Angiotensin II exerts glucose-dependent effects on K_v currents in mouse pancreatic β-cells via angiotensin II type 2 receptors

Hyperglycemia-associated glucotoxicity induces β-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 voltagegated outward potassium (K_v) current, which governs β-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 β-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. β-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 β-cell primary K_v channel subunit, K_v2.1, expression and K_v current amplitude. Enhanced expression of ANG II type 1 receptor (AT₁R) was also observed under high glucose conditions, whereas blockade of AT₁R 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 Kv channel gating was abolished by ANG II type 2 receptor (AT₂R) antagonism. These data suggest that hyperglycemia alters β-cell function through modification of the K_v channel which may be associated with the RAS.