Chronic exposure to valproic acid promotes insulin release, reduces KATP channel current and does not affect Ca2+ signaling in mouse islets

Abstract

Hyperinsulinemia is one of the reported side effects of valproic acid (VPA), a medicine used to treat epilepsy. However, its underlying mechanism remains unknown. The present study was designed to investigate a direct effect of VPA on insulin secretion by using mouse pancreactic islets and β-cells. VPA had no acute effect on insulin secretion from islets, or on cytosolic Ca(2+) ([Ca(2+)]i) in single β-cells. However, following long-term exposure to VPA (48h), both basal and glucose-stimulated insulin secretion were markedly elevated (5-fold), while the insulin gene expression level was unaltered. Following long-term exposure to VPA, β-cells showed a decrease in whole cell KATP channel current. However, the increase in [Ca(2+)]i in response to the sulfonylurea drug, tolbutamide was attenuated. The present study shows that VPA has no acute effects, but long-term treatment results in enhancement of both basal and glucose-stimulated insulin secretion. This long-term effect may mediate the KATP channel, while VPA can also attenuate the effect of the KATP channel blocker tolbutamide.