Clinical and Experimental Studies of Insulin Secretion Following Tolbutamide and Metahexamide Administration

Abstract

An increasing body of evidence supporting the concept that liberation of pancreatic insulin represents an important action of the sulfonylurea drugs has accumulated since publication of the monograph The Effects of the Suljonylureas and Related Compounds in Experimental Diabetes in 1957 by The New York Academy of Sciences.'As is apparent from the topics of a number of the papers included in the present monograph, the question is no longer whether or not stimulation of endogenous insulin secretion occurs following the administration of tolbutamide, but whether the different findings still observed after treatment with sulfonylureas or with exogenous insulin can be ascribed to the specific nature of tolbutamide-released pancreatic insulin or whether they should better be attributed to some other factor?One point, however, should be given special attention in the present phase of interest in endogenous insulin discharged from the pancreas after the administration of tolbutamide. In spite of the recent data on hepatic trapping of pancreatic insulin, the question remains as to why many investigators have failed to demonstrate increased plasma insulin levels in man following tolbutamide therapy. I t is not likely that all the pancreatic insulin remains in the liver, therefore not appearing in peripheral circulation. It is true that only recently we ourselves also tried to offer a positive solution to the problem of the failure of increases in peripheral insulin levels in man on this bask3 However, even in those experiments performed in dogs in which the plasma insulin levels were determined in the portal and the femoral venous blood simultaneously after a single dose of tolbutamide, the increases in plasma insulin in the portal vein were found in 2 animals only and did not appear in the peripheral circulation. In the other experiments a significant elevation of plasma insulinlike activity was established in both portal and peripheral circulations following the injection of tolbutamide.Consequently, it appeared feasible to reinvestigate the whole problem of peripheral blood insulin levels in man following the administration of a single dose of tolbutamide by using the same bioassay procedure for measuring insulin in blood (the rat adipose tissue method4), which wasalready found to be reliable in experiments on dogs.3 This project appeared even more justified when a new compound of the sulfonylurea family, metahexamide, was being investigated. In view of the fact that a very low dose of this drug is effective in producing hypoglycemia in normal humans and elderly diabetics, information regarding its insulin-stimulating capacity seemed particularly desirable.The studies presented here were undertaken in humans as well as in animals. With the former, major attention was given to the possible variations of blood insulin levels in the various groups of patients submitted to the test. In the 479

Glibenclamide and Gliquidone in the Treatment of Non‐Insulin‐Dependent Diabetes Mellitus

“…The hypoglycaemic effect of sulfonylurea drugs is at least partly due to a drug-induced release of insulin from the pancreatic p-cell (16,17,19). Several studies suggest, however, that sulfonylureas in chronic use lower blood glucose through mechanisms other than stimulation of insulin secretion (3, 5,6).…”