Fig. 8: Model of PIEZO1 functions in the regulation of insulin secretion in healthy and diabetic β cells.

a An increase in plasma glucose and intracellular accumulation of glucose metabolites induce cell swelling and this leads to the activation of plasmalemmal PIEZO1 channels. The opening of these cation-conducting PIEZO1 channels leads to a small membrane depolarization, which in turn leads to activation of voltage-gated Ca²⁺ channels (VGCC) culminating in the elevation of [Ca²⁺]_i and stimulation of insulin release. Other channels, including (but not limited to) SWELL1, also provide a depolarizing current but full glucose-induced depolarization requires the cooperation of PIEZO1 and these additional conductances. b In β cells from individuals with T2D, PIEZO1 is translocated into the nucleus and the resultant reduction of membrane-associated PIEZO1 curtails the depolarization that would normally result from the glucose metabolism-induced cell swelling, culminating in impaired glucose-stimulated insulin secretion. c Left: Changes in membrane potential occurring when G_KATP is reduced from 4 to 1 nS and G_PIEZO1 then increases from 0 to 0.5 nS. The associated depolarization approaches the threshold for action potential firing (dotted lines). Right: Changes in membrane potential when G_KATP is increased to 2 nS and G_PIEZO1 then increases to 0.5 nS. In this case, depolarization is not sufficient for action potential firing to occur, explaining the suppression of insulin secretion. Membrane potential changes estimated from Eq. 1. AP action potential.