背景:已经认识到胰岛素分泌过多可导致胰岛素抵抗和2型糖尿病的发展。有大量证据表明噻唑烷二酮能够延迟和预防胰腺β细胞功能障碍的进展。然而,噻唑烷二酮对β细胞功能的保护作用的潜在机制仍然难以捉摸。
方法:我们在各种条件下同步检测了曲格列酮对分离的大鼠胰岛和MIN6细胞中胰岛素分泌和AMP激活的蛋白激酶(AMPK)活性的影响。
结果:长期暴露于高糖刺激胰岛素分泌过多,抑制大鼠胰岛AMPK活性。曲格列酮抑制胰岛素高分泌与AMPK的激活密切相关。这种作用在中等浓度的葡萄糖下最为突出。长期曲格列酮治疗可减少葡萄糖刺激的胰岛素分泌,但停药后显著增加。化合物C,AMPK抑制剂,逆转曲格列酮抑制MIN6细胞和大鼠胰岛中的胰岛素分泌。AMPKα2的敲低显示出类似的结果。在MIN6细胞,曲格列酮阻断高糖封闭的ATP敏感性K(+)(KATP)通道并降低膜电位,随着电压依赖性钾通道电流的增加。曲格列酮抑制细胞内Ca(2+)对高糖的反应,
结论:我们的结果表明,曲格列酮通过激活AMPK和抑制胰岛素分泌过多提供β细胞“休息”,从而恢复了对葡萄糖的反应。
结论:这些数据支持AMPK激活可能是噻唑烷二酮保护β细胞功能的重要机制。
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 β-cell dysfunction. However, the mechanism underlying the protective effect of thiazolidinediones on β-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 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 Ca(2+) response to high glucose, which was abolished by treatment with compound C.
CONCLUSIONS: Our results suggest that troglitazone provides β-cell \"a rest\" through activating AMPK and inhibiting insulin hypersecretion, and thus restores its response to glucose.
CONCLUSIONS: These data support that AMPK activation may be an important mechanism for thiazolidinediones preserving β-cell function.