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Stimulates secretion of pepsin and HC1 by the

stomach stomach

" IAPP is structurally homologous to calcitonin gene-related peptide (CGRP); see Figure 9-4.

6 The chromogranins A, B, and C are a family of closely related acidic proteins that are produced by many neuroendocrine cells. Chromogran-ins A are produced by pancreatic a, /3, and F cells of the pancreatic islet.

c The B cells also secrete small quantities of procathepsin B, carboxypeptidase H, endopeptidases I and II, and peptidylglycan a-amidating monooxygenase.

FIGURE 7-2 Gross anatomical features of the pancreas, liver, and biliary system.

num. It has been generally accepted that the endocrine cells of the pancreas develop from pancreatic ducts originally of endodermal origin. In the developing

What Types Cells Potato
Insulin

FIGURE 7-3 Schematic diagram of a pancreatic islet. (Left) Schematic representation of the number and distribution of insulin-, glucagon-, and somatostatin-containing cells in the normal rat islet. Note the characteristic position of most glucagon- and somatostatin-containing cells at the periphery of the islet, surrounding the centrally located insulin-containing cells. Cell types in the islet for which a characteristic function and/or morphology are not defined are intentionally omitted. (Right) Schematic representation of the number and distribution of insulin-, glucagon-, and somatostatin-containing cells in the normal human islet. Large vascular channels penetrate the islet and are surrounded by glucagon- and somatostatin-containing cells. This pattern divides the total islet mass into small subunits, each of which contains a center formed mainly of insulin-containing cells and surrounded by glucagon- and somatostatin-containing cells. Cell types for which definite functions and/or morphologies have not yet been determined are intentionally omitted. [Reproduced with permission from Orci, L. (1977). In "Insulin and Metabolism" (J. S. Bajaj, ed.), p. 262. Excerpta Medica, Amsterdam.]

rat embryo, insulin biosynthesis can be detected by day 16.

C. Ultrastructure of Pancreatic Islets

In both humans and rats, pancreatic islets are composed of at least three major cell types: the a or A (glucagon-secreting) cells, the /3orB (insulin-secreting) cells, and the 8 or D cells. By histological staining with neutral red it has been estimated that there are 13,500 or 890,000 islets, respectively, in the rat or human pancreas. The islets in the rat pancreas range in diameter from 50 to 400 /xm. The distribution of cells in a typical rat islet is 15-18% a, 75-80% /3, and 2-10% 8. The islets are surrounded by a basement membrane that encloses all three cell types.

The pancreatic /3-cell also produces and secretes a neuropeptide-like molecule known as islet amyloid polypeptide (IAPP). IAPP was first described as a major protein component of the amyloid deposits that are found in the islets of elderly type I diabetics. The physiological function of IAPP is not yet known.

The pancreas of a number of species also secretes a substance known as pancreatic polypeptide (PP). Avian PP is a potent gastric secretagogue; it stimulates the release of both pepsin and HC1. In the chicken pancreas, immunofluorescent studies have indicated that PP is present in cells scattered throughout the exocrine pancreas. A peptide homologous to avian PP has been isolated from the human pancreas; immunofluorescent studies have indicated human PP present in cells that are localized on the periphery of the human islet. Low concentrations of cells that secrete gastrin are also dispersed throughout the endocrine portions of the pancreas.

As enumerated in Table 7-6, there are a number of other hormones and proteins that are produced and secreted by the endocrine pancreas. In most instances their precise physiological role remains to be clarified.

The a-cells can be differentiated from other islet cells (see Figure 7-4) on the basis of the ultrastructural appearance of their secretory granules. Usually the center of the granule is exceedingly electron-dense. The /8-cells can be specifically identified histochemically by staining with aldehyde fuchsin or aldehyde thionin, which apparently reacts with sulfhydryl groups present in insulin. A remarkable feature of most /3-cells is the visible presence of a crystalline matrix or array; in the /3-cells of the human, bat, or dog, there is a repeating periodicity of —50 A. This may be related to the property of insulin to form dimers and hexamers (discussed later).

FIGURE 7-4 Electron micrograph of normal a (A), ¡3 (B), and <5 (D) cells of a human pancreatic islet (X 32,000). [Reproduced with permission from Lacy, P. E., and Greider, M. H. (1979). Anatomy and ultrastructural organization of pancreatic islets. In "Endocrinology" (L. J. DeGroot et al„ eds.), Vol. 2, p. 909. Grune & Stratton, New York.]

FIGURE 7-4 Electron micrograph of normal a (A), ¡3 (B), and <5 (D) cells of a human pancreatic islet (X 32,000). [Reproduced with permission from Lacy, P. E., and Greider, M. H. (1979). Anatomy and ultrastructural organization of pancreatic islets. In "Endocrinology" (L. J. DeGroot et al„ eds.), Vol. 2, p. 909. Grune & Stratton, New York.]

