Insulin Glucagon and Diabetes Mellitus

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The pancreas, in addition to its digestive functions, secretes two important hormones, insulin and glucagon, that are crucial for normal regulation of glucose, lipid, and protein metabolism. Although the pancreas secretes other hormones, such as amylin, somatostatin, and pancreatic polypeptide, their functions are not as well established. The main purpose of this chapter is to discuss the physiologic roles of insulin and glucagon and the pathophysiology of diseases, especially diabetes mellitus, caused by abnormal secretion or activity of these hormones.

Physiologic Anatomy of the Pancreas. The pancreas is composed of two major types of tissues, as shown in Figure 78-1: (1) the acini, which secrete digestive juices into the duodenum, and (2) the islets of Langerhans, which secrete insulin and glucagon directly into the blood. The digestive secretions of the pancreas are discussed in Chapter 64.

The human pancreas has 1 to 2 million islets of Langerhans, each only about 0.3 millimeter in diameter and organized around small capillaries into which its cells secrete their hormones. The islets contain three major types of cells, alpha, beta, and delta cells, which are distinguished from one another by their morphological and staining characteristics.

The beta cells, constituting about 60 per cent of all the cells of the islets, lie mainly in the middle of each islet and secrete insulin and amylin, a hormone that is often secreted in parallel with insulin, although its function is unclear. The alpha cells, about 25 per cent of the total, secrete glucagon. And the delta cells, about 10 per cent of the total, secrete somatostatin. In addition, at least one other type of cell, the PP cell, is present in small numbers in the islets and secretes a hormone of uncertain function called pancreatic polypeptide.

The close interrelations among these cell types in the islets of Langerhans allow cell-to-cell communication and direct control of secretion of some of the hormones by the other hormones. For instance, insulin inhibits glucagon secretion, amylin inhibits insulin secretion, and somatostatin inhibits the secretion of both insulin and glucagon.

Insulin and Its Metabolic Effects

Insulin was first isolated from the pancreas in 1922 by Banting and Best, and almost overnight the outlook for the severely diabetic patient changed from one of rapid decline and death to that of a nearly normal person. Historically, insulin has been associated with "blood sugar," and true enough, insulin has profound effects on carbohydrate metabolism. Yet it is abnormalities of fat metabolism, causing such conditions as acidosis and arteriosclerosis, that are the usual causes of death in diabetic patients. Also, in patients with prolonged diabetes, diminished ability to synthesize proteins leads to wasting of the tissues as well as many cellular functional disorders. Therefore, it is clear that insulin affects fat and protein metabolism almost as much as it does carbohydrate metabolism.

Insulin Is a Hormone Associated with Energy Abundance

As we discuss insulin in the next few pages, it will become apparent that insulin secretion is associated with energy abundance. That is, when there is great abundance of energy-giving foods in the diet, especially excess amounts of carbohydrates, insulin is secreted in great quantity. In turn, the insulin plays an important role in storing the excess energy. In the case of excess carbohydrates, it causes them to be stored as glycogen mainly in the liver and muscles. Also, all the excess carbohydrates that cannot be stored as glyco-gen are converted under the stimulus of insulin into fats and stored in the adipose tissue. In the case of proteins, insulin has a direct effect in promoting amino acid uptake by cells and conversion of these amino acids into protein. In addition, it inhibits the breakdown of the proteins that are already in the cells.

Insulin Chemistry and Synthesis

Insulin is a small protein; human insulin has a molecular weight of 5808. It is composed of two amino acid chains, shown in Figure 78-2, connected to each other by disulfide linkages. When the two amino acid chains are split apart, the functional activity of the insulin molecule is lost.

Insulin is synthesized in the beta cells by the usual cell machinery for protein synthesis, as explained in

Figure 78-1

Physiologic anatomy of an islet of Langerhans in the pancreas.

Chapter 3, beginning with translation of the insulin RNA by ribosomes attached to the endoplasmic reticulum to form an insulin preprohormone. This initial preprohormone has a molecular weight of about 11,500, but it is then cleaved in the endoplasmic retic-ulum to form a proinsulin with a molecular weight of about 9000; most of this is further cleaved in the Golgi apparatus to form insulin and peptide fragments before being packaged in the secretory granules. However, about one sixth of the final secreted product is still in the form of proinsulin. The proinsulin has virtually no insulin activity.

When insulin is secreted into the blood, it circulates almost entirely in an unbound form; it has a plasma half-life that averages only about 6 minutes, so that it is mainly cleared from the circulation within 10 to 15 minutes. Except for that portion of the insulin that combines with receptors in the target cells, the remainder is degraded by the enzyme insulinase mainly in the liver, to a lesser extent in the kidneys and muscles, and slightly in most other tissues. This rapid removal from the plasma is important, because, at times, it is as important to turn off rapidly as to turn on the control functions of insulin.

Activation of Target Cell Receptors by Insulin and the Resulting Cellular Effects

To initiate its effects on target cells, insulin first binds with and activates a membrane receptor protein that has a molecular weight of about 300,000 (Figure 78-3). It is the activated receptor, not the insulin, that causes the subsequent effects.

The insulin receptor is a combination of four sub-units held together by disulfide linkages: two alpha subunits that lie entirely outside the cell membrane and two beta subunits that penetrate through the membrane, protruding into the cell cytoplasm. The insulin binds with the alpha subunits on the outside of the cell, but because of the linkages with the beta subunits, the portions of the beta subunits protruding into the cell become autophosphorylated. Thus, the insulin receptor is an example of an enzyme-linked receptor, discussed in Chapter 74. Autophosphorylation of the beta subunits of the receptor activates a local tyrosine

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