketogenic. It acts on G-protein coupled receptors with a molecular weight of about 190,000. In the liver, it acts via Gs to activate adenylyl cyclase and increase intracellular cAMP. This leads via protein kinase A to activation of phosphorylase and therefore to increased breakdown of glycogen and an increase in plasma glucose. However, glucagon acts on different glucagon receptors located on the same hepatic cells to activate phospholipase C, and the resulting increase in cytoplasmic Ca2+ also stimulates glycogenolysis. Protein kinase A also decreases the metabolism of glucose 6-phosphate (Figure 24–13) by inhibiting the conversion of phosphoenolpyruvate to pyruvate. It also decreases the concentration of fructose 2,6-diphosphate and this in turn inhibits the conversion of fructose 6-phosphate to fructose 1,6-diphosphate. The resultant buildup of glucose 6-phosphate leads to increased glucose synthesis and release.


FIGURE 24–13 Mechanisms by which glucagon increases glucose output from the liver. Solid arrows indicate facilitation; dashed arrows indicate inhibition.

Glucagon does not cause glycogenolysis in muscle. It increases gluconeogenesis from available amino acids in the liver and elevates the metabolic rate. It increases ketone body formation by decreasing malonyl-CoA levels in the liver. Its lipolytic activity, which leads in turn to increased ketogenesis, is discussed in Chapter 1. The calorigenic action of glucagon is not due to the hyperglycemia per se but probably to the increased hepatic deamination of amino acids.

Large doses of exogenous glucagon exert a positive inotropic effect on the heart (see Chapter 30) without producing increased myocardial excitability, presumably because they increase myocardial cAMP. Use of this hormone in the treatment of heart disease has been advocated, but there is no evidence for a physiologic role of glucagon in the regulation of cardiac function. Glucagon also stimulates the secretion of growth hormone, insulin, and pancreatic somatostatin.


Glucagon has a half-life in the circulation of 5–10 min. It is degraded by many tissues but particularly by the liver. Because glucagon is secreted into the portal vein and reaches the liver before it reaches the peripheral circulation, peripheral blood levels are relatively low. The rise in peripheral blood glucagon levels produced by excitatory stimuli is exaggerated in patients with cirrhosis, presumably because of decreased hepatic degradation of the hormone.


The principal factors known to affect glucagon secretion are summarized in Table 24–5. Secretion is increased by hypoglycemia and decreased by a rise in plasma glucose. Pancreatic B cells contain GABA, and evidence suggests that coincident with the increased insulin secretion produced by hyperglycemia, GABA is released and acts on the A cells to inhibit glucagon secretion by activating GABAA receptors. The GABAA receptors are Cl channels, and the resulting Cl influx hyperpolarizes the A cells.


TABLE 24–5 Factors affecting glucagon secretion.

Secretion is also increased by stimulation of the sympathetic nerves to the pancreas, and this sympathetic effect is mediated via β-adrenergic receptors and cAMP. It appears that the A cells are like the B cells in that stimulation of β-adrenergic receptors increases secretion and stimulation of α-adrenergic receptors inhibits secretion. However, the pancreatic response to sympathetic stimulation in the absence of blocking drugs is increased secretion of glucagon, so the effect of β-receptors predominates in the glucagon-secreting cells. The stimulatory effects of various stresses and possibly of exercise and infection are mediated at least in part via the sympathetic nervous system. Vagal stimulation also increases glucagon secretion.

A protein meal and infusion of various amino acids increase glucagon secretion. It seems appropriate that the glucogenic amino acids are particularly potent in this regard, since these are the amino acids that are converted to glucose in the liver under the influence of glucagon. The increase in glucagon secretion following a protein meal is also valuable, since the amino acids stimulate insulin secretion and the secreted glucagon prevents the development of hypoglycemia while the insulin promotes storage of the absorbed carbohydrates and lipids. Glucagon secretion increases during starvation. It reaches a peak on the third day of a fast, at the time of maximal gluconeogenesis. Thereafter, the plasma glucagon level declines as fatty acids and ketones become the major sources of energy.

During exercise, there is an increase in glucose utilization that is balanced by an increase in glucose production caused by an increase in circulating glucagon levels.

