Medical Physiology A Cellular and Molecular Approach, Updated 2nd Ed.


Eugene J. Barrett


The pancreas contains two types of glands: (1) exocrine glands, which secrete digestive enzymes and HCO3 into the intestinal lumen (see Chapter 43); and (2) endocrine glands, called the islets of Langerhans.

The normal human pancreas contains between 500,000 and several million islets. Islets can be oval or spherical and measure between 50 and 300 μm in diameter. Islets contain at least four types of secretory cells—α cells, β cells, Δ cells, and F cells—in addition to various vascular and neural elements (Fig. 51-1 and Table 51-1). β Cells secrete insulin, proinsulin, C peptide, and a recently described protein, amylin. β cells are the most numerous type of secretory cell within the islets; they are located throughout the islet but are particularly numerous in the center. α Cells principally secrete glucagon, δ cells secrete somatostatin, and F cells (also called pancreatic polypeptide cells) secrete pancreatic polypeptide.


Figure 51-1 Islet of Langerhans.

Table 51-1Products of Pancreatic Islet Cells

Cell Type









C peptide






Pancreatic polypeptide

The cells within an islet receive information from the world outside the islet. These cells also can communicate with each other and influence each other’s secretion. We can group these communication links into three categories:

1. Humoral communication.  The blood supply of the islet courses outward from the center of the islet toward the periphery, carrying glucose and other secretagogues. In the rat—and less strikingly in humans—β cells are more abundant in the center of the islet, whereas α and Δ cells are more abundant in the periphery. Cells within a given islet can influence the secretion of other cells as the blood supply courses outward through the islet carrying the secreted hormonal product of each cell type with it. For example, glucagon is a potent insulin secretagogue, insulin modestly inhibits glucagon release, and somatostatin potently inhibits the secretion of both insulin and glucagon (as well as the secretion of growth hormone and other non-islet hormones).

2. Cell-cell communication. Both gap and tight junctional structures connect islet cells with one another. Cells within an islet can communicate through gap junctions, which may be important for the regulation of both insulin and glucagon secretion.

3. Neural communication. Another level of regulation of islet secretion occurs through innervation from both the sympathetic and the parasympathetic divisions of the autonomic nervous system (ANS). Cholinergic stimulation augments insulin secretion. Adrenergic stimulation can have either a stimulatory or inhibitory effect, depending on whether β-adrenergic (stimulatory) or α-adrenergic stimulation (inhibitory) dominates (see Chapter 50).

These three communication mechanisms allow for tight control over the synthesis and secretion of islet hormones.


The discovery of insulin was among the most exciting and dramatic events in the history of endocrine physiology and therapy. In the United States and Europe, insulin-dependent diabetes mellitus (IDDM), or type 1 diabetes, develops in ~1 in every 600 children in their lifetime. However, the prevalence is only ~1 in 10,000 in eastern Asia. Before 1922, all children with diabetes died within 1 or 2 years of diagnosis. It was an agonizing illness; the children lost weight despite eating well, became progressively weaker and cachectic, were soon plagued by infections, and eventually died of overwhelming acidosis. No effective therapy was available, and few prospects were on the horizon. It was known that the blood sugar was elevated in this disease, but beyond that, there was little understanding of its pathogenesis.

In 1889, Minkowski and von Mering demonstrated that removing the pancreas from dogs caused hyperglycemia, excess urination, thirst, weight loss, and death—in short, a syndrome closely resembling type 1 diabetes. Following this lead, a group of investigators in the Department of Physiology at the University of Toronto prepared extracts of pancreas and tested the ability of these extracts to lower plasma [glucose] in pancreatectomized dogs. Despite months of failures, these investigators persisted in their belief that such extracts could be beneficial. Finally, by the winter of 1921, Banting and Best were able to demonstrate that an aqueous extract of pancreas could lower blood glucose and prolong survival in a pancreatectomized dog. Within 2 months, a more purified extract was shown to lower blood glucose in a young man with diabetes. By the end of 1923, insulin (as the islet hormone was named) was being prepared from beef and pork pancreas on an industrial scale, and patients from around the world were receiving effective treatment of their diabetes. (See Note: Fredrick Banting and Charles Best)

Since that time, the physiology of insulin synthesis, secretion, and action has been more extensively studied than that of any other hormone. Now, more than 85 years later, much is known about the metabolic pathways through which insulin regulates carbohydrate, lipid, and protein metabolism in its major targets: the liver, muscle, and adipose tissue. However, the sequence of intracellular signals that triggers insulin secretion by pancreatic β cells, the signal transduction process triggered when insulin binds to a plasma membrane receptor on target tissues, and the process by which the immune system recognizes and targets β cells for destruction remain areas of intense study.

Insulin replenishes fuel reserves in muscle, liver, and adipose tissue

What does insulin do? Succinctly put, insulin efficiently integrates body fuel metabolism both during periods of fasting and during feeding (Table 51-2). When an individual is fasting, the β cell secretes less insulin. When insulin levels decrease, lipids are mobilized from adipose tissue, and amino acids are mobilized from body protein stores within muscle and other tissues. These lipids and amino acids provide fuel for oxidation and serve as precursors for hepatic ketogenesis and gluconeogenesis, respectively. During feeding, insulin secretion increases. Elevated levels of insulin diminish the mobilization of endogenous fuel stores and stimulate carbohydrate, lipid, and amino acid uptake by specific, insulinsensitive target tissues. In this manner, insulin directs tissues to replenish the fuel reserves that were used during periods of fasting.

Table 51-2 Effects of Nutritional States


After a 24-Hr Fast

2 Hr After a Mixed Meal

Plasma [glucose], mg/dL






Plasma [insulin], μU/mL



Plasma [glucagon], pg/mL




↑ Glycogenolysis

↑ Glycogenolysis


↓ Gluconeogenesis

↓ Gluconeogenesis


↓ Glycogen synthesis

Adipose tissue

Lipids mobilized for fuel

Lipids synthesized


Lipids metabolized

Glucose oxidized or stored as glycogen


Protein degraded and amino acids exported

Protein preserved

As a result of its ability to regulate the mobilization and storage of fuels carefully, insulin maintains the concentration of glucose in the plasma within narrow limits. Such regulation provides the central nervous system (CNS) with a constant supply of glucose for fuel to maintain cortical function. In higher organisms, if the plasma glucose concentration declines to less than 2 to 3 mM (hypoglycemia) for even a brief period, confusion, seizures, and coma may result. Conversely, persistent elevations of plasma [glucose] are characteristic of the diabetic state. Severe hyper glycemia (plasma glucose levels >30 to 40 mM) produces osmotic diuresis (see Chapter 35 for the box on this topic) and can lead to severe dehydration, hypotension, and vascular collapse.

β cells synthesize and secrete insulin

The Insulin GeneInsulin is made only in the β cells of the pancreatic islet. It is encoded by a single gene on the short arm of chromosome 11. Insulin synthesis and secretion are stimulated when islets are exposed to glucose. These effects require that glucose be metabolized. However, the molecular mechanisms by which glucose metabolites regulate insulin synthesis are not known.

Clinical Manifestations of Hypoglycemia and Hyperglycemia


Early manifestations include palpitations, tachycardia, diaphoresis, anxiety, hyperventilation, shakiness, weakness, hunger, and nausea. For prolonged or severe hypoglycemia, manifestations include confusion, unusual behavior, hallucinations, seizures, hypothermia, focal neurologic deficits, and coma.


Early manifestations include weakness, polyuria, polydipsia, altered vision, weight loss, and mild dehydration. For prolonged or severe hyperglycemia (accompanied by metabolic acidosis or diabetic ketoacidosis), manifestations include Kussmaul hyperventilation (deep, rapid breathing), stupor, coma, hypotension, and cardiac arrhythmias.

