Dual mechanism of the potentiation by glucose of insulin secretion induced by arginine and tolbutamide in mouse islets

Glucose induces insulin secretion ( IS) and also potentiates the insulin-releasing action of secretagogues such as arginine and sulfonylureas. This potentiating effect is known to be impaired in type 2 diabetic patients, but its cellular mechanisms are unclear. IS and cytosolic Ca2+ concentration ([Ca2+](i)) were measured in mouse islets during perifusion with 3 - 15 mmol/l glucose (G3 - G15, respectively) and pulse or stepwise stimulation with 1 - 10 mmol/l arginine or 5 - 250 mu mol/l tolbutamide. In G3, arginine induced small increases in [Ca2+](i) but no IS. G7 alone only slightly increased [Ca2+](i) and IS but markedly potentiated arginine effects on [Ca2+](i), which resulted in significant IS (already at 1 mmol/l). For each arginine concentration, both responses further increased at G10 and G15, but the relative change was distinctly larger for IS than [Ca2+](i). At all glucose concentrations, tolbutamide dose dependently increased [Ca2+](i) and IS with thresholds of 25 mu mol/l for [Ca2+](i) and 100 mu mol/l for IS at G3 and of 5 mu mol/l for both at G7 and above. Between G7 and G15, the effect of tolbutamide on [Ca2+](i) increased only slightly, whereas that on IS was strongly potentiated. The linear relationship between IS and [Ca2+](i) at increasing arginine or tolbutamide concentrations became steeper as the glucose concentration was raised. Thus glucose augmented more the effect of each agent on IS than that on [Ca2+](i). In conclusion, glucose potentiation of arginine- or tolbutamide-induced IS involves increases in both the rise of [Ca2+](i) and the action of Ca2+ on exocytosis. This dual mechanism must be borne in mind to interpret the alterations of the potentiating action of glucose in type 2 diabetic patients.