The glucagon response to oral administration of amino acids is greater than the response to intravenous infusion of amino acids, suggesting that a glucagon-stimulating factor is secreted from the gastrointestinal mucosa. CCK and gastrin increase glucagon secretion, whereas secretin inhibits it. Because CCK and gastrin secretion are both increased by a protein meal, either hormone could be the gastrointestinal mediator of the glucagon response. The inhibition produced by somatostatin is discussed below.

Glucagon secretion is also inhibited by FFA and ketones. However, this inhibition can be overridden, since plasma glucagon levels are high in diabetic ketoacidosis.


As noted previously, insulin is glycogenic, antigluconeogenetic, antilipolytic, and antiketotic in its actions. It thus favors storage of absorbed nutrients and is a “hormone of energy storage.” Glucagon, on the other hand, is glycogenolytic, gluconeogenetic, lipolytic, and ketogenic. It mobilizes energy stores and is a “hormone of energy release.” Because of their opposite effects, the blood levels of both hormones must be considered in any given situation. It is convenient to think in terms of the molar ratios of these hormones.

The insulin–glucagon molar ratios fluctuate markedly because the secretion of glucagon and insulin are both modified by the conditions that preceded the application of any given stimulus (Table 24–6). Thus, for example, the insulin–glucagon molar ratio on a balanced diet is approximately 2.3. An infusion of arginine increases the secretion of both hormones and raises the ratio to 3.0. After 3 days of starvation, the ratio falls to 0.4, and an infusion of arginine in this state lowers the ratio to 0.3. Conversely, the ratio is 25 in individuals receiving a constant infusion of glucose and rises to 170 on ingestion of a protein meal during the infusion (Table 24–6). The rise occurs because insulin secretion rises sharply, while the usual glucagon response to a protein meal is abolished. Thus, when energy is needed during starvation, the insulin–glucagon molar ratio is low, favoring glycogen breakdown and gluconeogenesis; conversely, when the need for energy mobilization is low, the ratio is high, favoring the deposition of glycogen, protein, and fat (Clinical Box 24–4).


TABLE 24–6 Insulin-glucagon molar ratios (I/G) in blood in various conditions.


Macrosomia & GLUT 1 Deficiency

Infants born to diabetic mothers often have high birth weights and large organs (macrosomia). This condition is caused by excess circulating insulin in the fetus, which in turn is caused in part by stimulation of the fetal pancreas by high blood glucose and amino acids from the diabetic mother. Free insulin in maternal blood is destroyed by proteases in the placenta, but antibody-bound insulin is protected, so it reaches the fetus. Therefore, fetal macrosomia also occurs in women who develop antibodies against various animal insulins and then continue to receive the animal insulin during pregnancy.

Infants with GLUT 1 deficiency have defective transport of glucose across the blood–brain barrier. They have low cerebrospinal fluid glucose in the presence of normal plasma glucose, seizures, and developmental delay.


In addition to insulin and glucagon, the pancreatic islets secrete somatostatin and pancreatic polypeptide into the bloodstream. In addition, somatostatin may be involved in regulatory processes within the islets that adjust the pattern of hormones secreted in response to various stimuli.


Somatostatin and its receptors are discussed in Chapter 7. Somatostatin 14 (SS 14) and its amino terminal-extended form somatostatin 28 (SS 28) are found in the D cells of pancreatic islets. Both forms inhibit the secretion of insulin, glucagon, and pancreatic polypeptide and act locally within the pancreatic islets in a paracrine fashion. SS 28 is more active than SS 14 in inhibiting insulin secretion, and it apparently acts via the SSTR5 receptor (see Chapter 7). Patients with somatostatin-secreting pancreatic tumors (somatostatinomas) develop hyperglycemia and other manifestations of diabetes that disappear when the tumor is removed. They also develop dyspepsia due to slow gastric emptying and decreased gastric acid secretion, and gallstones, which are precipitated by decreased gallbladder contraction due to inhibition of CCK secretion. The secretion of pancreatic somatostatin is increased by several of the same stimuli that increase insulin secretion, that is, glucose and amino acids, particularly arginine and leucine. It is also increased by CCK. Somatostatin is released from the pancreas and the gastrointestinal tract into the peripheral blood.