Insulin Synthesis Transcription of the insulin gene product and subsequent processing result in production of the full-length mRNA that encodes preproinsulin. Starting from its 5′ end, this mRNA encodes a leader sequence and then peptide domains B, C, and A. Insulin is a secretory protein (see Chapter 2). As the preprohormone is synthesized, the leader sequence of ~24 amino acids is cleaved from the nascent peptide as it enters the rough endoplasmic reticulum. The result is proinsulin (Fig. 51-2), which consists of domains B, C, and A. As the trans-Golgi packages the proinsulin and creates secretory granules, proteases slowly begin to cleave the proinsulin molecule at two spots and thus excise the 31–amino acid C peptide. The resulting insulin molecule has two peptide chains, designated the A and B chains, that are joined by two disulfide linkages. The mature insulin molecule has a total of 51 amino acids, 21 on the A chain and 30 on the B chain. In the secretory granule, the insulin associates with zinc. The secretory vesicle contains this insulin, as well as proinsulin and C peptide. All three are released into the portal blood when glucose stimulates the β cell.


Figure 51-2 Synthesis and processing of the insulin molecule. The mature mRNA of the insulin gene product contains the following: a 5′ untranslated region (UTR); nucleotide sequences that encode a 24–amino acid leader sequence, as well as B, C, and A peptide domains; and a 3′ UTR. Together, the leader and the B, C, and A domains constitute preproinsulin. During translation of the mRNA, the leader sequence is cleaved in the lumen of the rough endoplasmic reticulum (ER). What remains is proinsulin, which consists of the B, C, and A domains. Beginning in the trans-Golgi, proteases cleave the proinsulin at two sites and release the C peptide as well as the mature insulin molecule, which consists of the B and A chains that are connected by two disulfide bonds. The secretory granule contains equimolar amounts of insulin and the C peptide, as well as a small amount of proinsulin. These components all are released into the extracellular space during secretion.

Secretion of Insulin, Proinsulin, and C Peptide C peptide has no established biological action. However, because it is secreted in a 1 : 1 molar ratio with insulin, it is a useful marker for insulin secretion. Proinsulin does have modest insulin-like activities; it is ~1/20th as potent as insulin on a molar basis. In addition, the β cell secretes only ~5% as much proinsulin as insulin. As a result, proinsulin does not play a major role in the regulation of blood glucose.

Most of the insulin (~60%) that is secreted into the portal blood is removed in a first pass through the liver. In contrast, C peptide is not extracted by the liver at all. As a result, whereas measurements of the insulin concentration in systemic blood do not quantitatively mimic the secretion of insulin, measurements of C peptide do. C peptide is eventually excreted in the urine, and measurements of the quantity of C peptide excreted in a 24-hour period therefore reflect—on a molar basis—the amount of insulin made during that time. Measurements of urinary C peptide can be used clinically to assess a person’s insulin secretory capability.

Glucose is the major regulator of insulin secretion

In healthy individuals, plasma [glucose] remains within a remarkably narrow range. After an overnight fast, it typically runs between 4 and 5 mM; the plasma [glucose] rises after a meal, but even with a very large meal it does not exceed 10 mM. Modest increases in plasma [glucose] provoke marked increases in insulin secretion and hence marked increases in the plasma [insulin], as illustrated in Figure 51-3A by an oral glucose tolerance test. Conversely, a decline in plasma [glucose] of only 20% markedly lowers plasma [insulin]. The change in the concentration of plasma glucose that occurs in response to feeding or fasting is the main determinant of insulin secretion. In a patient with type 1 diabetes mellitus caused by destruction of pancreatic islets, an oral glucose challenge evokes either no response or a much smaller insulin response, but a much larger increment in plasma [glucose] that lasts for a much longer time (Fig. 51-3B).


Figure 51-3 Glucose tolerance test. A, When a person ingests a glucose meal (75 g), plasma [glucose], shown by the green curve, rises slowly, reflecting the intestinal uptake of the glucose. In response, the pancreatic β cells secrete insulin, and plasma [insulin], shown by the solid red curve, rises sharply. When the glucose is given intravenously rather than orally—but in a manner that exactly reproduces the time course of plasma [glucose] in response to oral glucose in the green curve—the time course of plasma [insulin] follows the dashed red curve. The difference between the insulin responses in the solid and dashed red lines is the result of the incretin effect of oral glucose ingestion. B, In a patient with type 1 diabetes, the same glucose load as that in A causes plasma [glucose] to rise to a higher level and to remain there longer. The reason is that plasma [insulin] rises very little in response to the glucose challenge, so the tissues fail to dispose of the glucose load as rapidly as normal. The diagnosis of diabetes is made if the plasma glucose is higher than 200 mg/dL at the second hour. C, If the glucose challenge (0.5 g glucose/kg body weight given as a 25% glucose solution) is given intravenously, then the plasma [glucose] rises much more rapidly than it does with an oral glucose load. Sensing a rapid rise in [glucose], the β cells first secrete some of their stores of presynthesized insulin. Following this acute phase, the cells secrete both presynthesized and newly manufactured insulin in the chronic phase, which lasts as long as the glucose challenge. IV, intravenous.

Nonhuman and Mutant Insulin

Cloning of the insulin gene has led to an important therapeutic advance, namely, the use of recombinant human insulin for the treatment of diabetes. Human insulin was the first recombinant protein available for routine clinical use. Before the availability of human insulin, either pork or beef insulin was used to treat diabetes. Pork and beef insulin differ from human insulin by one and three amino acids, respectively. The difference, although small, is sufficient to be recognized by the immune system, and antibodies to the injected insulin develop in most patients treated with beef or pork insulin; occasionally, the reaction is severe enough to cause a frank allergy to the insulin. This problem is largely avoided by using human insulin.

Sequencing of the insulin gene has not led to a major understanding of the genesis of the common forms of human diabetes. However, we have learned that rare patients with diabetes make a mutant insulin molecule. In these patients, the abnormal insulin possesses a single amino acid substitution in either the A or B chain. In each case that has been described, these changes lead to a less active insulin molecule (typically only ~1% as potent as insulin on a molar basis). These patients have either glucose intolerance or frank diabetes, but very high concentrations of immunoreactive insulin in their plasma. In these individuals, the immunoreactivity of insulin is not affected to the same extent as the bioactivity.

In addition to identifying these mutant types of insulin, sequencing of the insulin gene has allowed identification of a flanking polymorphic site upstream of the insulin gene that contains one of several common alleles. In some populations, one of these alleles is associated with an increased risk for the development of type 1 diabetes mellitus. The mechanism by which this increased risk is conferred is not known.

A glucose challenge of 0.5 g/kg body weight given as an intravenous bolus raises the plasma glucose concentration more rapidly than if given orally. Such a rapid rise in plasma glucose leads to two distinct phases of insulin secretion (Fig. 51-3C). The acute-phase or first-phase insulin response lasts only 2 to 5 minutes; the duration of the second insulin response persists as long as the blood glucose level remains elevated. The insulin released during the acute-phase insulin response to intravenous glucose arises from preformed insulin that has been packaged in secretory vesicles in the cytosol of the β cell. The late-phase insulin response also comes from preformed insulin with some contribution from newly synthesized insulin. One of the earliest detectable metabolic defects that occurs in diabetes is loss of the first phase of insulin secretion, which can be detected experimentally by an intravenous glucose tolerance test. If a subject consumes glucose or a mixed meal, plasma [glucose] rises much more slowly—as in Figure 51-3A—because the appearance of glucose depends on intestinal absorption. Given that plasma [glucose] rises so slowly, the acute-phase insulin response can no longer be distinguished from the chronic response, and only a single phase of insulin secretion is apparent. However, the total insulin response to an oral glucose challenge exceeds the response observed when comparable changes in plasma [glucose] are produced by intravenously administered glucose (Fig. 51-3A). This difference is referred to as the incretin effect.

Metabolism of glucose by the β cell triggers insulin secretion

The pancreatic β cells take up and metabolize glucose, galactose, and mannose, and each can provoke insulin secretion by the islet. Other hexoses (e.g., 3-O-methylglucose or 2-deoxyglucose) that are transported into the β cell but that cannot be metabolized do not stimulate insulin secretion. Although glucose itself is the best secretagogue, some amino acids (especially arginine and leucine) and small keto acids (α-ketoisocaproate), as well as ketohexoses (fructose), can also weakly stimulate insulin secretion. The amino acids and keto acids do not share any metabolic pathway with hexoses other than terminal oxidation through the citric acid cycle (see Chapter 58). These observations have led to the suggestion that the ATP generated from the metabolism of these varied substances may be involved in insulin secretion. In the laboratory, depolarizing the islet cell membrane by raising extracellular [K+] provokes insulin secretion. In addition, glucagon has long been known to be a strong insulin secretagogue.

