The Endocrine Pancreas

The islets of Langerhans are endocrine and paracrine tissue

The pancreas contains two types of glands: (1) exocrine glands, which secrete digestive enzymes (see p. 882 ) and (see pp. 885–886 ) into the intestinal lumen; and (2) endocrine glands, called the islets of Langerhans. The islets are spread throughout the pancreas and in aggregate comprise only 1% to 2% of its tissue mass.

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 newly described protein, amylin (or IAPP for islet amyloid polypeptide). 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.

The islets are richly perfused (blood flow per gram of tissue is >5 times that of the myocardium) and receive both sympathetic and parasympathetic innervation. 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 communicate via gap junctions, which may be important for the regulation of both insulin and glucagon secretion.

• 3

  Neural communication. Both the sympathetic and parasympathetic divisions of the autonomic nervous system (ANS) regulate islet secretion. Cholinergic stimulation augments insulin secretion. Adrenergic stimulation can have either a stimulatory or inhibitory effect, depending on whether β-adrenergic (stimulatory) or α-adrenergic (in­hibitory) stimulation dominates (see p. 1033 ). N51-1

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

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 promptly, which diminishes the mobilization of endogenous fuel stores and stimulates the uptake of carbohydrates, lipids, and amino acids by insulin-sensitive target tissues. In this manner, insulin directs tissues to replenish the fuel reserves depleted during periods of fasting.

As a result of its ability to regulate the mobilization and storage of fuels, insulin maintains plasma [glucose] within narrow limits. Such regulation provides the central nervous system (CNS) with a constant supply of glucose needed to fuel cortical function. In higher organisms, if plasma [glucose] (normally ≅ 5 mM) declines to <2 to 3 mM (hypoglycemia; Box 51-1 ) 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 > 15 mM) produces an osmotic diuresis (see Box 35-1 ) that, when severe, can lead to dehydration, hypotension, and vascular collapse.

β cells synthesize and secrete insulin

Insulin Synthesis

Transcription of the insulin gene product and subsequent processing produces full-length messenger RNA (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 pp. 34–35 ). 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.

Glucose is the major regulator of insulin secretion

In healthy individuals, the plasma glucose concentration remains within a remarkably narrow range. After an overnight fast, it typically averages 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 the secretion of insulin and C peptide and hence raise plasma [insulin], as illustrated by the results of an oral glucose tolerance test (OGTT) as shown in Figure 51-3 A . 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 (see Fig. 51-3 B ).

A glucose challenge of 0.5 g/kg body weight given as an intravenous bolus raises the plasma glucose concentration more rapidly than glucose given orally. Such a rapid rise in plasma glucose concentration leads to two distinct phases of insulin secretion (see Fig. 51-3 C ). The acute-phase or first-phase insulin response lasts only 2 to 5 minutes, whereas the second-phase 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 had been packaged in secretory vesicles docked at, or residing near, the β-cell plasma membrane. The second-phase insulin response also comes from preformed insulin within the vesicles with some contribution from newly synthesized insulin. One of the earliest detectable metabolic defects that occurs in both type 1 and type 2 diabetes is loss of the first phase of insulin secretion, as determined by an intravenous glucose tolerance test. If a subject consumes glucose or a mixed meal, plasma [glucose] rises much more slowly—as in Figure 51-3 A —because the appearance of glucose in plasma depends on gastric emptying and 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 (see Fig. 51-3 A ). This difference is referred to as the incretin effect ( Box 51-2 ).

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 that are transported into the β cell but that cannot be metabolized (e.g., 3- O -methylglucose or 2-deoxyglucose) do not stimulate insulin secretion. Although glucose itself is the best secretagogue, some amino acids (especially arginine and leucine) and small keto acids (e.g., α-ketoisocaproate, α-ketoglutarate), 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 oxidation via the citric acid cycle (see p. 1185 ). 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.

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 Ca ²⁺ channel in the plasma membrane ( Fig. 51-4 ). The K ⁺ channel ( K _ATP ; see p. 198 ) is an octamer of four Kir6.2 channels (see p. 196 ) and four sulfonylurea receptors ( SURs; see p. 199 ; Box 51-3 ), Glucose triggers insulin release in a seven-step process:

• Step 1: Glucose enters the β cell via the GLUT2 glucose transporter by facilitated diffusion (see p. 114 ). Amino acids enter through a different set of transporters.

• Step 2: In the presence of glucokinase (the rate-limiting enzyme in glycolysis), the entering glucose undergoes glycolysis as well as oxidation via the citric acid cycle (see p. 1185 ), phosphorylating ADP and raising [ATP] _i . Some amino acids also enter the citric acid cycle. In both cases, the following ratios increase: [ATP] _i /[ADP] _i , [NADH] _i /[NAD ⁺ ] _i , and [NADPH] _i /[NADP ⁺ ] _i (NADH and NAD ⁺ are the reduced and oxidized forms of nicotinamide adenine dinucleotide [NAD], and NADPH and NADP ⁺ are the reduced and oxidized forms of NAD phosphate) N51-5

• Step 3: The increase in the ratio [ATP] _i /[ADP] _i , or [NADH] _i /[NAD ⁺ ] _i , or [NADPH] _i /[NADP ⁺ ] _i causes K _ATP channels (see p. 198 ) to close.

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

• Step 5: This depolarization activates voltage-gated Ca ²⁺ channels (see pp. 190–191 ).

• Step 6: The increased Ca ²⁺ permeability leads to increased Ca ²⁺ influx and increased intracellular free Ca ²⁺ . This rise in [Ca ²⁺ ] _i additionally triggers Ca ²⁺ -induced Ca ²⁺ release (see pp. 242–243 ).

• Step 7: The increased [Ca ²⁺ ] _i , perhaps by activation of a Ca ²⁺ -calmodulin phosphorylation cascade, ultimately leads to insulin release.