Human pancreatic polypeptide is a linear polypeptide that contains 36 amino acid residues and is produced by F cells in the islets. It is closely related to two other 36-amino acid polypeptides, polypeptide YY, a gastrointestinal peptide (see Chapter 25), and neuropeptide Y, which is found in the brain and the autonomic nervous system (see Chapter 7). All end in tyrosine and are amidated at their carboxyl terminal. At least in part, pancreatic polypeptide secretion is under cholinergic control; plasma levels fall after administration of atropine. Its secretion is increased by a meal containing protein and by fasting, exercise, and acute hypoglycemia. Secretion is decreased by somatostatin and intravenous glucose. Infusions of leucine, arginine, and alanine do not affect it, so the stimulatory effect of a protein meal may be mediated indirectly. Pancreatic polypeptide slows the absorption of food in humans, and it may smooth out the peaks and valleys of absorption. However, its exact physiologic function is still uncertain.


The presence in the pancreatic islets of hormones that affect the secretion of other islet hormones suggests that the islets function as secretory units in the regulation of nutrient homeostasis. Somatostatin inhibits the secretion of insulin, glucagon, and pancreatic polypeptide (Figure 24–14); insulin inhibits the secretion of glucagon; and glucagon stimulates the secretion of insulin and somatostatin. As noted above, A and D cells and pancreatic polypeptide-secreting cells are generally located around the periphery of the islets, with the B cells in the center. There are clearly two types of islets, glucagon-rich islets and pancreatic polypeptide-rich islets, but the functional significance of this separation is not known. The islet cell hormones released into the ECF probably diffuse to other islet cells and influence their function (paracrine communication; see Chapter 25). It has been demonstrated that gap junctions are present between A, B, and D cells and that these permit the passage of ions and other small molecules from one cell to another, which could coordinate their secretory functions.


FIGURE 24–14 Effects of islet cell hormones on the secretion of other islet cell hormones. Solid arrows indicate stimulation; dashed arrows indicate inhibition.


Exercise has direct effects on carbohydrate metabolism. Many hormones in addition to insulin, IGF-I, IGF-II, glucagon, and somatostatin also have important roles in the regulation of carbohydrate metabolism. They include epinephrine, thyroid hormones, glucocorticoids, and growth hormone. The other functions of these hormones are considered elsewhere, but it seems wise to summarize their effects on carbohydrate metabolism in the context of the present chapter.


The entry of glucose into skeletal muscle is increased during exercise in the absence of insulin by causing an insulin-independent increase in the number of GLUT 4 transporters in muscle cell membranes (see above). This increase in glucose entry persists for several hours after exercise, and regular exercise training can also produce prolonged increases in insulin sensitivity. Exercise can precipitate hypoglycemia in diabetics not only because of the increase in muscle uptake of glucose but also because absorption of injected insulin is more rapid during exercise. Patients with diabetes should take in extra calories or reduce their insulin dosage when they exercise.


The activation of phosphorylase in liver by catecholamines is discussed in Chapter 1. Activation occurs via β-adrenergic receptors, which increase intracellular cAMP, and α-adrenergic receptors, which increase intracellular Ca2+. Hepatic glucose output is increased, producing hyperglycemia. In muscle, the phosphorylase is also activated via cAMP and presumably via Ca2+, but the glucose 6-phosphate formed can be catabolized only to pyruvate because of the absence of glucose 6-phosphatase. For reasons that are not entirely clear, large amounts of pyruvate are converted to lactate, which diffuses from the muscle into the circulation (Figure 24–15). The lactate is oxidized in the liver to pyruvate and converted to glycogen. Therefore, the response to an injection of epinephrine is an initial glycogenolysis followed by a rise in hepatic glycogen content. Lactate oxidation may be responsible for the calorigenic effect of epinephrine (see Chapter 20). Epinephrine and norepinephrine also liberate FFA into the circulation, and epinephrine decreases peripheral utilization of glucose.


