10 - The molecular basis of experimental diabetes

Summary

Introduction

Diabetes can be usefully studied at an experimental level by methods that make use of either surgical techniques or chemical agents. Many of the acute metabolic derangements of severe human insulinopenic diabetes can be reproduced by the removal of insulin-producing pancreatic B-cells of the islets of Langerhans. This artificial form of diabetes was first produced by von Mering & Minkowski (1890) when they removed the pancreases of dogs. The same model of diabetes was adopted by Banting & Best (1922) for their historic observations on the hypoglycemic properties of a crude pancreatic extract of insulin.

Of chemical agents, alloxan (2,4,5,6-tetraoxohexahydropyrimidine) (Dunn et al., 1943) and streptozotocin (2-deoxy-2-(3-methyl-3- nitrosoureido)-D-glucopyranose) (Rakieten et al., 1963) have been found to be particularly instructive: they exert selective cytotoxic effects on pancreatic B-cells in animals and are extremely potent diabetogenic substances. Since the original discoveries were made by Dunn and Rakieten, alloxan and streptozotocin have been widely used to produce diabetes in experimental animals because of their particular advantages of specificity and convenience. How the B-cytotoxins produce impaired function and degenerative changes in the B-cell has been the subject of much debate in the literature (Dulin & Soret, 1977; Cooperstein & Watkins, 1981; Chang & Diani, 1985).

Recently, a hypothesis has been offered by Okamoto and coworkers, who present a unifying concept as to the diabetogenic effect of both alloxan and streptozotocin (Okamoto, 1981, 1985a; Okamoto & Yamamoto, 1983; Okamoto et al., 1988). These workers suggest that the principal action of B-cytotoxins on pancreatic B-cells is the induction of lesions in the DNA strand through the formation of free radicals.