The Pulsatility Nature of Glucose‐Induced Insulin Secretion is a Consequence of the Bioenergetic Regulation of the β‐Cell, as Predicted by Different Hypotheses

Since the pioneering work of Dean P. M. and Matthew E. K. (1970), four decades have elapsed without any consensus on the mechanism responsible for the oscillations of the plasma membrane voltage exhibited by pancreatic β-cells stimulated by glucose. In this review, the different hypothesis dealing with the cause of voltage oscillations that lead to insulin secretion pulsatility will be commented. The earliest explanation attributed the voltage oscillations (bursting) to glycolytic oscillations, taking as a reference skeletal muscle glycolysis oscillations. Later, the scientific interest moved to glucose oxidation after discovering that some mitochondrial parameters also oscillated in synchrony with membrane voltage oscillations. As [Ca2+]cyt increases resultant from membrane depolarization oscillated in synchrony with membrane bursting, it competed with metabolic oscillations (e.g. cytosolic ATP/ADP) for being the cause or the effect of insulin pulsatility; it was demonstrated that metabolic oscillations preceded [Ca2+]cyt oscillations. We are contributing with the hypothesis attributing the cause of voltage oscillations to a sequential competition of two β-cell plasma membrane channels: K+ATP channel and Cx36 hemichannel (Cx36H). Whereas increased glucose metabolism (increased ATP/ADP) closures K+ATP channels and depolarizes the plasma membrane (active phase of a bursting), Cx36Hs are opened and repolarize the membrane potential with a certain delay by inhibiting glucose metabolism (silent phase of a bursting). Repolarization, in turn, closes Cx36H and allows the recovery of glucose oxidation and beginning of a new active phase.