Intracellular calcium, insulin secretion, and action

Abstract

Changes in cytosolic free calcium concentration [( Ca2+]i) constitute an important element of signal transduction in various cells. These changes either reflect alterations in calcium (Ca2+) fluxes or result from mobilization of intracellular Ca2+ stores. In pancreatic islet cells, an increase in [Ca2+]i is critical for secretagogue-induced insulin release. Thus, glucose evokes a rapid increase in [Ca2+]i, primarily by stimulating Ca2+ influx. Under physiologic conditions, glucose may also promote mobilization of intracellular Ca2+ stores by virtue of stimulating membrane phospholipid hydrolysis and formation of inositol triphosphate, a potent stimulus for Ca2+ mobilization. This action of glucose requires the presence of extracellular Ca2+. The magnitude of change in [Ca2+]i may not parallel the level of insulin release, suggesting that the role of [Ca2+]i in the process of insulin release must be considered in concert with other cellular mechanisms. The role of [Ca2+]i in promoting insulin action is a subject of continuous controversy. Recent observations that chelation of intracellular Ca2+ with quin-2 diminishes insulin action (and that of insulin mimetics) support the role of Ca2+ in mediating the insulin-generated signal. Insulin has also been demonstrated to increase [Ca2+]i in adipocytes in close association with its effect on 2-deoxyglucose uptake. Finally, in both pancreatic islet cells and adipocytes, high concentrations of either extracellular or intracellular Ca2+ inhibit cellular responsiveness. The optimal concentrations of cytosolic Ca2+ appear to be within the 140 to 350 nM range. When Ca2+ concentrations are too low or too high, the ability of pancreatic islets and insulin target cells to respond appropriately to physiologic stimuli is significantly diminished. Impaired cellular Ca2+ homeostasis (either primary or secondary to other cellular lesions) may represent a crucial and identical link in the pathogenesis of impaired insulin secretion and in the pathogenesis of impaired insulin action.