Shortcomings of current models of glucose-induced insulin secretion

Glucose-induced insulin secretion by pancreatic beta-cells is generally schematized by a 'consensus model' that involves the following sequence of events: acceleration of glucose metabolism, closure of ATP-sensitive potassium channels (K(ATP) channels) in the plasma membrane, depolarization, influx of Ca(2+) through voltage-dependent calcium channels and a rise in cytosolic-free Ca(2+) concentration that induces exocytosis of insulin-containing granules. This model adequately depicts the essential triggering pathway but is incomplete. In this article, we first make a case for a model of dual regulation in which a metabolic amplifying pathway is also activated by glucose and augments the secretory response to the triggering Ca(2+) signal under physiological conditions. We next discuss experimental evidence, largely but not exclusively obtained from beta-cells lacking K(ATP) channels, which indicates that these channels are not the only possible transducers of glucose effects on the triggering Ca(2+)signal. We finally address the identity of the widely neglected background inward current (Cl(-) efflux vs. Na(+) or Ca(2+) influx through voltage-independent channels) that is necessary to cause beta-cell depolarization when glucose closes K(ATP) channels. More attention should be paid to the possibility that some components of this background current are influenced by glucose metabolism and have their place in a model of glucose-induced insulin secretion.