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Biosynthesis, Secretion, and Metabolism

Insulin is composed of two unbranched peptide chains joined together by two disulfide bridges (Fig. 9). The single gene that encodes the preproinsulin molecule consists of three exons and two introns and is located on chromosome 11. The two chains of insulin and their disulfide cross bridges are derived from the single-chain proinsulin molecule, from which a 31-residue peptide, called the connecting peptide (C peptide), is excised by stepwise actions of two trypsin-like enzymes called prohormone convertases. Conversion of proinsulin to insulin takes place slowly within storage granules. The C peptide therefore accumulates within granules in equi-molar amounts with insulin. When insulin is secreted, the entire contents of secretory vesicles are disgorged into extracellular fluid. Consequently, the C peptide and any remaining proinsulin and processing intermediates are released into the circulation. When secretion is rapid, proinsulin may comprise as much as 20% of the circulating peptides detected by insulin antibodies, but it contributes little biological activity. Although several biological actions of the C peptide have been described, no physiologic role for the C peptide has yet been established.

The insulin storage granule contains a variety of proteins that are also released whenever insulin is secreted. Most of these proteins are thought to maintain optimal conditions for storage and processing of insulin, but some may also have biological activity. Their fate and actions, if any, are largely unknown. One such protein, however, called amylin, may contribute to the amyloid that accumulates in and around beta cells in states of insulin hypersecretion and may contribute to islet pathology. A wide variety of biological actions of amylin have been described including antagonism to the actions of insulin in various tissues, suppression of appetite, and delaying of gastric emptying, but a physiologic role for amylin remains to be established and is the subject of some controversy.

Insulin is cleared rapidly from the circulation with a half-life of 4-6 min and is destroyed by a specific enzyme, called insulinase or insulin degrading enzyme, that is present in liver, muscle, kidney, and other tissues. The first step in insulin degradation is receptor-mediated internalization through an endosomal mechanism. Degradation may take place within endosomes or after fusion of endosomes with lysosomes. The liver is the principal site of insulin degradation and inactivates about 30-70% of the insulin that reaches it in hepatic portal blood. Insulin degradation in the liver appears to be a regulated process governed by changes in availability of metabolic fuels and changing physiologic circumstances. The liver may thus regulate the amount of insulin that enters the systemic circulation. The kidneys destroy about half of the insulin that reaches the general circulation following receptor-mediated uptake both from the glomerular filtrate and from postglomer-ular blood plasma. Normally, little or no insulin is found in urine. Muscle and other insulin-sensitive tissues throughout the body apparently account for destruction of the remainder. Proinsulin has a half-life that is at least twice as long as insulin and is not converted to insulin outside the pancreas. The kidney is the principal site of degradation of proinsulin and the C peptide. Because little degradation of the C peptide occurs in the liver, its concentration in blood is useful for estimating the rate of insulin secretion and evaluation of beta-cell function in patients who are receiving injections of insulin.

Physiologic Actions of Insulin

The physiologic role of insulin is to promote storage of metabolic fuel. Insulin has many effects on different

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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