Insulin receptor signaling and sarco/endoplasmic reticulum calcium ATPase in beta-cells.

Glucose is the main physiological secretagogue for insulin secretion by pancreatic beta-cells, and the major biochemical mechanisms involved have been elucidated. In particular, an increase in intracellular calcium is important for insulin exocytosis. More recently, it has become apparent that the beta-cell also has many of the elements of the insulin receptor signal transduction pathway, including the insulin receptor and insulin receptor substrate (IRS) proteins 1 and 2. Studies with transgenic models have shown that the beta-cell-selective insulin receptor knockout and the IRS-1 knockout lead to reduced glucose-induced insulin secretion. Overexpression of the insulin receptor and IRS-1 in beta-cells results in increased insulin secretion and increased cytosolic Ca(2+). We have thus postulated the existence of a novel autocrine-positive feedback loop of insulin on its own secretion involving interaction with the insulin receptor signal transduction pathway and regulation of intracellular calcium homeostasis. Our current working hypothesis is that this glucose-dependent interaction occurs at the level of IRS-1 and the sarco(endo)plasmic reticulum calcium ATPase, the calcium pump of the endoplasmic reticulum.