From these data has emerged a relatively unified picture of how various secretagogues trigger insulin secretion. Key to this picture is the presence in the islet of an ATP-sensitive K+ channel and a voltage-gated Ca2+ channel in the plasma membrane (Fig. 51-4). The K+ channel (KATP) is an octamer of four Kir 6.2 channels and four sulfonylurea receptors (SURs); see Chapter 7). Glucose triggers insulin release in a seven-step process:

1. Glucose enters the β cell through the GLUT2 glucose transporter by facilitated diffusion (see Chapter 5). Amino acids enter through a different set of transporters.

2. In the presence of glucokinase (the rate-limiting enzyme in glycolysis), the entering glucose undergoes glycolysis and raises [ATP]i by phosphorylating ADP. Some amino acids also enter the citric acid cycle and produce similar changes in [ATP]i and [ADP]i. In both cases, the NADH/NAD+ ratio (see Chapter 58) also would increase.

3. The increased [ATP]i, the increased [ATP]i/[ADP]i ratio, or the elevated [NADH]i/[NAD+]i ratio causes KATP channels (see Chapter 7) to close.

4. Reducing the K+ conductance of the cell membrane causes the β cell to depolarize (i.e., the membrane potential is less negative).

5. This depolarization activates voltage-gated Ca2+ channels (see Chapter 7).

6. The increased Ca2+ permeability leads to increased Ca2+ influx and increased intracellular free Ca2+. This rise in [Ca2+]i additionally triggers Ca2+-induced Ca2+ release (see Chapter 9).

7. The increased [Ca2+]i, perhaps by activation of a Ca2+ calmodulin phosphorylation cascade, ultimately leads to insulin release.


Figure 51-4 Mechanism of insulin secretion by the pancreatic β cell. Increased levels of extracellular glucose trigger the β cell to secrete insulin in the seven steps outlined in this figure. Metabolizable sugars (e.g., galactose and mannose) and certain amino acids (e.g., arginine and leucine) can also stimulate the fusion of vesicles that contain previously synthesized insulin. In addition to these fuel sources, certain hormones (e.g., glucagon, somatostatin, cholecystokinin [CCK]) can also modulate insulin secretion. DAG, diacylglycerol; ER, endoplasmic reticulum; IP3, inositol 1, 4, 5-triphosphate; PIP2, phosphatidylinositol 4,5-biphosphate.

In addition to the pathway just outlined, other secretagogues can also modulate insulin secretion through the phospholipase C pathway or through the adenylyl cyclase pathway (see Chapter 3). For example, glucagon, which stimulates insulin release, may bypass part or all of the glucose/[Ca2+]i pathway by stimulating the adenylyl cyclase, thus raising cAMP levels and activating protein kinase A (PKA). Conversely, somatostatin, which inhibits insulin release, may act by inhibiting adenylyl cyclase.

Neural and humoral factors modulate insulin secretion

The islet is richly innervated by both the sympathetic and the parasympathetic divisions of the ANS. Neural signals appear to play an important role in the β-cell response in several settings. β-Adrenergicstimulation augments islet insulin secretion, whereas α-adrenergic stimulation inhibits it (Fig. 51-4). Isoproterenol, a synthetic catecholamine that is a specific agonist for the β-adrenergic receptor, potently stimulates insulin release. In contrast, norepinephrine and synthetic α-adrenergic agonists suppress insulin release both basally and in response to hyperglycemia. Because the postsynaptic sympathetic neurons of the pancreas release norepinephrine, which stimulates α more than β adrenoceptors, sympathetic stimulation through the celiac nerves inhibits insulin secretion. In contrast to α-adrenergic stimulation, parasympathetic stimulation through the vagus nerve, which releases acetylcholine, causes an increase in insulin release.

Exercise The effect of the sympathetic division on insulin secretion may be particularly important during exercise, when adrenergic stimulation of the islet increases. The major role for α-adrenergic inhibitionof insulin secretion during exercise is to prevent hypoglycemia. Exercising muscle tissue uses glucose even when plasma [insulin] is low. If insulin levels were to rise, glucose use by the muscle would increase even further and promote hypoglycemia. Furthermore, an increase in [insulin] would inhibit lipolysis and fatty acid release from adipocytes and would thus diminish the availability of fatty acids, which the muscle can use as an alternative fuel to glucose (see Chapter 60). Finally, a rise in [insulin] would decrease glucose production by the liver. Suppression of insulin secretion during exercise may thus serve to prevent excessive glucose uptake by muscle, which if it were to exceed the ability of the liver to produce glucose, would lead to severe hypoglycemia, compromise the brain, and abruptly end any exercise.

Feeding Another important setting in which neural and humoral factors regulate insulin secretion is during feeding. Food ingestion triggers a complex series of neural, endocrine, and nutritional signals to many body tissues. The cephalic phase (see Chapters 4243, and 45) of eating, which occurs before food is ingested, results in stimulation of gastric acid secretion and a small rise in plasma insulin. This response appears to be mediated by the vagus nerve in both cases. If no food is forthcoming, blood [glucose] declines slightly and insulin secretion is again suppressed. If food ingestion does occur, the acetylcholine released by postganglionic vagal fibers in the islet augments the insulin response of the β cell to glucose.

As already discussed, after a subject drinks a glucose solution, the total amount of insulin secreted is greater than when the same amount of glucose is administered intravenously (Fig. 51-3A versus C). This observation has led to a search for enteric factors or incretins that could augment the islet β-cell response to an oral glucose stimulus. Currently, three peptides, cholecystokinin, glucagon-like intestinal peptide 1 (GLP-1), and gastric inhibitory polypeptide (GIP)—all of which are released by gut tissues in response to feeding—have been found to enhance insulin secretion. GLP-1, discussed later, may be the most important incretin yet discovered. A peptide analogue of GLP-1 that is found in the salivary secretion of the Gila monster has been approved for use in treating diabetic patients, based on the ability of this agent to enhance insulin secretion and to ameliorate hyperglycemia.


An entire class of drugs—the sulfonylurea agents—is used in the treatment of patients with adult-onset diabetes, also called type 2 diabetes or non–insulin-dependent diabetes mellitus (NIDDM). Patients with type 2 diabetes have two defects: (1) although their β cells are capable of making insulin, they do not respond normally to increased blood glucose levels; and (2) the target tissues are less sensitive to insulin.

The sulfonylurea agents were discovered accidentally. During the development of sulfonamide antibiotics after the Second World War, investigators noticed that the chemically related sulfonylurea agents produced hypoglycemia. These drugs turned out to have no value as antibiotics, but they did prove effective in treating the hyperglycemia of NIDDM. The sulfonylureas enhance insulin secretion by β cells by binding to the SUR subunits (see Chapter 7) of KATP channels, thereby decreasing the likelihood that these channels will be open. This action enhances glucose-stimulated insulin secretion (Fig. 51-4). By increasing insulin secretion and decreasing blood glucose, the sulfonylureas decrease the insulin resistance that is seen in these patients.

Unlike insulin, which must be injected, sulfonylureas can be taken orally and are therefore preferred by many patients. However, they have a therapeutic role only in NIDDM; the β cells in patients with type 1 or juvenile-onset diabetes (i.e., IDDM) are nearly all destroyed, and these patients must be treated with insulin replacement therapy.

In the laboratory, incretins stimulate insulin secretion by isolated islets of Langerhans, and glucose increases this secretion even further. The presence of these incretins in the gut mucosa gives the islets advance notice that nutrients are being absorbed, and it primes the β cells to amplify their response to glucose. In addition, vagal stimulation of the β cells primes the islets for an amplified response.

The insulin receptor is a receptor tyrosine kinase

Once insulin is secreted into the portal blood, it first travels to the liver, where more than half is bound and removed from the circulation. The insulin that escapes the liver is available to stimulate insulin-sensitive processes in other tissues. At each target tissue, the first action of insulin is to bind to a specific receptor tyrosine kinase (see Chapter 3) on the plasma membrane (Fig. 51-5).


