Chronic exposure to valproic acid promotes insulin release, reduces KSubscriptATP/Subscript channel current and does not affect CaSuperscript2+/Superscript signaling in mouse islets

摘要

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 ?2-cells. VPA had no acute effect on insulin secretion from islets, or on cytosolic Ca2+ ([Ca2+]i) in single ?2-cells. However, following long-term exposure to VPA (48??h), 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, ?2-cells showed a decrease in whole cell KATP channel current. However, the increase in [Ca2+]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.