Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Key Laboratory of Drug Quality Control and Pharmacovigilance China Pharmaceutical University, Nanjing, China.
J Cell Physiol. 2019 May;234(5):7510-7523. doi: 10.1002/jcp.27512. Epub 2018 Oct 26.
Pre-diabetes is characterized by impaired glucose tolerance (IGT) and/or impaired fasting glucose. Impairment of skeletal muscle function is closely associated with the progression of diabetes. However, the entire pathological characteristics and mechanisms of pre-diabetes in skeletal muscle remain fully unknown. Here, we established a mouse model of pre-diabetes, in which 6-week-old male C57BL6/J mice were fed either normal diet or high-fat diet (HFD) for 8 or 16 weeks. Both non-fasting and fasting glucose levels and the results of glucose and insulin tolerance tests showed that mice fed an 8-week HFD developed pre-diabetes with IGT; whereas mice fed a 16-week HFD presented with impaired fasting glucose and impaired glucose tolerance (IFG-IGT). Mice at both stages of pre-diabetes displayed decreased numbers of mitochondria in skeletal muscle. Moreover, IFG-IGT mice exhibited decreased mitochondrial membrane potential and ATP production in skeletal muscle and muscle degeneration characterized by a shift in muscle fibers from predominantly oxidative type I to glycolytic type II. Western blotting and histological analysis confirmed that myoblast differentiation was only inhibited in IFG-IGT mice. For primary skeletal muscle satellite cells, inhibition of differentiation was observed in palmitic acid-induced insulin resistance model. Moreover, enhanced myoblast differentiation increased glucose uptake and insulin sensitivity. These findings indicate that pre-diabetes result in mitochondrial dysfunction and inhibition of myoblast differentiation in skeletal muscle. Therefore, interventions that enhance myoblast differentiation may improve insulin resistance of diabetes at the earlier stage.
糖尿病前期的特征为葡萄糖耐量受损（IGT）和/或空腹血糖受损。骨骼肌功能障碍与糖尿病的进展密切相关。然而，糖尿病前期在骨骼肌中的全部病理特征和机制仍完全未知。在这里，我们建立了一个糖尿病前期的小鼠模型，其中 6 周龄雄性 C57BL6/J 小鼠分别用正常饮食或高脂肪饮食（HFD）喂养 8 或 16 周。非空腹和空腹血糖水平以及葡萄糖和胰岛素耐量试验的结果表明，用 HFD 喂养 8 周的小鼠出现了 IGT 糖尿病前期；而用 HFD 喂养 16 周的小鼠则表现出空腹血糖受损和葡萄糖耐量受损（IFG-IGT）。处于糖尿病前期两个阶段的小鼠骨骼肌中线粒体数量减少。此外，IFG-IGT 小鼠的骨骼肌中线粒体膜电位和 ATP 生成减少，并且肌肉变性以肌纤维从主要氧化型 I 向糖酵解型 II 转变为特征。Western blot 和组织学分析证实，只有 IFG-IGT 小鼠的成肌细胞分化受到抑制。对于原代骨骼肌卫星细胞，在棕榈酸诱导的胰岛素抵抗模型中观察到分化抑制。此外，增强成肌细胞分化可增加葡萄糖摄取和胰岛素敏感性。这些发现表明，糖尿病前期导致骨骼肌中线粒体功能障碍和成肌细胞分化抑制。因此，增强成肌细胞分化的干预措施可能会改善糖尿病前期的胰岛素抵抗。
