Naomi Berrie Diabetes Center and Departments of Medicine, Columbia University, New York, NY 10032, USA.
Department of Neurology, Columbia University, New York, NY 10032, USA.
Mol Metab. 2020 Apr;34:97-111. doi: 10.1016/j.molmet.2019.12.008. Epub 2020 Feb 4.
Diabetes is characterized by pancreatic β-cell dedifferentiation. Dedifferentiating β cells inappropriately metabolize lipids over carbohydrates and exhibit impaired mitochondrial oxidative phosphorylation. However, the mechanism linking the β-cell's response to an adverse metabolic environment with impaired mitochondrial function remains unclear.
Here we report that the oxidoreductase cytochrome b5 reductase 3 (Cyb5r3) links FoxO1 signaling to β-cell stimulus/secretion coupling by regulating mitochondrial function, reactive oxygen species generation, and nicotinamide actin dysfunction (NAD)/reduced nicotinamide actin dysfunction (NADH) ratios.
The expression of Cyb5r3 is decreased in FoxO1-deficient β cells. Mice with β-cell-specific deletion of Cyb5r3 have impaired insulin secretion, resulting in glucose intolerance and diet-induced hyperglycemia. Cyb5r3-deficient β cells have a blunted respiratory response to glucose and display extensive mitochondrial and secretory granule abnormalities, consistent with altered differentiation. Moreover, FoxO1 is unable to maintain expression of key differentiation markers in Cyb5r3-deficient β cells, suggesting that Cyb5r3 is required for FoxO1-dependent lineage stability.
The findings highlight a pathway linking FoxO1 to mitochondrial dysfunction that can mediate β-cell failure.
糖尿病的特征是胰岛β细胞去分化。去分化的β细胞不恰当地代谢脂质而不是碳水化合物，并表现出受损的线粒体氧化磷酸化。然而，将β细胞对不利代谢环境的反应与受损的线粒体功能联系起来的机制尚不清楚。
在这里，我们报告了氧化还原酶细胞色素 b5 还原酶 3（Cyb5r3）通过调节线粒体功能、活性氧生成和烟酰胺腺嘌呤二核苷酸（NAD）/还原型烟酰胺腺嘌呤二核苷酸（NADH）比值，将 FoxO1 信号与β细胞刺激/分泌偶联联系起来。
Cyb5r3 在 FoxO1 缺陷的β细胞中的表达减少。β细胞特异性缺失 Cyb5r3 的小鼠胰岛素分泌受损，导致葡萄糖不耐受和饮食诱导的高血糖。Cyb5r3 缺陷的β细胞对葡萄糖的呼吸反应减弱，并表现出广泛的线粒体和分泌颗粒异常，与分化改变一致。此外，FoxO1 无法维持 Cyb5r3 缺陷的β细胞中关键分化标志物的表达，表明 Cyb5r3 是 FoxO1 依赖性谱系稳定性所必需的。
这些发现强调了一条将 FoxO1 与线粒体功能障碍联系起来的途径，该途径可介导β细胞衰竭。