Figure 51-5 The insulin receptor. The insulin receptor is a heterotetramer that consists of two extracellular α chains and two membrane-spanning β chains. Insulin binding takes place on the cysteine-rich region of the α chains.

As discussed in Chapter 3, the insulin receptor—as well as the closely related insulin-like growth factor 1 (IGF-1) receptor—is a heterotetramer, with two identical α chains and two identical β chains. The α and β chains are synthesized as a single polypeptide that is subsequently cleaved. The two chains are joined by disulfide linkage (reminiscent of the synthesis of the A and B chains of insulin itself) in the sequence β-α-α-β. The insulin receptor shares considerable structural similarity with the IGF-1 receptor (see Chapter 48). The overall sequence homology is ~50%, and this figure rises to more than 80% in the tyrosine kinase region. This similarity is sufficient that very high concentrations of insulin can stimulate the IGF-1 receptor, and, conversely, high levels of IGF-1 can stimulate the insulin receptor.

The insulin receptor’s extracellular α chains have multiple N-glycosylation sites. The β chains have an extracellular, a membrane spanning, and an intracellular portion. The β subunit of the receptor is glycosylated on its extracellular domains; receptor glycosylation is required for insulin binding and action. The intracellular domain of the β chain possesses tyrosine kinase activity, which increases markedly when insulin binds to sites on the α chains of the receptor. The insulin receptor can phosphorylate both itself and other intracellular substrates at tyrosine residues. The targets of tyrosine phosphorylation include a family of cytosolic proteins known as insulin-receptor substrates (IRS-1, IRS-2, IRS-3, and IRS-4) as well as Src h omology C terminus (SHC), as illustrated in Figure 51-6. This phosphorylation mechanism appears to be the major one by which insulin transmits its signal across the plasma membrane of insulin target tissues.


Figure 51-6 The insulin signal transduction system. When insulin binds to its receptor—which is a receptor tyrosine kinase (RTK)—tyrosine kinase domains on the intracellular portion of the β chains become active. The activated receptor transduces its signals to downstream effectors by phosphorylating at tyrosine residues the receptor itself, the insulin-receptor substrate family (IRS-1, IRS-2, IRS-3, IRS-4), and other cytosolic proteins (e.g., SHC). SH2-containing proteins dock onto certain phosphorylated tyrosine groups on the IRSs and thus become activated. Not all the signaling pathways are active in all of insulin’s target cells. For example, the liver cell does not rely on the GLUT4 transporter to move glucose in and out of the cell. Similarly, the liver is a very important target for regulation by insulin of the gluconeogenic enzymes, whereas muscle and adipose tissue are not. MAPK, MAP kinase.

The IRS proteins are docking proteins to which various downstream effector proteins bind and thus become activated. IRS-1 has at least eight tyrosines within specific motifs that generally bind proteins containing SH2 (Src homology domain 2) domains, so that a single IRS molecule simultaneously activates multiple pathways. The IGF-1 receptor, which is closely related to the insulin receptor, also acts through IRS proteins.

Figure 51-6 illustrates three major signaling pathways triggered by the aforementioned tyrosine phosphorylations. The first begins when phosphatidylinositol 3-kinase (PI3K) binds to phosphorylated IRS and becomes activated. PI3K phosphorylates a membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to form PIP3, and it leads to major changes in glucose and protein metabolism. (See Note: Insulin Signal Transduction)

The second signaling pathway begins in one of two ways: (1) the insulin receptor phosphorylates SHC, or (2) GRB2 binds to an IRS and becomes activated. As illustrated in Figure 51-6, both phosphorylated SHC and activated GRB2 trigger the Ras signaling pathway, leading through MEK and MAP kinases to increased gene expression and growth (see Chapter 4). Gene deletion studies in mice show that IRS-1 deletion does not cause diabetes, but it results in small mice. In contrast, IRS-2 deletion does cause diabetes, in part because of impaired insulin secretion by the pancreatic β cell.

The Insulin Receptor and Rare Forms of Diabetes

The ability of insulin to act on a target cell depends on three things: the number of receptors present on the target cell, the receptor’s affinity for insulin, and the receptor’s ability to transduce the insulin signal.

Several disorders have been described in which a mutation of the insulin receptor blunts or prevents insulin’s actions. One such mutation markedly affects growth in utero, as well as after birth. This rare disorder is called leprechaunism, and it is generally lethal within the first year of life. Other mutations of the receptor have less devastating consequences.

Some individuals make antibodies to their own insulin receptors. Insulin, produced either endogenously or administered to these patients, does not work well because it must compete with these antibodies for sites on the receptor; as a result, these patients are hyperglycemic. Other antibodies can be insulin mimetic; that is, not only do the antibodies bind to the receptor, but they also actually mimic insulin’s action. This mimicry causes severe hypoglycemia in affected individuals.

Neither receptor mutations nor antireceptor antibodies appear to be responsible for any of the common forms of diabetes seen clinically. However, abnormal function of the insulin receptor may be involved. Indeed, activation of inflammatory pathways involving p38 MAP kinase and nuclear factor-κβ can lead to phosphorylation of the insulin receptor (and of IRS proteins), principally at serine residues. This serine phosphorylation occurs commonly in animal models of insulin resistance and type 2 diabetes, as well as in human diabetes.

The third signaling pathway begins with the binding of SH2-containing proteins—other than PI3K and GRB2, already discussed—to specific phosphotyrosine groups on either the insulin receptor or IRS proteins. This binding activates the SH2-containing protein.

High levels of insulin lead to downregulation of insulin receptors

The number of insulin receptors expressed on the cell surface is far greater than that needed for the maximal biological response to insulin. In fact, in a physiologically normal individual, the glucose response to insulin is maximal when only ~5% of the receptors are occupied; that is, the target cells have many “spare” receptors for insulin.

The number of insulin receptors present on a target cell is determined by the balance among three factors: (1) receptor synthesis, (2) endocytosis of receptors followed by recycling of receptors back to the cell surface, and (3) endocytosis followed by degradation of receptors. Cells chronically exposed to high concentrations of insulin have fewer receptors than do those exposed to lower concentrations. This dynamic ability of cells to decrease the number of specific receptors on their surface is called downregulation. Insulin downregulates insulin receptors by decreasing receptor synthesis and increasing degradation. Such downregulation is one mechanism by which target tissues modulate their response to hormones. Downregulation of insulin receptors results in a decrease in the sensitivity of the target tissue to insulin without diminishing insulin’s maximal effect.

One example of how downregulation can affect insulin’s action is shown in Figure 51-7, which illustrates the effect of increases in insulin concentration on glucose uptake in adipocytes from normal individuals or type 2 diabetics. Adipocytes from patients with type 2 diabetes (see box on Diabetes Mellitus) have fewer insulin receptors per unit of surface area than do adipocytes from normal individuals. The markedly lower glucose transport across the entire physiological range of insulin concentrations in diabetic adipocytes is characteristic of insulin resistance. In healthy controls, glucose transport is maximal when only a few (~5%) of the receptors are occupied. In diabetic adipocytes, a much higher concentration of insulin is required, and a larger fraction of the insulin receptors is occupied. However, the major effects in type 2 diabetes are apparently not the result of a decrease in receptor number, but rather are caused by impairment in signaling downstream from the receptor. This impairment includes diminished activity of the insulin receptor tyrosine kinase, PI3K activity, and perhaps other steps along the pathway to GLUT4 recruitment to the plasma membrane (Fig. 51-6). The summation of these multiple defects, only some of which have been identified, leads to insulin resistance.


Figure 51-7 Response to insulin of normal and downregulated adipocytes.

In liver, insulin promotes storage of glucose as glycogen, as well as conversion of glucose to triglycerides

Insulin’s actions on cellular targets frequently involve numerous different enzymatic and structural processes. These effects are illustrated as I consider—in this and the next two sections—the three principal targets for insulin action: the liver, muscle, and adipose tissue.

Because the pancreatic veins drain into the portal venous system, all hormones secreted by the pancreas must traverse the liver before entering the systemic circulation. For insulin, the liver is both a target tissue for hormone action and a major site of degradation.

The concentration of insulin in portal venous blood before extraction by the liver is three to four times greater than its concentration in the systemic circulation. The hepatocyte is therefore bathed in a relatively high concentration of insulin and is thus well positioned to respond acutely to changes in plasma [insulin].