FIGURE 24–15 Effect of epinephrine on tissue glycogen, plasma glucose, and blood lactate levels in fed rats. (Reproduced with permission from Ruch TC, Patton HD [editors]: Physiology and Biophysics, 20th ed, Vol 3. Saunders, 1973.)


Thyroid hormones make experimental diabetes worse; thyrotoxicosis aggravates clinical diabetes; and metathyroid diabetes can be produced in animals with decreased pancreatic reserve. The principal diabetogenic effect of thyroid hormones is to increase absorption of glucose from the intestine, but the hormones also cause (probably by potentiating the effects of catecholamines) some degree of hepatic glycogen depletion. Glycogen-depleted liver cells are easily damaged. When the liver is damaged, the glucose tolerance curve is diabetic because the liver takes up less of the absorbed glucose. Thyroid hormones may also accelerate the degradation of insulin. All these actions have a hyperglycemic effect and, if the pancreatic reserve is low, may lead to B cell exhaustion.


Glucocorticoids from the adrenal cortex (see Chapter 20) elevate blood glucose and produce a diabetic type of glucose tolerance curve. In humans, this effect may occur only in individuals with a genetic predisposition to diabetes. Glucose tolerance is reduced in 80% of patients with Cushing syndrome (see Chapter 20), and 20% of these patients have frank diabetes. The glucocorticoids are necessary for glucagon to exert its gluconeogenic action during fasting. They are gluconeogenic themselves, but their role is mainly permissive. In adrenal insufficiency, the blood glucose is normal as long as food intake is maintained, but fasting precipitates hypoglycemia and collapse. The plasma-glucose-lowering effect of insulin is greatly enhanced in patients with adrenal insufficiency. In animals with experimental diabetes, adrenalectomy markedly ameliorates the diabetes. The major diabetogenic effects are an increase in protein catabolism with increased gluconeogenesis in the liver; increased hepatic glycogenesis and ketogenesis; and a decrease in peripheral glucose utilization relative to the blood insulin level that may be due to inhibition of glucose phosphorylation.


Human growth hormone makes clinical diabetes worse, and 25% of patients with growth hormone-secreting tumors of the anterior pituitary have diabetes. Hypophysectomy ameliorates diabetes and decreases insulin resistance even more than adrenalectomy, whereas growth hormone treatment increases insulin resistance.

The effects of growth hormone are partly direct and partly mediated via IGF-I (see Chapter 18). Growth hormone mobilizes FFA from adipose tissue, thus favoring ketogenesis. It decreases glucose uptake into some tissues (“anti-insulin action”), increases hepatic glucose output, and may decrease tissue binding of insulin. Indeed, it has been suggested that the ketosis and decreased glucose tolerance produced by starvation are due to hypersecretion of growth hormone. Growth hormone does not stimulate insulin secretion directly, but the hyperglycemia it produces secondarily stimulates the pancreas and may eventually exhaust the B cells.



“Insulin reactions” are common in type 1 diabetics and occasional hypoglycemic episodes are the price of good diabetic control in most diabetics. Glucose uptake by skeletal muscle and absorption of injected insulin both increase during exercise (see above).

Symptomatic hypoglycemia also occurs in nondiabetics, and a review of some of the more important causes serves to emphasize the variables affecting plasma glucose homeostasis. Chronic mild hypoglycemia can cause incoordination and slurred speech, and the condition can be mistaken for drunkenness. Mental aberrations and convulsions in the absence of frank coma also occur. When the level of insulin secretion is chronically elevated by an insulinoma, a rare, insulin-secreting tumor of the pancreas, symptoms are most common in the morning. This is because a night of fasting has depleted hepatic glycogen reserves. However, symptoms can develop at any time, and in such patients, the diagnosis may be missed. Some cases of insulinoma have been erroneously diagnosed as epilepsy or psychosis. Hypoglycemia also occurs in some patients with large malignant tumors that do not involve the pancreatic islets, and the hypoglycemia in these cases is apparently due to excess secretion of IGF-II.

