ABSTRACT
In pancreatic ß-cells, closure of the ATP-sensitive K(+) (K(ATP)) channel is an initial process triggering glucose-stimulated insulin secretion. In addition, constitutive opening of background nonselective cation channels (NSCCs) is essentially required to effectively evoke depolarization as a consequence of K(ATP) channel closure. Thus, it is hypothesized that further opening of NSCC facilitates membrane excitability. We identified a class of NSCC that was activated by exendin (ex)-4, GLP-1, and its analog liraglutide at picomolar levels. This NSCC was also activated by increasing the glucose concentration. NSCC activation by glucose and GLP-1 was a consequence of the activated cAMP/EPAC-mediated pathway and was attenuated in TRPM2-deficient mice. The NSCC was not activated by protein kinase A (PKA) activators and was activated by ex-4 in the presence of PKA inhibitors. These results suggest that glucose- and incretin-activated NSCC (TRPM2) works in concert with closure of the KATP channel to effectively induce membrane depolarization to initiate insulin secretion. The current study reveals a new mechanism for regulating electrical excitability in ß-cells and for mediating the action of glucose and incretin to evoke insulin secretion, thereby providing an innovative target for the treatment of type 2 diabetes.
Subject(s)
Acetylcysteine/analogs & derivatives , Cyclic AMP/metabolism , Erythromycin/analogs & derivatives , Insulin-Secreting Cells/metabolism , Insulin/metabolism , Signal Transduction/physiology , TRPM Cation Channels/metabolism , Acetylcysteine/metabolism , Animals , Calcium/metabolism , Erythromycin/metabolism , Exenatide , Glucose/pharmacology , Incretins/pharmacology , Insulin Secretion , Insulin-Secreting Cells/drug effects , Male , Mice , Mice, Knockout , Peptides/pharmacology , Rats, Wistar , Signal Transduction/drug effects , Venoms/pharmacologyABSTRACT
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 ß-cells. VPA had no acute effect on insulin secretion from islets, or on cytosolic Ca(2+) ([Ca(2+)]i) in single ß-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, ß-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.
