Effect of Long Term Tolbutamide Treatment on Glucose Tolerance and Insulin Secretion in Maturity-Onset Diabetes Without Obesity

Abstract

Since diazoxide causes hyperglycemia and since it has been demonstrated that tolbutamide and chlorpropamide are capable of reversing this hyperglycemia (Kvam and Stanton 1964, Tabachnick, Culbenkian and Seidman 1964), it appears probable that the large increase in insulin secretion seen with tolbutamide and chlorpropamide in these animaIs results from a necessity to overcome diazoxide-induced glucose elevations. Loubatieres has suggested that there is an antagonism between the eff~cts of sulfonylurea hypoglycemic agents and diazoxide on insulin secretion at a cellular level in the ß-cell of the pancreas (Loubatieres, Mariani, Alric, Chapal and Portal 1967). Thus, the large insulin increases seen in mice receiving the combination of diazoxide pretreatment followed by a sulfonylurea could be a reflection of inhibition of insulin release resulting in a buildup of available insulin in the pancreas. The reversal of this inhibition by tl;le sulfonylurea, plus the stimulation by the high circulating glucose concentration results in an exaggerated insulin release. This hypo thesis is supported by the morphologicaI studies of Creutzfeldt. Creutzfeldt. Frerichs, Pering, and Sicklinger (l969), and Yoshinaga (1969).

Hormonal and metabolic effects of chlorpropamide, glibenclamide and placebo in a cross-over study in diabetics not controlled by diet alone

“…Whilst all have found improvements in glucose tolerance, the effects on insulin secretion have varied. Some authors have described, as we have, an increase in insulin concentrations after sulphonylureas [15][16][17][18][19][20][21][22] although some workers have noted an initial increase followed by a decrease in plasma insulin concentrations [17,18,21,23]. Other studies have found insulin to be unchanged [24][25][26][27], although transient early increases in insulin secretion were found in two of these studies [25,27].…”