After feeding, the plasma [insulin] rises, triggered by glucose and by neural and incretin stimulation of β cells. In the liver, this insulin rise acts on four main processes involved in fuel metabolism (Fig. 51-7). These divergent effects of insulin entail the use of multiple enzymatic control mechanisms.

Glycogen Synthesis and Glycogenolysis Physiological increases in plasma [insulin] decrease the breakdown and utilization of glycogen and—conversely—promote the formation of glycogen from plasma glucose. Although moderately increased levels of insulin allow gluconeogenesis to persist, the hepatocytes store the newly formed glucose 6-phosphate as glycogen rather than releasing it as glucose to the bloodstream. At high concentrations, insulin can inhibit the gluconeogenic conversion of lactate/pyruvate and amino acids to glucose 6-phosphate.

Glucose enters the hepatocyte from the blood through GLUT2, which mediates the facilitated diffusion of glucose (numbered boxes in Fig. 51-8). GLUT2 is present in abundance in the liver plasma membrane, even in the absence of insulin, and its activity is not influenced by insulin. Insulin stimulates glycogen synthesis from glucose by activating glucokinase (1) and glycogen synthase (2). The latter enzyme contains multiple serine phosphorylation sites. Insulin causes a net dephosphorylation of the protein, thus increasing the enzyme’s activity. At the same time that glycogen synthase is being activated, increases in both insulin and glucose diminish glycogen phosphorylase activity (3). This enzyme is rate limiting for the breakdown of glycogen. The same enzyme that dephosphorylates (and thus activates) glycogen synthase also dephosphorylates (and thus inhibits) phosphorylase. Thus, insulin has opposite effects on the opposing enzymes, with the net effect that it promotes glycogen formation. Insulin also inhibits glucose-6-phosphatase (G6Pase) (4), which converts glucose 6-phosphate to glucose and thus completes the conversion of glycogen to glucose. Glycogen is an important storage form of carbohydrate in both liver and muscle. The glycogen stored during the postprandial period is then available for use many hours later as a source of glucose.


Figure 51-8 Effect of insulin on hepatocytes. Insulin has four major effects on liver cells. First, insulin promotes glycogen synthesis from glucose by enhancing the transcription of glucokinase (1) and by activating glycogen synthase (2). Additionally, insulin together with glucose inhibits glycogen breakdown to glucose by diminishing the activity of G6Pase (4). Glucose also inhibits glycogen phosphorylase (3). Second, insulin promotes glycolysis and carbohydrate oxidation by increasing the activity of glucokinase (1), phosphofructokinase (5), and pyruvate kinase (6). Insulin also promotes glucose metabolism through the hexose monophosphate shunt (7). Finally, insulin promotes the oxidation of pyruvate by stimulating pyruvate dehydrogenase (8). Insulin also inhibits gluconeogenesis by inhibiting the activity of PEPCK (9), FBPase (10), and G6Pase (4). Third, insulin promotes the synthesis and storage of fats by increasing the activity of acetyl CoA carboxylase (11) and fatty acid synthase (12) as well as the synthesis of several apoproteins packaged with VLDL. Insulin also indirectly inhibits fat oxidation because the increased levels of malonyl CoA inhibit CAT I (13). The inhibition of fat oxidation helps shunt fatty acids to esterification as triglycerides and storage as VLDL or lipid droplets. Fourth, by mechanisms that are not well understood, insulin promotes protein synthesis (14) and inhibits protein breakdown (15).

Glycolysis and Gluconeogenesis Insulin promotes the conversion of some of the glucose taken up by the liver into pyruvate and—conversely—diminishes the use of pyruvate and other three-carbon compounds for gluconeogenesis (numbered boxes in Fig. 51-8). Insulin induces transcription of the glucokinase gene (1) and thus results in increased synthesis of this enzyme, which is responsible for phosphorylating glucose to glucose 6-phosphate and initiating the metabolism of glucose. In acting to promote glycolysis and diminish gluconeogenesis, insulin induces the synthesis of a glucose metabolite, fructose 2, 6-bisphosphate. This compound is a potent allosteric activator of phosphofructokinase (5), a key regulatory enzyme in glycolysis. Insulin also stimulates pyruvate kinase (6), which forms pyruvate, and stimulates pyruvate dehydrogenase (8), which catalyzes the first step in pyruvate oxidation. Finally, insulin promotes glucose breakdown by the hexose monophosphate shunt (7).

In addition, insulin also inhibits gluconeogenesis at several steps. Insulin diminishes transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene (9), thus reducing the synthesis of a key regulatory enzyme required to form phosphoenolpyruvate from oxaloacetate early in the gluconeogenic pathway. The increased levels of fructose 2, 6-bisphosphate also inhibit the activity of fructose-1, 6-bisphosphatase (FBPase) (10), which is also part of the gluconeogenic pathway.

Lipogenesis Insulin promotes the storage of fats and inhibits the oxidation of fatty acids (see Fig. 58-9) through allosteric and covalent modification of key regulatory enzymes, as well as by transcription of new enzymes (numbered boxes in Fig. 51-8). The pyruvate that is now available from glycolysis can be used to synthesize fatty acids. Insulin promotes dephosphorylation of acetyl coenzyme A (CoA) carboxylase 2 (ACC2) (11), the first committed step in fatty acid synthesis in the liver. This dephosphorylation leads to increased synthesis of malonyl CoA, which allosterically inhibits carnitine acyltransferase I (CAT I). This enzyme (13) converts acyl CoA and carnitine to acyl carnitine. Thus, malonyl CoA inhibits fatty acid transport into the mitochondria, where fat oxidation occurs. At the same time, insulin stimulates fatty acid synthase (12), which generates fatty acids. Thus, because insulin promotes the formation of malonyl CoA and fatty acids but inhibits fatty acid oxidation, this hormone favors esterification of the fatty acids with glycerol within the liver, thus forming triglycerides. The liver can either store these triglycerides in lipid droplets or export them as very-low-density lipoprotein (VLDL) particles (see Chapter 46). Indeed, insulin induces the synthesis of several of the apoproteins that are packaged with the VLDL particle. The hepatocyte then releases these VLDLs, which leave the liver through the hepatic vein. Muscle and adipose tissue subsequently take up the lipids in these VLDL particles and either store them or oxidize them for fuel. Thus, by regulation of transcription, by allosteric activation, and by regulation of protein phosphorylation, insulin acts to promote the synthesis and storage of fat and diminish its oxidation in liver.

Protein Metabolism Insulin stimulates the synthesis of protein and simultaneously reduces the degradation of protein within the liver (numbered boxes in Fig. 51-8). The general mechanism by which insulin stimulates net protein synthesis (14) and restrains proteolysis (15) by the liver has not been nearly as well defined as have its effects on the enzymes involved in carbohydrate and lipid metabolism. The regulatory steps in these pathways appear more complex and are less well understood.

In summary, insulin modulates the activity of multiple regulatory enzymes, which are responsible for the hepatic metabolism of carbohydrates, fat, and protein. Insulin causes the liver to take up glucose from the blood and either store the glucose as glycogen or break it down into pyruvate. The pyruvate provides the building blocks for storage of the glucose carbon atoms as fat. Insulin also diminishes the oxidation of fat, which normally supplies much of the ATP used by the liver. As a result, insulin causes the liver, as well as other body tissues, to burn carbohydrates preferentially.

In muscle, insulin promotes the uptake of glucose and its storage as glycogen

Muscle is a major insulin-sensitive tissue and the principal site of insulin-mediated glucose disposal. Insulin has four major effects on muscle. First, in muscle, unlike the liver, glucose crosses the plasma membrane principally through GLUT4, an insulin-sensitive glucose transporter. GLUT4, which is found virtually exclusively in striated muscle and adipose tissue, belongs to a family of proteins that mediate the facilitated diffusion of glucose (see Chapter 5). Insulin markedly stimulates GLUT4 in both muscle and fat (see later) by a process involving recruitment of preformed transporters from a membranous compartment in the cell cytosol out to the plasma membrane (Fig. 51-9). Recruitment places additional glucose transporters in the plasma membrane, thus increasing the Vmax of glucose transport into muscle and increasing the flow of glucose from the interstitial fluid to the cytosol. As discussed earlier, a different glucose transporter, GLUT2, mediates glucose transport into hepatocytes (Fig. 51-8), and insulin does not increase the activity of that transporter.


