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

It is accepted that insulin-secreting β-cells release insulin in response to glucose even in the absence of functional ATP-sensitive K(+) (K(ATP))-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 β-cell electrical activity and therefore insulin secretion. It is now clear that, in addition to metabolically regulated K(ATP)-channels, β-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 β-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.