Chloride transporters and channels in β-cell physiology: revisiting a 40-year-old model

It is accepted that insulin-secreting beta-cells release insulin in response to glucose even in the absence of functional ATP-sensitive K+ (KATP)-channels, which play a central role in a 'consensus model' of secretion broadly accepted and widely reproduced in textbooks. A major shortcoming of this consensus model is that it ignores any and all anionic mechanisms, known for more than 40 years, to modulate beta-cell electrical activity and therefore insulin secretion. It is now clear that, in addition to metabolically regulated KATP-channels, beta-cells are equipped with volume-regulated anion (Cl-) channels (VRAC) responsive to glucose concentrations in the range known to promote electrical activity and insulin secretion. In this context, the electrogenic efflux of Cl- through VRAC and other Cl- channels known to be expressed in beta-cells results in depolarization because of an outwardly directed Cl- gradient established, maintained and regulated by the balance between Cl- transporters and channels. This review will provide a succinct historical perspective on the development of a complex hypothesis: Cl- transporters and channels modulate insulin secretion in response to nutrients.