Acute exposure of beta-cells to troglitazone decreases insulin hypersecretion via activating AMPK
Acute exposure of beta-cells to troglitazone decreases insulin hypersecretion via activating AMPK
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β 细胞急性暴露于曲格列酮可通过激活 AMPK 降低胰岛素分泌过多
DOI：
10.1016/j.bbagen.2013.10.021
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发表时间：
2014-01-01
影响因子：
3
通讯作者：
Ning, Guang
中科院分区：
文献类型：
--
作者：
Deng, Ruyuan;Nie, Aifang;Ning, Guang
背景：胰岛素高分泌可导致胰岛素抵抗和2型糖尿病的发生。有大量证据表明，噻唑烷二酮类药物能够延缓和预防胰腺β细胞功能障碍的进展。然而，噻唑烷二酮类药物对β细胞功能的保护作用机制尚不清楚。方法：同步检测不同条件下曲格列酮对离体大鼠胰岛和MIN6细胞胰岛素分泌及amp活化蛋白激酶（AMPK）活性的影响。结果：长期高糖刺激大鼠胰岛胰岛素高分泌，抑制AMPK活性。曲格列酮抑制胰岛素高分泌与AMPK的激活密切相关。这种作用在葡萄糖浓度适中时最为明显。长期服用曲格列酮后，血糖刺激胰岛素分泌降低，停药后明显升高。化合物C，一种AMPK抑制剂，逆转了曲格列酮抑制的MIN6细胞和大鼠胰岛胰岛素分泌。敲除AMPK α 2也显示出类似的结果。在MIN6细胞中，曲格列酮阻断了高糖封闭的atp敏感K+ (KATp)通道，降低了膜电位，同时增加了电压依赖性钾通道电流。结论：我们的研究结果表明，曲格列酮通过激活AMPK和抑制胰岛素高分泌来为β细胞提供“休息”，从而恢复β细胞对葡萄糖的反应。一般意义：这些数据支持AMPK激活可能是噻唑烷二酮保持β细胞功能的重要机制。(C) 2013 Elsevier B.V.版权所有
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.