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

Unité d'Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, Brussels, Belgium Submitted 25 January 2005 ; accepted in final form 17 October 2005 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+ ] 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 µmol/l tolbutamide. In G3, arginine induced small increases in [Ca 2+ ] i but no IS. G7 alone only slightly increased [Ca 2+ ] i and IS but markedly potentiated arginine effects on [Ca 2+ ] 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 [Ca 2+ ] i . At all glucose concentrations, tolbutamide dose dependently increased [Ca 2+ ] i and IS with thresholds of 25 µmol/l for [Ca 2+ ] i and 100 µmol/l for IS at G3 and of 5 µmol/l for both at G7 and above. Between G7 and G15, the effect of tolbutamide on [Ca 2+ ] i increased only slightly, whereas that on IS was strongly potentiated. The linear relationship between IS and [Ca 2+ ] 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 [Ca 2+ ] i . In conclusion, glucose potentiation of arginine- or tolbutamide-induced IS involves increases in both the rise of [Ca 2+ ] i 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. insulin release; sulfonylureas; glucose potentiation; -cell cytosolic calcium ion; type 2 diabetes Address for reprint requests and other correspondence: J. C. Henquin, Unité d'Endocrinologie et Métabolisme, UCL 55.30, Ave. Hippocrate 55, B-1200 Brussels, Belgium (e-mail: henquin{at}endo.ucl.ac.be )