Acute exposure of beta-cells to troglitazone decreases insulin hypersecretion via activating AMPK |
| |
Authors: | Ruyuan Deng Aifang Nie Fangfang Jian Yun Liu Hongju Tang Juan Zhang Yuqing Zhang Li Shao Fengying Li Libin Zhou Xiao Wang Guang Ning |
| |
Institution: | 1. Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China;2. Department of Geratology, East Hospital, Shanghai Tongji University, Shanghai 200120, China |
| |
Abstract: | BackgroundIt 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 β-cell dysfunction. However, the mechanism underlying the protective effect of thiazolidinediones on β-cell function remains elusive.MethodsWe 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.ResultsLong-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 AMPKα2 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.ConclusionOur results suggest that troglitazone provides β-cell “a rest” through activating AMPK and inhibiting insulin hypersecretion, and thus restores its response to glucose.General significanceThese data support that AMPK activation may be an important mechanism for thiazolidinediones preserving β-cell function. |
| |
Keywords: | AMPK AMP-activated protein kinase TZD thiazolidinediones IGT impaired glucose tolerance IFG impaired fasting glucose GSIS glucose-stimulated insulin secretion ACC acetyl-CoA carboxylase PPARγ peroxisome proliferator-activated receptor γ shRNA short hairpin RNA KATP ATP-sensitive K+ channel Kv voltage-dependent potassium channel |
本文献已被 ScienceDirect 等数据库收录! |
|