Figure 2. Hypothesis model: Cl^– transporters and channels regulate insulin secretion.

Represented is a β-cell expressing glucose transporter (Glut), K_ATP-channels, voltage-gated Ca²⁺ channels (VGCC), Cl^– loaders, extruders and channels, including VRAC. Upon facilitative transport of glucose into the β-cell, the sugar is metabolized producing ATP and osmotically active metabolites, including lactate [32], hypothesized to promote the uptake of water to increase cell volume. The former closes K_ATP-channels, leading to reduced K⁺ permeability and PM depolarization, and the latter activates a VRAC-mediated inward Cl^– current that depolarizes the PM as well. Additional Cl^– channels are expected to contribute to Cl^– currents, which altogether are sufficient to activate VGCC provoking Ca²⁺ entry, action potentials, electrical activity and insulin secretion.