Figure 51-9 Effect of insulin on muscle. Insulin has four major effects on muscle cells. First, insulin promotes glucose uptake by recruiting GLUT4 transporters to the plasma membrane. Second, insulin promotes glycogen synthesis from glucose by enhancing the transcription of hexokinase (1) and by activating glycogen synthase (2). Third, insulin promotes glycolysis and carbohydrate oxidation by increasing the activity of hexokinase (1), phosphofructokinase (3), and pyruvate dehydrogenase (4). These actions are similar to those in liver; little or no gluconeogenesis occurs in muscle. Fourth, insulin promotes protein synthesis (5) and inhibits protein breakdown (6).

The second effect of insulin on muscle (Fig. 51-9) is to enhance the conversion of glucose to glycogen by activating hexokinase ([1] different from the glucokinase in liver) and glycogen synthase (2). Third, insulin increases glucose breakdown and oxidation by increasing phosphofructokinase (3) and pyruvate dehydrogenase (4) activity. Fourth, insulin also stimulates the synthesis of protein in skeletal muscle (5) and slows the degradation of existing proteins (6). The result is preservation of muscle protein mass, which has obvious beneficial effects in preserving strength and locomotion. The insulin-induced increase in glucose utilization permits the muscle to diminish fat utilization and allows it to store as triglycerides some of the fatty acid that it removes from the circulation. The stored triglycerides and glycogen are major sources of energy that muscle can use later when called on to exercise or generate heat.

Exercise and insulin have some interesting parallel effects on skeletal muscle. Both increase the recruitment of GLUT4 transporters to the sarcolemma, and both increase glucose oxidation; therefore, both increase glucose uptake by muscle. Additionally, exercise and insulin appear to have synergistic effects on the foregoing processes. Clinically, this synergism is manifested as a marked increase in insulin sensitivity induced by exercise and is exploited as part of the treatment of patients with diabetes mellitus.

In muscle, as in the liver, insulin directs the overall pattern of cellular fuel metabolism by acting at multiple sites. In both tissues, insulin increases the oxidation of carbohydrate, thus preserving body protein and fat stores. Carbohydrate ingested in excess of that used immediately as an oxidative fuel is either stored as glycogen in liver and muscle or is converted to lipid in the liver and exported to adipose tissue and muscle.

In adipocytes, insulin promotes uptake of glucose and its conversion to triglycerides for storage

Adipose tissue is the third major insulin-sensitive tissue involved in the regulation of body fuel. Again, insulin has several sites of action in adipocytes. All begin with the same receptor-mediated action of insulin to stimulate several cellular effector pathways. Insulin has four major actions on adipocytes. First, like muscle, adipose contains the insulin-sensitive GLUT4 glucose transporter. In insulin-stimulated cells, preformed transporters are recruited from an intracellular compartment to the cell membrane, thus markedly accelerating the entry of glucose into the cell.

Second, insulin promotes the breakdown of glucose to metabolites that will eventually be used to synthesize triglycerides (Fig. 51-10). Unlike muscle or liver, little of the glucose taken up is stored as glycogen. Instead, the adipocyte glycolytically metabolizes much of the glucose to α-glycerol phosphate, which it will use in the synthesis of triglycerides. The glucose that is not converted to α-glycerol phosphate goes on to form acetyl CoA and then malonyl CoA and fatty acids. Insulin enhances this flow of glucose to fatty acids by stimulating pyruvate dehydrogenase (1) and acetyl CoA carboxylase (2).


Figure 51-10 Effect of insulin on adipocytes. Insulin has four major effects on adipocytes. First, insulin promotes glucose uptake by recruiting GLUT4 transporters to the plasma membrane. Second, insulin promotes glycolysis, leading to the formation of α-glycerol phosphate. Insulin also promotes the conversion of pyruvate to fatty acids by stimulating pyruvate dehydrogenase (1) and acetyl CoA carboxylase (2). Third, insulin promotes the esterification of α-glycerol phosphate with fatty acids to form triglycerides, which the adipocyte stores in fat droplets. Conversely, insulin inhibits hormone-sensitive triglyceride lipase (3), which would otherwise break the triglycerides down into glycerol and fatty acids. Fourth, insulin promotes the synthesis of LPL in the adipocyte. The adipocyte then exports this enzyme to the endothelial cell, where it breaks down the triglycerides contained in chylomicrons and VLDL, thus yielding fatty acids. These fatty acids then enter the adipocyte for esterification and storage in fat droplets as triglycerides.

Third, insulin promotes the formation of triglycerides by simple mass action; the increased levels of α-glycerol phosphate increase its esterification with fatty acids (principally C-16 and C-18) to yield triglycerides. Some of the fatty acids are a result of the glucose metabolism noted earlier. Most of the fatty acids, however, enter the adipocyte from chylomicrons and VLDLs (see Table 46-5) in the blood (see later). The cell sequesters these triglycerides in lipid droplets, which form most of the mass of the adipose cell. Conversely, insulin restrains the activity of a hormone-sensitive triglyceride lipase (HSL) (3). In fat, this enzyme mediates the conversion of stored triglyceride to fatty acids and glycerol for export to other tissues.

Fourth, insulin induces the synthesis of a different enzyme—lipoprotein lipase (LPL). This lipase does not act on the lipid stored within the adipose cell. Rather, the adipocyte exports the LPL to the endothelial cell, where it resides on the extracellular surface of the endothelial cell, facing the blood and anchored to the plasma membrane. In this location, the LPL acts on triglycerides in chylomicrons and VLDLs and cleaves them into glycerol and fatty acids. These fatty acids are then available for uptake by nearby adipocytes, which esterify them with glycerol phosphate to form triglycerides. This mechanism provides an efficient means by which insulin can promote the storage of lipid in adipose tissue.


Glucagon is the other major pancreatic islet hormone that is involved in the regulation of body fuel metabolism. Ingestion of protein appears to be the major stimulus to secretion of glucagon. Glucagon’s principal target tissue is the liver. Like insulin, glucagon is secreted first into the portal blood and is therefore anatomically well positioned to regulate hepatic metabolism.

Although the amino acids released by digestion of a protein meal appear to be the major glucagon secretagogue, glucagon’s main actions on the liver appear to involve the regulation of carbohydrate and lipidmetabolism. Glucagon is particularly important in stimulating glycogenolysis, gluconeogenesis, and ketogenesis. Glucagon does not act solely on the liver, but also has glycogenolytic action on cardiac and skeletal muscle and lipolytic action on adipose tissue, and it promotes the breakdown of protein by several tissues. However, these effects on protein tissue breakdown appear to be more prominent when tissues are exposed to pharmacological concentrations of glucagon. At more physiological concentration, the liver appears to be the major target tissue.

In many circumstances, the actions of glucagon antagonize those of insulin. Unlike the cellular mechanism of action of insulin, the mechanism of glucagon action is understood in considerable detail.

Pancreatic α cells secrete glucagon in response to ingested protein

Glucagon is a 31–amino acid peptide (molecular weight, ~3500 Da) synthesized by α cells in the islets of Langerhans. In humans, the glucagon gene is located on chromosome 2. The initial gene product is the mRNA encoding preproglucagon. As is the case for insulin, a peptidase removes the signal sequence of preproglucagon during translation of the mRNA in the rough endoplasmic reticulum to yield proglucagon. Proteases in the α cells subsequently cleave the proglucagon (molecular weight, ~9000 Da) into the mature glucagon molecule and several biologically active peptides (Fig. 51-11). Neuroendocrine cells (i.e., L cells) within the gut process the proglucagon differently to yield not glucagon, but GLP-1—a potent incretin—and other peptides.


Figure 51-11 The synthesis of the glucagon molecule. The proglucagon molecule includes amino acid sequences that, depending on how the peptide chain is cleaved, can yield glucagon-related polypeptide (GRPP), glucagon, IP-1, GLP-1, IP-2, and GLP-2. Proteases in the pancreatic α cells cleave proglucagon at points that yield GRPP, glucagon, and a C-terminal fragment. Proteases in neuroendocrine cells in the intestine cleave proglucagon to yield glicentin, GLP-1, IP-2, and GLP-2.

