Signal transduction: regulation of insulin secretion by changes in Ca2+ concentration and action in pancreatic B-cells

Henquin, Jean-Claude [UCL] Jonas, Jean-Christophe [UCL] Sato, Yoshihiko [UCL] de Timary, Philippe [UCL] Gilon, Patrick [UCL]

Defects in the regulation of insulin secretion from pancreatic β-cells largely contribute to the perturbations of glucose homeostasis in noninsulin-dependent diabetes (Type 2 diabetes). Under physiological conditions, the rate of insulin release is controlled by variations in the concentration of circulating nutrients and by various hormonal and neural signals. Hormones and neurotransmitters modulate β-cell function by binding to membrane receptors and activating transduction pathways essentially similar to those existing in other cell types. In contrast, glucose, the major physiological stimulus, does not bind to a receptor but must be metabolized to induce insulin secretion. The acceleration of β-cell metabolism results in the production of a number of potential second messengers that might trigger or modulate exocytosis of storage granules containing insulin. Another peculiarity of β-cells is not so much that they are electrically excitable, but that their membrane potential is controlled by metabolism. The electrical activity induced by glucose involves marked changes in the flux of many ions across the plasma membrane. One of these ions, Ca2+, plays a pre-eminent role in the regulation of insulin secretion. The first indication that Ca2+ ions are essential players in stimulus-secretion coupling in β-cells dates back to the observation that the stimulation of insulin secretion by glucose and other agents was abrogated by omission of extracellular Ca2+.