Acute exposure of beta-cells to troglitazone decreases insulin hypersecretion via activating AMPK

Background: It has been recognized that insulin hypersecretion can lead to the development of insulin resistance and type 2 diabetes mellitus. There is substantial evidence demonstrating that thiazolidinediones are able to delay and prevent the progression of pancreatic beta-cell dysfunction. However, the mechanism underlying the protective effect of thiazolidinediones on beta-cell function remains elusive. Methods: We synchronously detected the effects of troglitazone on insulin secretion and AMP-activated protein kinase (AMPK) activity under various conditions in isolated rat islets and MIN6 cells. Results: Long-term exposure to high glucose stimulated insulin hypersecretion and inhibited AMPK activity in rat islets. Troglitazone-suppressed insulin hypersecretion was closely related to the activation of AMPK. This action was most prominent at the moderate concentration of glucose. Glucose-stimulated insulin secretion was decreased by long-term troglitazone treatment, but significantly increased after the drug withdrawal. Compound C, an AMPK inhibitor, reversed troglitazone-suppressed insulin secretion in MIN6 cells and rat islets. Knockdown of AMPK alpha 2 showed a similar result. In MIN6 cells, troglitazone blocked high glucose-closed ATP-sensitive K+ (KATp) channel and decreased membrane potential, along with increased voltage-dependent potassium channel currents. Troglitazone suppressed intracellular Ca2+ response to high glucose, which was abolished by treatment with compound C. Conclusion: Our results suggest that troglitazone provides beta-cell "a rest" through activating AMPK and inhibiting insulin hypersecretion, and thus restores its response to glucose. General significance: These data support that AMPK activation may be an important mechanism for thiazolidinediones preserving beta-cell function. (C) 2013 Elsevier B.V. All rights reserved.