It has been proposed by R. Unger, L. Orci and others that the a-, (i-, and possibly S-cells function together as a hormonal secretory unit; this unit releases suitable proportions of glucagon and insulin necessary to regulate the minute-to-minute blood glucose levels and also modulates metabolism either toward anabolism or ca-tabolism in accordance with physiological needs. The integrated secretion of glucagon and insulin by the a-and /3-cells may well have a functional basis due to the close anatomic intimacy of these two cells. Orci has identified, by electron microscopic, freeze-fracture methods, a preponderance of both gap junctions and tight junctions between adjacent a- and /3-cells. It is believed that the tight junctions may form dynamically to trap insulin released extracellularly from secretory granules, thus effectively compartmentalizing the in tercellular space between the islet cells and providing channels of access to the pancreatic capillary bed. The gap junctions also could well serve as pathways of intercellular communication between adjacent cells. In other systems, gap junctions have been shown to permit the interchange between cells of molecules of under 500 Da. The role of the S-cells and their secretory product somatostatin, which can inhibit both insulin and glucagon secretion, is not yet known. Somatostatin possibly functions in the pancreas as a paracrine substance.

D. Vascularization and Innervation of Pancreatic Islets

Figure 7-3 illustrates the gross anatomical features of the pancreas in relation to the biliary system and liver.

The arterial supply of the pancreas arises from the splenic, hepatic, and mesenteric arteries, and venous drainage is into the splenic and mesenteric veins. As shown in Figure 7-5, the individual islets of the pancreas are vascularized by an extensive labyrinth of capillaries. Each islet is normally vascularized by 1-3 arterioles, which abruptly terminate into capillaries and 1-6 veinules, depending upon the size of the islet (see also Figure 15-6B). Morphological studies of the islets indicate that their endocrine cells are arranged in cords or short bands of cells, with each islet cell being adjacent to a capillary. This permits the rapid

FIGURE 7-5 Scanning electron micrograph of the capillary network in a pancreatic islet. [Reproduced with permission from Lacy, P. E., and Greider, M. H. (1979). Anatomy and ultrastructural organization of pancreatic islets. In "Endocrinology" (L. J. DeGroot et al., eds.), Vol. 3, p. 911. Grune & Stratton, New York.]

FIGURE 7-5 Scanning electron micrograph of the capillary network in a pancreatic islet. [Reproduced with permission from Lacy, P. E., and Greider, M. H. (1979). Anatomy and ultrastructural organization of pancreatic islets. In "Endocrinology" (L. J. DeGroot et al., eds.), Vol. 3, p. 911. Grune & Stratton, New York.]

transfer of the secreted hormones into the general vascular system.

The capillaries present in the pancreatic islets comprise endothelial cells that are fenestrated to permit the rapid uptake of the peptide hormones (see Figure 2-34 for an example of capillary wall fenestration). It has been estimated from an infusion of horseradish peroxidase (40 kDa) that the fenestrated islet capillary is 4-7 times more permeable than a nonfenestrated capillary. The hormonal products secreted by islet cells into the surrounding extracellular fluid must traverse the basement membrane of the endothelium before entering the bloodstream.

Figure 7-6 schematically illustrates the innervation of the pancreatic islets by both parasympathetic cholinergic neurons and sympathetic adrenergic neurons. There are no specialized morphological membrane structures in the islet cells characteristic of neuromuscular synapses; the nerve terminals end abruptly within the islet, underneath the basal lamina that surrounds the islet cell.

Both adrenergic and cholinergic nerve fibers are present in both the acinar and the islet regions of the

Islet Innervation

Glucagon

-eel Pancreatic Polypeptide

Glucagon

Capillary blood containing substrates.hormones S amines

Capillary blood containing substrates.hormones S amines

FIGURE 7-6 Schematic representation of the autonomic innervation of the pancreatic islets. Abbreviations: VMH, ventromedial hypothalamus; VLH, ventrolateral hypothalamus; CNS, central nervous system [Reproduced with permission from Woods, S. C. et al. (1981). The role of the nervous system in metabolic regulation and its effect on diabetes and obesity. In "Handbook of Diabetes Melli-tus" (M. Brownlee, ed.), p. 213. Garland Publishing Co., New York.]

FIGURE 7-6 Schematic representation of the autonomic innervation of the pancreatic islets. Abbreviations: VMH, ventromedial hypothalamus; VLH, ventrolateral hypothalamus; CNS, central nervous system [Reproduced with permission from Woods, S. C. et al. (1981). The role of the nervous system in metabolic regulation and its effect on diabetes and obesity. In "Handbook of Diabetes Melli-tus" (M. Brownlee, ed.), p. 213. Garland Publishing Co., New York.]

pancreas. Stimulation of the parasympathetic nervous system leads to insulin secretion and inhibition of glucagon secretion, irrespective of whether the stimuli occur at the lateral hypothalamic nuclei, the motor nuclei of the vagus, or the mixed pancreatic nerves. Stimulation of the sympathetic nervous system or application of epinephrine likewise can stimulate glucagon production and inhibit insulin secretion. The hypothalamus appears to play the major integrating role in the balance between sympathetic and parasympathetic regulation of the islet.

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