Regulation of Insulin Release

The insulin gene is expressed in the b cells of the pancreatic islets ( Fig. 24-27 ). Preproinsulin is synthesized in the rough endoplasmic reticulum from insulin mRNA and delivered to

the Golgi apparatus. There, a series of proteolytic cleavage steps generate the mature insulin and a cleavage peptide, C-peptide. Both insulin and C-peptide are then stored in secretory

granules and secreted in equimolar quantities after physiologic stimulation; increasingly, C-peptide

Figure 24-27Hormone production in pancreatic islet cells. Immunoperoxidase staining shows a dark reaction product for insulin in b cells (A), glucagon in a cells (B), and somatostatin

in d cells (C). D, Electron micrograph of a b cell shows the characteristic membrane-bound granules, each containing a dense, often rectangular core and distinct halo. E, Portions of an

a cell (left) and a d cell (right) also exhibit granules, but with closely apportioned membranes. The a-cell granule exhibits a dense, round center. (Electron micrographs courtesy of Dr.

A. Like, University of Massachusetts Medical School, Worcester, MA.)

Figure 24-28Insulin synthesis and secretion. Intracellular transport of glucose is mediated by GLUT-2, an insulin-independent glucose transporter in b cells. Glucose undergoes

oxidative metabolism in the b cell to yield ATP. ATP inhibits an inward rectifying potassium channel receptor on the b-cell surface; the receptor itself is a dimeric complex of the

sulfonylurea receptor and a K+ -channel protein. Inhibition of this receptor leads to membrane depolarization, influx of Ca2+ ions, and release of stored insulin from b cells.

Figure 24-29Metabolic actions of insulin in striated muscle, adipose tissue, and liver.

Figure 24-30Insulin action on a target cell. Insulin binds to the a subunit of insulin receptor, leading to activation of the kinase activity in the b-subunit, and sets in motion a

phosphorylation (i.e., activation) cascade of multiple downstream target proteins. The mitogenic functions of insulin (and the related insulin-like growth factors) are mediated via the

mitogen-activated protein kinase (MAP kinase) pathway. The metabolic actions of insulin are mediated primarily by activation of the phosphatidylinositol-3-kinase (PI-3K) pathway.

The PI-3K-signaling pathway is responsible for a variety of effects on target cells, including translocation of GLUT-4 containing vesicles to the surface; increasing GLUT-4 density on

the membrane and rate of glucose influx; promoting glycogen synthesis via activation of glycogen synthase; and promoting protein synthesis and lipogenesis, while inhibiting lipolysis.

The PI-3K pathway also promotes cell survival and proliferation.

Figure 24-31Stages in the development of type 1 diabetes mellitus. The stages are listed from left to right, and hypothetical b-cell mass is plotted against age. (From Eisenbarth GE:

Type 1 diabetes: a chronic autoimmune disease. N Engl J Med 314:1360, 1986. Copyright © 1986, Massachusetts Medical Society. All rights reserved.)

Figure 24-33Obesity and insulin resistance: the missing links? Adipocytes release a variety of factors (free fatty acids and adipokines) that may play a role in modulating insulin

resistance in peripheral tissues (illustrated here is striated muscle). Excess free fatty acids (FFAs) and resistin are associated with insulin resistance; in contrast, adiponectin, whose levels

are decreased in obesity, is an insulin-sensitizing adipokine. Leptin is also an insulin-sensitizing agent, but it acts via central receptors (in the hypothalamus). The peroxisome

proliferator-activated receptor gamma (PPARg) is an adipocyte nuclear receptor that is activated by a class of insulin-sensitizing drugs called thiazolidinediones (TZDs). The mechanism

of action of TZDs may eventually be mediated through modulation of adipokine and FFA levels that favor a state of insulin sensitivity.

TABLE 24-7-- Effects of Advanced Glycation End Products (AGEs)

Date: 2016-04-22; view: 649