Inhibition of Glucose-Induced Release of Insulin by Aldose Reductase Inhibitors

Aldose reductase (alditol: NADP oxidoreductase, EC 1.1.1.21) is the enzyme responsible for the conversion of glucose to its sugar alcohol, sorbitol. In this study, aldose reductase and a closely related enzyme, L-hexonate dehydrogenase (L-gulonate: NADP oxidoreductase, EC 1.1.1.19), were purified from rat pancreas. Glutaric acid, 2,4-dimethyl glutaric acid, 3,3-tetramethylene glutaric acid, and colchicine inhibited both enzymes, albeit with different potencies. These compounds also inhibited both phases of glucose-induced release of insulin by the perfused rat pancreas. The potencies of these inhibitors in depressing the release of insulin correlated with their effectiveness in inhibiting aldose reductase. At higher concentrations of inhibitors, tolbutamide-induced release of insulin was also depressed. The addition of exogenous sorbitol to pancreases treated with glutaric acid restored their ability to respond to glucose and tolbutamide. These findings suggest that the conversion of free intracellular glucose to sorbitol in the beta cell is an essential step in the glucose-induced release mechanism.