Shortcomings of current models of glucose-induced insulin secretion

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2009-11, Vol.11 (s4), p.168-179
• Main Authors: Henquin, J.C, Nenquin, M, Ravier, M.A, Szollosi, A
• Format: Article
• Language: English
• Subjects: amplifying pathway; Animals; ATP-Binding Cassette Transporters - metabolism; Ca2+ oscillations; Calcium - metabolism; Ca²⁺ oscillations; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; electrophysiology; Glucose - pharmacology; Insulin - metabolism; insulin release; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; islet; KATP channel; KATP Channels - drug effects; KATP Channels - metabolism; Models, Biological; Potassium Channels, Inwardly Rectifying - metabolism; Receptors, Drug - metabolism; Signal Transduction; stimulus-secretion coupling; Sulfonylurea Receptors; TRP channels; β-cell
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2009.01109.x

Glucose-induced insulin secretion by pancreatic β-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 (KATP channels) in the plasma membrane, depolarization, influx of Ca²⁺ through voltage-dependent calcium channels and a rise in cytosolic-free Ca²⁺ 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 Ca²⁺ signal under physiological conditions. We next discuss experimental evidence, largely but not exclusively obtained from β-cells lacking KATP channels, which indicates that these channels are not the only possible transducers of glucose effects on the triggering Ca²⁺signal. We finally address the identity of the widely neglected background inward current (Cl⁻ efflux vs. Na⁺ or Ca²⁺ influx through voltage-independent channels) that is necessary to cause β-cell depolarization when glucose closes KATP 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.