Alloxan jj 1==0

Streptozotocin figure 7-27 (A) Structures of the most frequently employed oral antidiabetic compounds; the "active" portion of the molecule is the sulfonylurea radical. (B) Structures of alloxan and streptozotocin, 2-substituted D-glucose derivatives that are employed to selectively destroy pancreatic /3-cells.

ability to acutely stimulate the secretion of insulin by functionally responsive islets. Alternatively, there is some evidence to support a peripheral mode of action, wherein the sulfonylurea agents increase the sensitivity of tissues such as the liver to the prevailing levels of insulin.

The biguanides have long been known to be potent hypoglycemic agents; regrettably, they are also very toxic to many tissues. Although a detailed mode of action is not available, from in vivo studies it appears that these agents decrease the rate of intestinal absorption of glucose and increase the peripheral tissue uptake of blood glucose.

The principal agents that have been employed for the treatment of the some 6-10 million diabetic individuals in the United States who require drug-assisted management of their blood glucose levels are various preparations of insulin. These preparations have all been purified from extracts of either bovine or porcine pancreas. Because both bovine and porcine insulins have amino acid sequences significantly different from that of human insulin, a complicating problem has been the generation of antibodies by the patient to the heterologous insulin drug. Thus, a major success of the new recombinant DNA technology has been to clone the gene for human insulin and then mass-produce human insulin in quantities that have made it possible to provide human insulin as a drug for the diabetic population.

D. Metabolism of Insulin and Glucagon

The plasma half-life of insulin is 3-5 min. The principal pathway for the lowering of plasma insulin levels is receptor-mediated endocytosis of the insulin-receptor complex; a major site of this activity is in the liver, with the kidney as the second most important site. Mutant insulins that bind weakly to the insulin receptor are degraded 6-10 times more slowly.

The plasma half-life of glucagon is 6-7 min. Glucagon is largely inactivated by the liver and kidney. A glucagon-degrading enzyme has been purified from the liver; it specifically cleaves off the N-terminal tri-peptide, H2N-His-Ser-Gln-COOH.

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