Pancreatic α Cells The mature glucagon molecule is the major secretory product of the α cell. As in insulin, the fully processed glucagon molecule is stored in secretory vesicles within the cell’s cytosol. Although amino acids are the major secretagogues, the concentrations of amino acids required to provoke secretion of glucagon in vitro are higher than those generated in vivo. This observation suggests that other neural or humoral factors amplify the response in vivo, analogous to the effects of incretin on insulin secretion. Whereas glucose and several amino acids both stimulate insulin secretion by β cells, only amino acids stimulate glucagon secretion by α cells; glucose inhibits glucagon secretion. The signaling mechanism by which α cells recognize either amino acids or glucose is not known.

Glucagon, like the incretins, is a potent insulin secretagogue. Because most of the α cells are located downstream from the β cells (recall that the circulation of blood proceeds from the β cells and then out past the α cells), however, it is unlikely that glucagon exerts an important paracrine effect on insulin secretion.

Intestinal L Cells Proteases in neuroendocrine cells in the intestine process proglucagon differently than do α cells. L cells produce a peptide fragment called glicentin that contains the amino acid sequence of glucagon but does not bind to glucagon receptors. Downstream from the glucagon-coding region, the L cells generate two peptides from proglucagon: GLP-1 and GLP-2. Both are glucagon-like in that they cross-react with some antisera directed to glucagon, but GLP-1 and GLP-2 have very weak biological activity as glucagon analogues. However, GLP-1 is one of the most potent incretins, and it stimulates insulin secretion. GLP-1 is released by the gut into the circulation in response to carbohydrate or protein ingestion. GLP-2 is not an incretin, and its biological actions are not known.

Glucagon, acting through cAMP, promotes the synthesis of glucose by the liver

Glucagon is an important regulator of hepatic glucose production and ketogenesis in the liver. As shown in Figure 51-12, glucagon binds to a receptor that activates the heterotrimeric G protein Gαs, which stimulates membrane-bound adenylyl cyclase (see Chapter 3). The cAMP formed by the cyclase, in turn, activates PKA, which phosphorylates numerous regulatory enzymes and other protein substrates, thus altering glucose and fat metabolism in the liver. Whereas insulin leads to the dephosphorylation of certain key enzymes (i.e., glycogen synthase, acetyl CoA carboxylase, phosphorylase), glucagon leads to their phosphorylation.


Figure 51-12 Glucagon signal transduction. Glucagon generally antagonizes the effects of insulin in the liver. Glucagon binds to a Gαs-coupled receptor, thereby activating the adenylyl cyclase/cAMP/PKA cascade. Glucagon has three major effects on liver cells. First, glucagon promotes net glycogen breakdown. Glucagon inhibits glycogen synthesis by reducing the activity of glucokinase (1) and glycogen synthase (2). However, glucagon promotes glycogen breakdown by activating glycogen phosphorylase (3) and G6Pase (4). Second, glucagon promotes net gluconeogenesis. The hormone inhibits glycolysis and carbohydrate oxidation by reducing the activity glucokinase (1), phosphofructokinase (5), and pyruvate kinase (6). Glucagon also stimulates gluconeogenesis by increasing the transcription of PEPCK (9), FBPase (10), and G6Pase (4). Third, glucagon promotes the oxidation of fats. The hormone inhibits the activity of acetyl CoA carboxylase (11). Glucagon indirectly stimulates fat oxidation because the decreased levels of malonyl CoA relieve the inhibition of malonyl CoA on CAT (13). The numbering scheme for these reactions is the same as that in Figure 51-8.

A particularly clear example of the opposing actions of insulin and glucagon involves the activation of glycogenolysis, which is discussed in Chapter 3 (see Fig 3-7). PKA phosphorylates the enzyme phosphorylase kinase (see Fig. 59-8), thus increasing the activity of phosphorylase kinase and allowing it to increase the phosphorylation of its substrate, glycogen phosphorylase b. The addition of a single phosphate residue to phosphorylase b converts it to phosphorylase a. Liver phosphorylase b has little activity in breaking the 1 to 4 glycosidic linkages of glycogen, but phosphorylase a is very active. In addition to converting phosphorylase b to the active phosphorylase a form, PKA also phosphorylates a peptide called inhibitor I. In its phosphorylated form, inhibitor I decreases the activity of protein phosphatase 1 (PP1) that otherwise would dephosphorylate both phosphorylase kinase and phosphorylase a(converting them to their inactive forms). PP1 also activates glycogen synthase. Thus, through inhibitor I, glucagon modulates several of the enzymes involved in hepatic glycogen metabolism to provoke net glycogen breakdown. As a result of similar actions on the pathways of gluconeogenesis and lipid oxidation, glucagon also stimulates these processes. Conversely, glucagon restrains glycogen synthesis, glycolysis, and lipid storage.

The effects of the glucagon—as well as the effect of glucocorticoids—to enhance gluconeogenesis involve activation of the transcription factor CBP as well as PGC-1 (PPAR-γ coactivator-1), which enhances the transcription factor PPAR-γ (see Chapter 4). The net effect is an increase in the synthesis of such key regulatory enzymes as G6Pase and PEPCK—both of which promote the release of glucose. Insulin restrains the transcription of these two enzymes in two ways, both through the PI3K/protein kinase B pathway (Fig. 51-6). First, insulin increases the release of the transcription factor domain of SREBP-1 (see Chapter 3), which antagonizes the transcription of mRNA encoding the two enzymes. Second, insulin increases the phosphorylation of several transcription factors of the Foxo family, thereby promoting their movement out of the nucleus and preventing them from binding to the promoter regions of the two enzymes.

These actions of glucagon can be integrated with our understanding of insulin’s action on the liver in certain physiological circumstances. For example, after an overnight fast, when insulin concentrations are low, glucagon stimulates the liver to produce the glucose that is required by the brain and other tissues for their ongoing function. With ingestion of a protein meal, absorbed amino acids provoke insulin secretion, which can inhibit hepatic glucose production and promote glucose storage by liver and muscle (see earlier). If the meal lacked carbohydrate, the secreted insulin could cause hypoglycemia. However, glucagon secreted in response to a protein meal balances insulin’s action on the liver and thus maintains glucose production and avoids hypoglycemia.

Glucagon promotes the oxidation of fat in the liver, which can lead to the formation of ketone bodies

Glucagon plays a major regulatory role in hepatic lipid metabolism. As shown in the earlier discussion of insulin (Fig. 51-8), the liver can esterify fatty acids with glycerol to form triglycerides, which it can store or export as VLDL particles. Alternatively, the liver can partially oxidize fatty acids—and form ketones—or can fully oxidize them to CO2 (see Chapter 58). Whereas fatty acid esterification and storage occur in the liver cytosol, oxidation and ketogenesis occur within the mitochondria.

Glucagon stimulates fat oxidation indirectly by increasing the activity of the CAT system, which mediates the transfer of fatty acids across the mitochondrial membrane. Glucagon produces this stimulation by inhibiting acetyl CoA carboxylase, which generates malonyl CoA, the first committed intermediate in the synthesis of fatty acids by the liver. Malonyl CoA is also an inhibitor of the CAT system. By inhibiting acetyl CoA carboxylase, glucagon lowers the concentration of malonyl CoA, releases the inhibition of CAT, and allows fatty acids to be transferred into the mitochondria. These fatty acids are oxidized to furnish ATP to the liver cell. If the rate of fatty acid transport into the mitochondria exceeds the need of the liver to phosphorylate ADP, the fatty acids will be only partially oxidized, and the keto acids (or “ketone bodies”) β-hydroxybutyric acid and acetoacetic acid will accumulate. These keto acids can exit the mitochondria and the liver to be used by other tissues as oxidative fuel.

