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 Ca(2+) concentration (Ca(2+)) 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 micromol/l tolbutamide. In G3, arginine induced small increases in Ca(2+) but no IS. G7 alone only slightly increased Ca(2+) and IS but markedly potentiated arginine effects on Ca(2+), 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 Ca(2+). At all glucose concentrations, tolbutamide dose dependently increased Ca(2+) and IS with thresholds of 25 micromol/l for Ca(2+) and 100 micromol/l for IS at G3 and of 5 micromol/l for both at G7 and above. Between G7 and G15, the effect of tolbutamide on Ca(2+) increased only slightly, whereas that on IS was strongly potentiated. The linear relationship between IS and Ca(2+) 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 Ca(2+). In conclusion, glucose potentiation of arginine- or tolbutamide-induced IS involves increases in both the rise of Ca(2+) and the action of Ca(2+) 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.