Cardiac Diabetic Autonomic Neuropathy is Associated with Insulin Regulated GIRK4 Expression via Activation of Akt and SREBP‐1

Abstract

Diabetic Autonomic Neuropathy is characterized by parasympathetic dysfunction of the heart. Although GIRK4 is required for parasympathetic response, no data on the regulation are available. Here we describe insulin up‐regulation of GIRK4, via an Akt/GSK3β/SREBP‐1 dependant pathway. Type 1 diabetic Akita mice demonstrate parasympathetic dysfunction. Expression of GIRK4, SREBP1, and phosphorylation of Akt and GSK3β were decreased in the Akita mouse atrium, and was reversed by insulin. Insulin stimulated Akt phophorylation, increased GIRK4 promoter activity and protein in atrial myocytes, which was inhibited by the PI3 kinase inhibitor, LY294002. Active myristoylated Akt (MyrAkt) induced the expression of SREBP1 and GIRK4. Insulin increased nuclear SREBP level and DN SREBP1 reversed the insulin effect on GIRK4 protein. Reporter assays demonstrated that SREBPs stimulated GIRK4 promoter activity in a dose dependent manner, which was inhibited by LY. Inhibition of GSK3β also stimulated SREBP and GIRK4 protein. Our data suggest that insulin increases GIRK4 expression by activation of Akt, which phosphorylates and inhibits GSK3β, which involved in SREBP degradation. And SREBP up‐regulates GIRK4. So hypoinsulinemia in type 1 diabetes may result in parasympathetic dysfunction due to decreased SREBP and GIRK4 levels. The role of Akt and GSK3β may offer new therapeutic targets for this complication of diabetes.