Modeling the Pancreatic α-Cell: Dual Mechanisms of Glucose Suppression of Glucagon Secretion

The mechanism by which glucose induces insulin secretion in beta-cells is fairly well understood. Despite years of research, however, the mechanism of glucagon secretion in alpha-cells is still not well established. It has been proposed that glucose regulates glucagon secretion by decreasing the conductance of either outward ATP-dependent potassium channels (K(ATP)) or an inward store-operated current (SOC). We have developed a mathematical model based on mouse data to test these hypotheses and found that both mechanisms are possible. Glucose metabolism closes K(ATP) channels, which depolarizes the cell but paradoxically reduces calcium influx by inactivating voltage-dependent calcium and sodium channels and decreases secretion. Glucose metabolism also activates SERCA pumps, which fills the endoplasmic reticulum and hyperpolarizes the cells by reducing the inward current through SOC channels and again suppresses glucagon secretion. We find further that the two mechanisms can combine to account for the nonmonotonic dependence of secretion on glucose observed in some studies, an effect that cannot be obtained with either mechanism alone.