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FIGURE 7-15 Cleavage of preproinsulin by specific endopepti-dases to generate mature insulin and the C peptide. In the preproinsulin, the two pairs of dibasic signal residues (RR and KR) are indicated. Two specific endopeptidases, PC-2 and PC-3, cleave on the C-terminal side of each of the dibasic signal residues, releasing mature insulin and a C peptide with two additional amino acids (K and R) on the C-terminus. These two residues are removed by carboxypeptidase H (CPase) to generate the mature C peptide. [Modified with permission from Steiner, D. F., Bell, G. I., Tager, H. S., and Rubenstein, A.H. (1995). Chemistry and biosynthesis of the islet hormones: Insulin, islet amyloid polypeptide (amylin), glucagon, somatostatin and pancreatic polypeptide. In "Endocrinology" (L. DeGroot, M. Besser, H. G. Burger, J. L. Jameson, D. L. Loriaux, J. C. Marshall, W. D. Odell, J. T. Potts, Jr., and A. H. Rubenstein, eds.), 3rd ed„ Vol. 2, Chapter 76, PP. 1296-1328. W. B. Saunders, Philadelphia, PA.]

3. Biosynthesis of Pancreatic Polypeptide

The pathway of biosynthesis of PP is shown in Figure 7-20; the general features are similar to those employed by most peptide hormones (see Figure 1-10). The propancreatic peptide, which is 9-10 kDa, serves to ultimately generate the mature PP and a second secretory peptide, known as icosapeptide. The icosa-peptide has no known biological activity.

B. Secretion of Pancreatic Hormones

1. Background

The process of the regulated and integrated secretion of insulin and glucagon is very complex. Independently, the a- and /3-cells are exquisitely sensitive glu cose detectors; the output of glucagon is stimulated by a falling blood glucose level, while the output of insulin is stimulated by a rising blood glucose level. Together the pancreatic cells function as a "fuel molecule" ho-meostat for the organism. The /3-cell can be envisioned as a fuel receptor, which is responsible for the minute-to-minute monitoring of the changes in the organism's supply of calorigenic molecules. The jS-cell secretes insulin in response to D-glucose, L-amino acids, fatty acids, and ketones. There are no known inhibitors of /3-cell function among the fuel molecules. However, insulin is only released by the /3-cell in response to the L-amino acids, fatty acids, and ketones in the presence of glucose. In contrast, a-cells can be stimulated to secrete glucagon by L-amino acids and fatty acids in the absence of glucose; D-glucose is also a potent inhibitor of glucagon release. These relationships are summarized in Table 7-8.

The typical response of both a- and /3-cells to a maximal physiological signal for secretion is a biphasic output of their characteristic hormones (see Figure 721). Thus, in the isolated pancreas, infusion of 20 mM D-glucose will elicit within 1 min a rapid burst of insulin secretion; this will be followed by a resting interval of 5-7 min and then a slowly rising "second phase" of insulin secretion, which will last as long as the glucose is present. A similar biphasic release pattern is followed when the a-cells sense the presence of 1-5 mM amino acids in the absence of glucose.

2. Secretion of Insulin

Insulin is secreted from the /3-cells of the pancreatic islets by the process of emiocytosis (see Figure 7-22). In this process, the granules inside the cell are believed to migrate to the peripheral cell membrane down or along a microtubular network. In the region of the cell membrane, the microtubules coalesce into a microfil-amentous network that is immediately adjacent to the cell membrane. This microfilamentous system, which contains actin, has fibers that are 50-70 A in diameter. Once the /3-granules encounter the cell membrane there is a fusion of the cell and granule membranes (see Figure 7-22), which results in the dissolution of the membrane at the point of contact, with concomitant extrusion of the granule insulin contents out of the cell.

The most important physiological secretagogue for insulin release is glucose. There are two general models to describe how changes in the blood level of glucose both initiate and modulate the secretion of insulin from the pancreatic /3-cell; these include (i) the membrane glucose receptor model of stimulus recognition and (ii) the fuel metabolism model of stimulus recognition.

The operation of a /3-cell membrane receptor for glucose, which is coupled to the opening of an outward

7. Pancreatic Hormones

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