Inhibition of Cyclic 3′,5′-AMP Phosphodiesterase in Islet Cells and Other Tissues by Tolbutamide

Abstract

AN explanation of the intracellular mechanism by which sulphonylureas such as tolbutamide and chlorpropamide stimulate the release of insulin from the pancreas^1,2 (as in the treatment of diabetes mellitus) should also account for certain effects of these materials outside the pancreas^3–5. These include the effect of chlorpropamide in reducing polyuria in patients with diabetes insipidus⁴ and the possible involvement of tolbutamide in the increased cardiac mortality of patients treated with the drug⁵. It has been clear for some years that cyclic AMP (cyclic adenosine 3′,5′-monophosphate) plays an important part in the regulation of insulin secretion. For example, cyclic AMP causes the release of insulin from pancreas tissue in vitro⁶. Further, glucagon increases cyclic AMP activity in islet cells by activating the enzyme adenyl cyclase⁷, and theophylline increases cyclic AMP activity by inhibiting phosphodiesterase^8,9. It is known that the sulphonylureas can influence the activity of cyclic AMP^10,11, and tolbutamide and chlorpropamide inhibit the enzyme phosphodiesterase in the rat kidney¹². We have now shown that the sulphonylureas may regulate the levels of cyclic AMP not merely in islet cells but in kidney, lung, heart and brain. In particular, the sulphonylureas, like the methylxanthines, inhibit the activity of cyclic AMP phosphodiesterase, which hydrolyses cyclic AMP to 5′-AMP^8,9, which provides a plausible explanation for their effects in the pancreas and elsewhere.