Angiotensin II exerts glucose-dependent effects on Kv currents in mouse pancreatic beta-cells via angiotensin II type 2 receptors.

Hyperglycemia-associated glucotoxicity induces beta-cell apoptosis but the underlying mechanisms are unknown. Interestingly, prolonged exposure to high glucose upregulates the expression and function of the renin-angiotensin system (RAS). We hypothesize that the voltage-gated outward potassium (K(v)) current, which governs beta-cell membrane potential and insulin secretion, has a role in glucotoxicity. In this study, we investigated the effects of prolonged exposure to high glucose on mouse pancreatic beta-cells and concurrent effects on the RAS by examining changes in expression of angiotensin II (ANG II) receptors and changes in the expression and activity of K(v) channels. beta-Cells were incubated in high glucose medium for 1-7 days and then were examined with electrophysiological and molecular biology techniques. Prolonged exposure to high glucose produced a marked increase in beta-cell primary K(v) channel subunit, K(v)2.1, expression and K(v) current amplitude. Enhanced expression of ANG II type 1 receptor (AT(1)R) was also observed under high glucose conditions, whereas blockade of AT(1)R by losartan did not alter K(v) channel expression. External application of ANG II reduced K(v) current amplitude under normal, but not high, glucose conditions. The effect of ANG II on K(v) channel gating was abolished by ANG II type 2 receptor (AT(2)R) antagonism. These data suggest that hyperglycemia alters beta-cell function through modification of the K(v) channel which may be associated with the RAS.