Further Studies on the Significant Role of the Liver in Sulfonylurea Hypoglycemia*

Abstract

The most disturbing inconsistency between sulfonylurea-induced and insulin-induced hypoglycemia has been the repeated failure to demonstrate that the sulfonylureas induce hypoglycemia by either a direct or insulin-mediated action on glucose metabolism in the peripheral tissues. There now appears to be little question that the presence of the pancreas is an essential prerequisite for the hypoglycemic action of a sulfonylurea,'S2 and some studies indicate that part of the action of the sulfonylureas may depend on the presence of insulin?-6 The degree of granulation of the beta cells appears to be related to the insulin content of the p a n c r e a~,~,~ and the sulfonylureas have been shown to increase the quantity of islet tissue8 and to decrease beta cell granulati~n.~JO Root has demonstrated a decrease in the insulin cpntent of the pancreas following carbutamide administration," and the results of experiments where the pancreas was directly stimulated with the sulfonylureas1* ~3 support the insulinogenic action of the sulfonylureas. There are, however, only a few studies that actually show an increased insulin secretion when the insulin output is measured dire~t1y.l~ The nature of the continuous or intermittent stimulation of the pancreatic beta cells remains unknown. Other evidence has been cited to show that the sulfonylureas inhibit glucosed-phosphatase activity,16-17 and that they inhibit insulinase activity.18 Other studies in depancreatized animals have demonstrated a hepatotoxic effect.1B120 Some or all of these actions may contribute to the hypoglycemic action of the sulfonylureas in the absence of the pancreas. Nevertheless, the presence of the pancreas has proven vital to the action of the sulfonylureas; this being true, the absence of an increased peripheral "insulinlike action" following sulfonylurea administration remains a perplexing phenomenon.2lWe have suggested previously that the mode of action of the sulfonylureas might be resolved if their administration was presumed to result in an insulindependent action on hepatic glucose metabolism rather than an increased insulin action in the peripheral tissues.22 This hypothesis does not exclude the existence of a pancreatotropic action of tolbutamide, but merely transfers the emphasis on the major site of endogenous insulin action from the peripheral * The work reported in this paper was supported in part by the John A. Hartford Foundation, New York, N. Y., and The Upjohn Company, Kalamzaoo, Mich.