As noted above, the autonomic discharge caused by lowered blood glucose that produces shakiness, sweating, anxiety, and hunger normally occurs at plasma glucose levels that are higher than the glucose levels that cause cognitive dysfunction, thereby serving as a warning to ingest sugar. However, in some individuals, these warning symptoms fail to occur before the cognitive symptoms, due to cerebral dysfunction (desensitization), and this hypoglycemia unawareness is potentially dangerous. The condition is prone to develop in patients with insulinomas and in diabetics receiving intensive insulin therapy, so it appears that repeated bouts of hypoglycemia cause the eventual development of hypoglycemia unawareness. If blood sugar rises again for some time, the warning symptoms again appear at a higher plasma glucose level than cognitive abnormalities and coma. The reason why prolonged hypoglycemia causes loss of the warning symptoms is unsettled.

In liver disease, the glucose tolerance curve is diabetic but the fasting plasma glucose level is low (Figure 24–16). In functional hypoglycemia, the plasma glucose rise is normal after a test dose of glucose, but the subsequent fall overshoots to hypoglycemic levels, producing symptoms 3–4 h after meals. This pattern is sometimes seen in individuals who later develop diabetes. Patients with this syndrome should be distinguished from the more numerous patients with similar symptoms due to psychologic or other problems who do not have hypoglycemia when blood is drawn during the symptomatic episode. It has been postulated that the overshoot of the plasma glucose is due to insulin secretion stimulated by impulses in the right vagus, but cholinergic blocking agents do not routinely correct the abnormality. In some thyrotoxic patients and in patients who have had gastrectomies or other operations that speed the passage of food into the intestine, glucose absorption is abnormally rapid. The plasma glucose rises to a high, early peak, but it then falls rapidly to hypoglycemic levels because the wave of hyperglycemia evokes a greater than normal rise in insulin secretion. Symptoms characteristically occur about 2 h after meals.


FIGURE 24–16 Typical glucose tolerance curves after an oral glucose load in liver disease and in conditions causing excessively rapid absorption of glucose from the intestine. The horizontal line is the approximate plasma glucose level at which hypoglycemic symptoms may appear.


The incidence of diabetes mellitus in the human population has reached epidemic proportions worldwide and it is increasing at a rapid rate. In 2010 an estimated 285 million people worldwide had diabetes, according to the International Diabetes Federation. The federation predicts as many as 438 million will have diabetes by 2030. Ninety per cent of the present cases are type 2 diabetes, and most of the increase will be in type 2, paralleling the increase in the incidence of obesity.

Diabetes is sometimes complicated by acidosis and coma, and in long-standing diabetes additional complications occur. These include microvascular, macrovascular, and neuropathic disease. The microvascular abnormalities are proliferative scarring of the retina (diabetic retinopathy) leading to blindness; and renal disease (diabetic nephropathy) leading to renal failure. The macrovascular abnormalities are due to accelerated atherosclerosis, which is secondary to increased plasma LDL. The result is an increased incidence of stroke and myocardial infarction. The neuropathic abnormalities (diabetic neuropathy) involve the autonomic nervous system and peripheral nerves. The neuropathy plus the atherosclerotic circulatory insufficiency in the extremities and reduced resistance to infection can lead to chronic ulceration and gangrene, particularly in the feet.

The ultimate cause of the microvascular and neuropathic complications is chronic hyperglycemia, and tight control of the diabetes reduces their incidence. Intracellular hyperglycemia activates the enzyme aldose reductase. This increases the formation of sorbitol in cells, which in turn reduces cellular Na, K ATPase. In addition, intracellular glucose can be converted to so-called Amadori products, and these in turn can form advanced glycosylation end products (AGEs), which cross-link matrix proteins. This damages blood vessels. The AGEs also interfere with leukocyte responses to infection.


The cause of clinical diabetes is always a deficiency of the effects of insulin at the tissue level, but the deficiency may be relative. One of the common forms, type 1, or insulin-dependent diabetes mellitus (IDDM), is due to insulin deficiency caused by autoimmune destruction of the B cells in the pancreatic islets; the A, D, and F cells remain intact. The second common form, type 2, or noninsulin-dependent diabetes mellitus (NIDDM), is characterized by insulin resistance.

In addition, some cases of diabetes are due to other diseases or conditions such as chronic pancreatitis, total pancreatectomy, Cushing syndrome (see Chapter 20), and acromegaly (see Chapter 18). These make up 5% of the total cases and are sometimes classified as secondary diabetes.