During fasting, the decline in insulin and the increase in glucagon promote ketogenesis; this process is of vital importance to the CNS, which can use keto acids but not fatty acids as fuel. In the adaptation to fasting, glucagon therefore plays the important role of stimulating the conversion of fatty acids to ketones and provides the brain with the fuel that is needed to allow continued function during a fast. We discuss fasting in more depth beginning in Chapter 58. (See Note: Hypoglycemia)

Diabetes Mellitus

Diabetes is the most common serious metabolic disease in humans. The hallmark of diabetes is an elevated blood glucose concentration, but this abnormality is just one of many biochemical and physiological alterations that occur in the disease. Diabetes is not one disorder, but it can arise as a result of numerous defects in regulation of the synthesis, secretion, and action of insulin. The type of diabetes that most commonly affects children is called type 1 diabetes mellitus or IDDM. The diabetes that generally begins in adulthood and is particularly common in obese individuals is called type 2 diabetes mellitus or NIDDM. (See Note: Fasting)

Type 1 Diabetes

IDDM is caused by an immune-mediated selective destruction of the β cells of the pancreas. The other cell types present in the islet are spared. The consequence of the loss of insulin, with the preservation of glucagon, can be viewed as an accelerated form of fasting or starvation. A healthy person who is fasting for several days continues to secrete insulin at a low rate that is sufficient to balance the action of glucagon in modulating the production of glucose and ketones by the liver. However, in type 1 diabetes, insulin deficiency is severe, and glucose and ketone production by the liver occur at a rate that greatly exceeds the rate at which they are being used. As a result, the concentration of these substances in blood begins to rise. Even when glucose concentrations reach levels 5 to 10 times normal, no insulin is secreted because β cells are absent. The increased glucose and ketones provide an immense solute load to the kidney that causes osmotic diuresis. In addition, the keto acids that are produced are moderately strong organic acids (pK < 4.0), and their increased production causes severe metabolic acidosis (see Chapter 28). If these patients are not treated with insulin, the acidosis and dehydration lead to death from diabetic ketoacidosis.

With appropriate diagnosis and the availability of insulin as an effective treatment, persons with type 1 diabetes can lead full, productive lives. Indeed, some patients have been taking insulin successfully for treatment of type 1 diabetes for more than 75 years. As technology has improved, patients have been able to monitor their blood glucose themselves and adjust their insulin doses accordingly using specifically designed insulin analogues that have either short or very long half-lives. Thus, individuals with type 1 diabetes can avoid not only severe life-threatening episodes of ketoacidosis but also the chronic consequences of diabetes, namely, blood vessel injury that can lead to blindness, kidney failure, and accelerated atherosclerosis.

Type 2 Diabetes

In type 2 diabetes, the cause of hyperglycemia is more complex. These individuals continue to make insulin. β Cells not only are present but also are frequently hyperplastic (at least early in the course of the disease). For reasons still being defined, the β cells do not respond normally to increases in plasma glucose by increasing insulin secretion. However, altered insulin secretion is only part of the problem. If we administered identical doses of insulin to the liver, muscle, and adipose tissue of a person with type 2 diabetes and a healthy control, we would find that the patient with type 2 diabetes was resistant to the action of insulin. Thus, both the metabolism of glucose in response to insulin and the secretion of insulin are abnormal in type 2 diabetes. Which problem—decreased insulin release or insulin resistance—is more important in provoking development of the diabetic state likely varies among individuals. Usually, these subjects make enough insulin—and it is sufficiently active—that the severe ketoacidosis described earlier in patients with type 1 diabetes does not develop.

The insulin resistance seen in individuals with type 2 diabetes appears to bring with it an increase in the prevalence of hypertension, obesity, and a specific dyslipidemia characterized by elevated triglycerides and a low high-density cholesterol (see Fig. 46-15). Insulin resistance (along with one or more of these other metabolic abnormalities) is frequently found in individuals before the development of type 2 diabetes and is referred to as the metabolic syndrome. This constellation of abnormalities is estimated to affect more than 45 million individuals in the United States alone. Because each component of this syndrome has adverse effects on blood vessels, these individuals are at particularly increased risk for early atherosclerosis.

Studies have now shown that tight control of glucose concentrations in both type 1 and type 2 diabetes, together with careful management of blood pressure and plasma lipids, can retard the development of many of the chronic complications of diabetes.

In addition to its effects on hepatic glucose and lipid metabolism, glucagon also has the extrahepatic actions of accelerating lipolysis in adipose tissue and proteolysis in muscle. However, these effects are generally demonstrable only with high concentrations of glucagon, and although they may be important in certain pathologic situations associated with greatly elevated glucagon concentrations (e.g., ketoacidosis or sepsis), they appear less important in the day-to-day actions of glucagon.


Somatostatin inhibits the secretion of growth hormone, insulin, and other hormones

Somatostatin is made in the δ cells of the pancreatic islets (Fig. 51-1), as well as in the D cells of the gastrointestinal tract (see Chapter 42), in the hypothalamus, and in several other sites in the CNS (see Chapter 48). Somatostatin was first described as a hypothalamic peptide that suppressed the release of growth hormone—which had also been called somatotropin, thus accounting for the name somatostatin. In both pancreatic δ cells and the hypothalamus, somatostatin exists as both 14– and 28–amino acid peptides. In the hypothalamus, the 14–amino acid form is predominant, whereas in the gastrointestinal tract (including the δ cells), the 28–amino acid form predominates. The 14–amino acid form is the C-terminal portion of the 28–amino acid form. The biological activity of somatostatin resides in these 14 amino acids.

Somatostatin inhibits the secretion of multiple hormones, including growth hormone, insulin, glucagon, gastrin, vasoactive intestinal peptide (VIP), and thyroid-stimulating hormone. This property has led to therapeutic use of a long-acting somatostatin analogue (octreotide) in some difficult-to-treat endocrine tumors, including those that produce growth hormone (acromegaly), insulin (insulinoma), serotonin (carcinoid), among others. The concentrations of somatostatin found in pancreatic venous drainage are sufficiently high to inhibit basal insulin secretion. Recall that blood flows from the center of each islet—which is where the bulk of the β cells are—to the periphery of the islet—which is where the δ cells tend to be located (Fig. 51-1). This spatial arrangement minimizes the effect of somatostatin on the islet from which it is secreted. Whether somatostatin has important paracrine actions on some β cells or on α cells remains controversial.

The islet cells also make other peptides, for example, pancreatic polypeptide formed in the F cells of the pancreas. As with insulin and glucagon, the secretion of pancreatic polypeptide is altered by dietary intake of nutrients. However, whether pancreatic polypeptide has any actions in mammalian fuel metabolism is not clearly understood.

Occasionally, islet cell tumors may develop and secrete gastrin, VIP, growth hormone–releasing factor, or other hormones. Although these individual instances prove that these peptides can be made by islet tissue, they have no known normal function in the islet.


Books and Reviews

Alberti KG, Zimmet P, DeFronzo RA: International Textbook of Diabetes Mellitus, 2nd ed. New York: Wiley; 1997.

Cryer PE, Polonsky KS: Glucose homeostasis and hypoglycemia. In Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Williams Textbook of Endocrinology, 9th ed, Philadelphia: WB Saunders; 1998: 939-971.

Jones PM, Persaud SJ: Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells. Endocr Rev. 1998; 19:429-461.

Kimball SR, Vary TC, Jefferson LS: Regulation of protein synthesis by insulin. Annu Rev Physiol. 1994; 56:321-348.

Poitout V, Robertson RP: An integrated view of beta-cell dysfunction in type-II diabetes. Annu Rev Med . 1996; 47:69-83.

Journal Articles

Araki E, Lipes MA, Patti ME, et al: Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 1994; 372:186-190.

Bell GI, Pictet RL, Rutter WJ, et al: Sequence of the human insulin gene. Nature 1980; 284:26-32.

Cherrington AD: Banting lecture 1997: Control of glucose uptake and release by the liver in vivo. Diabetes 1999; 48:1198-1214.

Gribble FM, Tucker SJ, Haug T, Ashcroft FM: MgATP activates the beta cell KATP channel by interaction with its SUR1 subunit. Proc Natl Acad Sci U S A 1998; 95:7185-7190.

Miki T, Nagashima K, Tashiro F, et al: Defective insulin secretion and enhanced insulin action in KATP channel–deficient mice. Proc Natl Acad Sci U S A 1998; 95:10402-10406.

Pilch PF, Czech MP: Hormone binding alters the conformation of the insulin receptor. Science 1980; 210:1152-1153.