[Triggering and Amplifying Signals in the Control of Insulin-secretion By Glucose]

Henquin, Jean-Claude [UCL] Gilon, Patrick [UCL]

Pancreatic beta cells, which synthesize and secrete insulin, work as fuel-sensors. They adapt the rate of insulin secretion to the variations in plasma levels of glucose and ether nutrients. The stimulatory effect of glucose requires metabolism of the sugar by beta cells to generate both triggering and amplifying signals. The closure of ATP-sensitive K+ channels, probably mediated by an elevation in the ATP/ABP ratio in the cytoplasm, leads to membrane depolarization. The subsequent opening of voltage-dependent Ca2+ channels during bursts of action potentials produces an intermittent Ca2+ influx that causes an oscillatory rise of cytoplasmic Ca2+. This triggering signal entrains synchronous oscillations of insulin secretion. In addition, glucose increases the effectiveness of Ca2+ on the secretory machinery. The nature of this amplifying signal is still unclear, but adenine nucleotides might also be involved. Hierarchically, the control of the membrane potential by glucose metabolism is the most important site of regulation, because it modulates the production of the triggering signal, whereas the second site only serves to amplify the response.