Type 1 diabetes usually develops before the age of 40 and hence is called juvenile diabetes. Patients with this disease are not obese and they have a high incidence of ketosis and acidosis. Various anti-B cell antibodies are present in plasma, but the current thinking is that type 1 diabetes is primarily a T lymphocyte-mediated disease. Definite genetic susceptibility is present as well; if one identical twin develops the disease, the chances are 1 in 3 that the other twin will also do so. In other words, the concordance rate is about 33%. The main genetic abnormality is in the major histocompatibility complex on chromosome 6, making individuals with certain types of histocompatibility antigens (see Chapter 3) much more prone to the disease. Other genes are also involved.

Immunosuppression with drugs such as cyclosporine ameliorate type 1 diabetes if given early in the disease before all islet B cells are lost. Attempts have been made to treat type 1 diabetes by transplanting pancreatic tissue or isolated islet cells, but results to date have been poor, largely because B cells are easily damaged and it is difficult to transplant enough of them to normalize glucose responses.

As mentioned above, type 2 is the most common type of diabetes and is usually associated with obesity. It usually develops after age 40 and is not associated with total loss of the ability to secrete insulin. It has an insidious onset, is rarely associated with ketosis, and is usually associated with normal B cell morphology and insulin content if the B cells have not become exhausted. The genetic component in type 2 diabetes is actually stronger than the genetic component in type 1 diabetes; in identical twins, the concordance rate is higher, ranging in some studies to nearly 100%.

In some patients, type 2 diabetes is due to defects in identified genes. Over 60 of these defects have been described. They include defects in glucokinase (about 1% of the cases), the insulin molecule itself (about 0.5% of the cases), the insulin receptor (about 1% of the cases), GLUT 4 (about 1% of the cases), or IRS-1 (about 15% of the cases). In maturity-onset diabetes occurring in young individuals (MODY), which accounts for about 1% of the cases of type 2 diabetes, loss-of-function mutations have been described in six different genes. Five code for transcription factors affecting the production of enzymes involved in glucose metabolism. The sixth is the gene for glucokinase (Figure 24–11), the enzyme that controls the rate of glucose phosphorylation and hence its metabolism in the B cells. However, the vast majority of cases of type 2 diabetes are almost certainly polygenic in origin, and the actual genes involved are still unknown.


Obesity is increasing in incidence, and relates to the regulation of food intake and energy balance and overall nutrition. It deserves additional consideration in this chapter because of its special relation to disordered carbohydrate metabolism and diabetes. As body weight increases, insulin resistance increases, that is, there is a decreased ability of insulin to move glucose into fat and muscle and to shut off glucose release from the liver. Weight reduction decreases insulin resistance. Associated with obesity there is hyperinsulinemia, dyslipidemia (characterized by high circulating triglycerides and low high-density lipoprotein [HDL]), and accelerated development of atherosclerosis. This combination of findings is commonly called the metabolic syndrome, or syndrome X. Some of the patients with the syndrome are prediabetic, whereas others have frank type 2 diabetes. It has not been proved but it is logical to assume that the hyperinsulinemia is a compensatory response to the increased insulin resistance and that frank diabetes develops in individuals with reduced B cell reserves.

These observations and other data strongly suggest that fat produces a chemical signal or signals that act on muscles and the liver to increase insulin resistance. Evidence for this includes the recent observation that when GLUTs are selectively knocked out in adipose tissue, there is an associated decrease in glucose transport in muscle in vivo, but when the muscles of those animals are tested in vitro their transport is normal.

One possible signal is the circulating level of free fatty acids, which is elevated in many insulin-resistant states. Other possibilities are peptides and proteins secreted by fat cells. It is now clear that white fat depots are not inert lumps but are actually endocrine tissues that secrete not only leptin but also other hormones that affect fat metabolism. These adipose derived hormones are commonly termed adipokines as they are cytokines secreted by adipose tissue. Known adipokines are leptin, adiponectin, and resistin.

