Different effects of tolbutamide and diazoxide in α, and β-cells within intact islets of Langerhans

Abstract

Interaction between the different types of cells within the islet of Langerhans is vital for adequate control of insulin release. Once insulin secretion becomes defective, as in type 2 diabetes, the most useful drugs to increase insulin release are sulfonylureas. It is well-known that sulfonylureas block K(ATP) channels, which results in depolarization of the membrane that provokes calcium influx and increases intracellular calcium concentration ([Ca2+](i)), which thereby triggers insulin secretion. The sulfonamide diazoxide produces the opposite effect: it activates K(ATP) channels, resulting in a decreased insulin secretion. Despite such evidence, little is known about the effect of sulfonylureas and sulfonamides in non-β- cells of the islet of Langerhans. In this article, we describe the effects of tolbutamide and diazoxide on [Ca2+](i) in α-, β-, and δ-cells within intact islets of Langerhans. Tolbutamide elicits an increase in [Ca2+](i) in β- and δ-cells, regardless of glucose concentrations. Remarkably, tolbutamide is without effect in α-cells. When diazoxide is applied, glucose-induced [Ca2+](i) oscillations in β- and δ-cells are abolished, whereas [Ca2+](i) oscillations in α-cells remain unaltered. Furthermore, the existence of sulfonylurea receptors is demonstrated in β-cells but not in α-cells by using binding of glybenclamide-4,4-difluoro-4-bora-3a,4a- diaza-s-indacene (BODIPY) combined with immunostaining for insulin and glucagon.