Department of Medicine, Division of Endocrinology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Biol Chem. 2010 Jan 29;285(5):3191-200. doi: 10.1074/jbc.M109.047365. Epub 2009 Nov 20.
During the initial autoimmune response in type 1 diabetes, islets are exposed to a damaging mix of pro-inflammatory molecules that stimulate the production of nitric oxide by beta-cells. Nitric oxide causes extensive but reversible cellular damage. In response to nitric oxide, the cell activates pathways for functional recovery and adaptation as well as pathways that direct beta-cell death. The molecular events that dictate cellular fate following nitric oxide-induced damage are currently unknown. In this study, we provide evidence that AMPK plays a primary role controlling the response of beta-cells to nitric oxide-induced damage. AMPK is transiently activated by nitric oxide in insulinoma cells and rat islets following IL-1 treatment or by the exogenous addition of nitric oxide. Active AMPK promotes the functional recovery of beta-cell oxidative metabolism and abrogates the induction of pathways that mediate cell death such as caspase-3 activation following exposure to nitric oxide. Overall, these data show that nitric oxide activates AMPK and that active AMPK suppresses apoptotic signaling allowing the beta-cell to recover from nitric oxide-mediated cellular stress.
在 1 型糖尿病的初始自身免疫反应中，胰岛暴露于促炎分子的破坏性混合物中，这些分子刺激β细胞产生一氧化氮。一氧化氮会导致广泛但可逆的细胞损伤。为了应对一氧化氮，细胞会激活功能恢复和适应的途径，以及指导β细胞死亡的途径。目前尚不清楚决定一氧化氮诱导损伤后细胞命运的分子事件。在这项研究中，我们提供的证据表明 AMPK 在控制β细胞对一氧化氮诱导损伤的反应中起主要作用。在 IL-1 处理或外源性添加一氧化氮后，胰岛素瘤细胞和大鼠胰岛中的 AMPK 会被短暂激活。活性 AMPK 促进β细胞氧化代谢的功能恢复，并阻断介导细胞死亡的途径的诱导，如暴露于一氧化氮后 caspase-3 的激活。总的来说，这些数据表明，一氧化氮激活 AMPK，而活性 AMPK 抑制细胞凋亡信号，使β细胞能够从一氧化氮介导的细胞应激中恢复。
