Glucose or Insulin, but not Zinc Ions, Inhibit Glucagon Secretion From Mouse Pancreatic α-Cells

Abstract

The mechanisms by which hypoglycemia stimulates glucagon release are still poorly understood. In particular, the relative importance of direct metabolic coupling versus paracrine regulation by β-cell secretory products is unresolved. Here, we compare the responses to glucose of 1) α-cells within the intact mouse islet, 2) dissociated α-cells, and 3) clonal αTC1-9 cells. Free cytosolic concentrations of ATP ([ATP]c) or Ca2+ ([Ca2+]c) were imaged using α-cell–targeted firefly luciferase or a green fluorescent protein–based Ca2+ probe (“pericam”), respectively. Consistent with a direct effect of glucose on α-cell oxidative metabolism, an increase in glucose concentration (from 0 or 3 mmol/l to 20 mmol/l) increased [ATP]c by 7–9% in α-cells within the intact islet and by ∼4% in αTC1-9 cells. Moreover, glucose also dose-dependently decreased the frequency of [Ca2+]c oscillations in both dissociated α-cells and αTC1-9 cells. Although the effects of glucose were mimicked by exogenous insulin, they were preserved when insulin signaling was blocked with wortmannin. Addition of ZnCl2 slightly increased the frequency of [Ca2+]c oscillations but failed to affect glucagon release from either islets or αTC1-9 cells under most conditions. We conclude that glucose and insulin, but not Zn2+ ions, independently suppress glucagon secretion in the mouse.