Different effects of tolbutamide and diazoxide in alpha-, beta-, and delta-cells within intact islets of Langerhans

Interaction between the different types of cells within the islet of Langer hans is vital for adequate control of insulin release. Once insulin secreti on becomes defective, as in type 2 diabetes, the most useful drugs to incre ase 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 diazo xide produces the opposite effect: it activates K-ATP channels, resulting i n a decreased insulin secretion. Despite such evidence, little is known abo ut the effect of sulfonylureas and sulfonamides in non-beta-cells of the is let of Langerhans. In this article, me describe the effects of tolbutamide and diazoxide on [Ca2+](i) in alpha-, beta-, and delta-cells within intact islets of Langerhans. Tolbutamide elicits an increase in [Ca2+](i) in beta- and delta-cells, regardless of glucose concentrations. Remarkably, tolbuta mide is without effect in alpha-cells. When diazoxide is applied, glucose-i nduced [Ca2+](i) oscillations in beta- and delta-cells are abolished, where as [Ca2+](i) oscillations in alpha-cells remain unaltered. Furthermore, the existence of sulfonylurea receptors is demonstrated in beta-cells but not in alpha-cells by using binding of glybenclamide-4,4-difluoro-4-bora-3a,4a- diaza-s-indacene (BODIPY) combined with immunostaining for insulin and gluc agon.