399 399 400 400 Insulin is a peptide hormone consisting of two straight chains, an A chain (21 amino acids) and a B chain (30 amino acids). Two disulfide bridges link the A chain to the B chain, and a third disulfide bridge is located within the A chain. 401 401 402 402 The synthesis of insulin is directed by a gene on chromosome 11, a member of a superfamily of genes that encode related growth factors. The mRNA directs ribosomal synthesis of preproinsulin, which contains four peptides: a signal peptide, the A and B chains of insulin, and a connecting peptide (C peptide). The signal peptide is cleaved early in the biosynthetic process (while the peptide chains are still being assembled), yielding proinsulin (Fig. 9.28). Proinsulin is then shuttled to the endoplasmic reticulum, where, with the connecting peptide still attached, disulfide bridges form to yield a "folded" form of insulin. Proinsulin is packaged in secretory granules on the Golgi apparatus. 403 403 404 404 During this packaging process, proteases cleave the connecting peptide, yielding insulin. 405 405 406 406 Insulin and the cleaved connecting peptide are packaged together in secretory granules, and when the β cell is stimulated, they are released in equimolar quantities into the blood. The secretion of connecting peptide (C peptide) is the basis of a test for β cell function in persons with type I diabetes mellitus who are receiving injections of exogenous insulin. (In these persons, serum insulin levels do not reflect endogenous secretory rates.) 407 407 408 408 Insulin is metabolized in the liver and kidney by enzymes that break disulfide bonds. The A chains and B chains are released, now inactive, and are excreted in the urine. 409 409 410 410 411 411 ## Regulation of Insulin Secretion 412 412 413 413 Table 9.13 summarizes the factors that influence the secretion of insulin by β cells. Of these factors, the most important is glucose. Increases in blood glucose con-centration rapidly stimulate the secretion of insulin. Because of the preeminence of glucose as a stimulant, it is used to describe the mechanism of insulin secre-tion by the β cell, as illustrated in Figure 9.29. The circled numbers in the figure correlate with the steps described as follows: 414 414 415 415 1. Transport of glucose into the β cell. The β cell membrane contains GLUT2, a specific transporter for glucose that moves glucose from the blood into the cell by facilitated diffusion (Step 1). 416 416 417 417 2. Metabolism of glucose inside the β cell. Once inside the cell, glucose is phosphorylated to glucose-6-phosphate by glucokinase (Step 2), and glucose-6-phosphate is subsequently oxidized (Step 3). ATP, 418 418 419 419 *TABLE 9.13 Factors Affecting Insulin Secretion* 420 420 421 421 422 422

Stimulatory Factors	Inhibitory Factors
Increased glucose concentration	Decreased blood glucose
Increased amino acid concentration	Fasting
Increased fatty acid and ketoacid concentration	Exercise
Glucagon	Somatostatin
Cortisol	α-Adrenergic agonists
Glucose-dependent insulinotropic peptide (GIP)	Diazoxide
Potassium
Vagal stimulation; acetylcholine
Sulfonylurea drugs (e.g., tolbutamide, glyburide)
Obesity

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