Some adipokines decrease, rather than increase, insulin resistance. Leptin and adiponectin, for example, decrease insulin resistance, whereas resistin increases insulin resistance. Further complicating the situation, marked insulin resistance is present in the rare metabolic disease congenital lipodystrophy, in which fat depots fail to develop. This resistance is reduced by leptin and adiponectin. Finally, a variety of knockouts of intracellular second messengers have been reported to increase insulin resistance. It is unclear how, or indeed if, these findings fit together to provide an explanation of the relation of obesity to insulin tolerance, but the topic is obviously an important one and it is under intensive investigation.


image Four polypeptides with hormonal activity are secreted by the pancreas: insulin, glucagon, somatostatin, and pancreatic polypeptide.

image Insulin increases the entry of glucose into cells. In skeletal muscle cell it increases the number of GLUT 4 transporters in the cell membranes. In liver it induces glucokinase, which increases the phosphorylation of glucose, facilitating the entry of glucose into the cell.

image Insulin causes K+ to enter cells, with a resultant lowering of the extracellular K+ concentration. Insulin increases the activity of Na, K ATPase in cell membranes, so that more K+ is pumped into cells. Hypokalemia often develops when patients with diabetic acidosis are treated with insulin.

image Insulin receptors are found on many different cells in the body and have two subunits, α and β. Binding of insulin to its receptor triggers a signaling pathway that involves autophosphorylation of the β subunits on tyrosine residues. This triggers phosphorylation of some cytoplasmic proteins and dephosphorylation of others, mostly on serine and threonine residues.

image The constellation of abnormalities caused by insulin deficiency is called diabetes mellitus. Type 1 diabetes is due to insulin deficiency caused by autoimmune destruction of the B cells in the pancreatic islets; Type 2 diabetes is characterized by the dysregulation of insulin release from the B cells, along with insulin resistance in peripheral tissues such as skeletal muscle, brain, and liver.


For all questions, select the single best answer unless otherwise directed.

1. Which of the following are incorrectly paired?

A. B cells: insulin

B. D cells: somatostatin

C. A cells: glucagons

D. Pancreatic exocrine cells: chymotrypsinogen

E. F cells: gastrin

2. Which of the following are incorrectly paired?

A. Epinephrine: increased glycogenolysis in skeletal muscle

B. Insulin: increased protein synthesis

C. Glucagon: increased gluconeogenesis

D. Progesterone: increased plasma glucose level

E. Growth hormone: increased plasma glucose level

3. Which of the following would be least likely to be seen 14 days after a rat is injected with a drug that kills all of its pancreatic B cells?

A. A rise in the plasma H+ concentration

B. A rise in the plasma glucagon concentration

C. A fall in the plasma image concentration

D. A fall in the plasma amino acid concentration

E. A rise in plasma osmolality

4. When the plasma glucose concentration falls to low levels, a number of different hormones help combat the hypoglycemia. After intravenous administration of a large dose of insulin, the return of a low blood sugar level to normal is delayed in

A. adrenal medullary insufficiency.

B. glucagon deficiency.

C. combined adrenal medullary insufficiency and glucagon deficiency.

D. thyrotoxicosis.

E. acromegaly.

5. Insulin increases the entry of glucose into

A. all tissues.

B. renal tubular cells.

C. the mucosa of the small intestine.

D. most neurons in the cerebral cortex.

E. skeletal muscle.

6. Glucagon increases glycogenolysis in liver cells but ACTH does not because

A. cortisol increases the plasma glucose level.

B. liver cells have an adenylyl cyclase different from that in adrenocortical cells.

C. ACTH cannot enter the nucleus of liver cells.

D. the membranes of liver cells contain receptors different from those in adrenocortical cells.

E. liver cells contain a protein that inhibits the action of ACTH.

7. A meal rich in proteins containing the amino acids that stimulate insulin secretion but low in carbohydrates does not cause hypoglycemia because

A. the meal causes a compensatory increase in T4 secretion.

B. cortisol in the circulation prevents glucose from entering muscle.

C. glucagon secretion is also stimulated by the meal.

D. the amino acids in the meal are promptly converted to glucose.

E. insulin does not bind to insulin receptors if the plasma concentration of amino acids is elevated.


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