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

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• 作者：Ruyuan Deng ; Aifang Nie ; Fangfang Jian ; Yun Liu ; Hongju Tang ; Juan Zhang ; Yuqing Zhang ; Li Shao ; Fengying Li ; Libin Zhou ; Xiao Wang ; Guang Ning
• 关键词：AMPK ; AMP-activated protein kinase ; TZD ; thiazolidinediones ; IGT ; impaired glucose tolerance ; IFG ; impaired fasting glucose ; GSIS ; glucose-stimulated insulin secretion ; ACC ; acetyl-CoA carboxylase ; PPAR纬 ; peroxisome proliferator-activated receptor 纬 ; shRNA ; short hairpin RNA ; KATP ; ATP-sensitive K+ channel ; Kv ; voltage-dependent potassium channel
• 刊名：Biochimica et Biophysica Acta (BBA)/General Subjects
• 出版年：January, 2014
• 年：2014
• 卷：1840
• 期：1
• 页码：577-585
• 全文大小：1135 K

文摘

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 尾-cell dysfunction. However, the mechanism underlying the protective effect of thiazolidinediones on 尾-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伪2 showed a similar result. In MIN6 cells, troglitazone blocked high glucose-closed ATP-sensitive K⁺ (K_ATP) channel and decreased membrane potential, along with increased voltage-dependent potassium channel currents. Troglitazone suppressed intracellular Ca^2 + response to high glucose, which was abolished by treatment with compound C.

Conclusion

Our results suggest that troglitazone provides 尾-cell 鈥渁 rest鈥?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 尾-cell function.