Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Sci Transl Med. 2024 Oct 9;16(768):eado3022. doi: 10.1126/scitranslmed.ado3022.
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 (). 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 using small interfering RNA reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of in skeletal muscle of high-fat diet-fed male mice increased mitochondrial respiration, independent of creatine availability. Given that overexpression of 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.
血浆肌酸浓度升高与 2 型糖尿病的风险相关，但这种变化是否与代谢损伤有关或是否是其原因仍不清楚。由于骨骼肌既是肌酸又是葡萄糖的主要清除部位，我们研究了肌内肌酸代谢在 2 型糖尿病胰岛素抵抗发病机制中的作用。在 2 型糖尿病男性中，血浆肌酸浓度升高，肌内磷酸肌酸含量减少。这些变化与肌节线粒体肌酸激酶 2（）的表达减少有关。在高脂饮食喂养的 C57BL/6 小鼠中，肌酸补充 2 周或肌酸类似物 β-GPA 治疗 1 周均未引起葡萄糖耐量变化，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 沉默可降低线粒体呼吸、膜电位和葡萄糖氧化。电穿孔介导的骨骼肌中过表达在高脂饮食喂养的雄性小鼠中增加了线粒体呼吸，而与肌酸的可用性无关。鉴于过表达可改善线粒体功能，我们探讨了运动是否调节 CKMT2 的表达。对公共数据的分析表明，在人类和小鼠中，运动训练均可上调 CKMT2 含量。我们揭示了 CKMT2 在调节线粒体稳态方面的一个以前未被充分认识的作用，其作用超出了其对肌酸磷酸化的作用，且不依赖于胰岛素作用。总之，我们的数据提供了功能证据，表明 CKMT2 如何介导与 2 型糖尿病相关的线粒体功能障碍。
