Increased plasma creatine concentrations are associated with the risk of type 2 diabetes, but whether this alteration is associated with or causal for impairments in metabolism remains unexplored. Because skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. In men with type 2 diabetes, plasma creatine concentrations were increased, and intramuscular phosphocreatine content was reduced. These alterations were coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 ( CKMT2 ). In C57BL/6 mice fed a high-fat diet, neither supplementation with creatine for 2 weeks nor treatment with the creatine analog β-GPA for 1 week induced changes in glucose tolerance, suggesting that increased circulating creatine was associated with insulin resistance rather than causing it. In C2C12 myotubes, silencing Ckmt2 using small interfering RNA reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of Ckmt2 in skeletal muscle of high-fat diet–fed male mice increased mitochondrial respiration, independent of creatine availability. Given that overexpression of Ckmt2 improved mitochondrial function, we explored whether exercise regulates CKMT2 expression. Analysis of public data revealed that CKMT2 content was up-regulated by exercise training in both humans and mice. We reveal a previously underappreciated role of CKMT2 in mitochondrial homeostasis beyond its function for creatine phosphorylation, independent of insulin action. Collectively, our data provide functional evidence for how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.

中文翻译：

---

在 2 型糖尿病中，线粒体肌酸激酶 2 降低会独立于胰岛素损害骨骼肌线粒体功能


血浆肌酸浓度升高与 2 型糖尿病的风险相关，但这种改变是否与代谢损伤有关或因果关系仍未得到探索。由于骨骼肌是肌酸和葡萄糖的主要处理部位，我们研究了肌内肌酸代谢在 2 型糖尿病胰岛素抵抗病理生理学中的作用。在 2 型糖尿病男性中，血浆肌酸浓度增加，肌内磷酸肌酸含量降低。这些改变与肌节线粒体肌酸激酶 2 （CKMT2） 的表达降低相结合。在饲喂高脂饮食的 C57BL/6 小鼠中，补充肌酸 2 周和肌酸类似物 β-GPA 治疗 1 周均未诱导葡萄糖耐量的变化，这表明循环肌酸增加与胰岛素抵抗有关，而不是引起胰岛素抵抗。在 C2C12 肌管中，使用小干扰 RNA 沉默 Ckmt2 会降低线粒体呼吸、膜电位和葡萄糖氧化。电穿孔介导的 Ckmt2 过表达在高脂肪饮食喂养的雄性小鼠的骨骼肌中增加了线粒体呼吸，与肌酸可用性无关。鉴于 Ckmt2 的过表达改善了线粒体功能，我们探讨了运动是否调节 CKMT2 表达。对公共数据的分析显示，CKMT2 含量在人类和小鼠的运动训练中均上调。我们揭示了 CKMT2 在线粒体稳态中以前被低估的作用，超出了其肌酸磷酸化功能，独立于胰岛素作用。总的来说，我们的数据为 CKMT2 如何介导与 2 型糖尿病相关的线粒体功能障碍提供了功能证据。