2024-10-10 カロリンスカ研究所(KI)
<関連情報>
- https://news.ki.se/new-study-shows-how-muscle-energy-production-is-impaired-in-type-2-diabetes
- https://www.science.org/doi/10.1126/scitranslmed.ado3022
ミトコンドリアのクレアチンキナーゼ2の減少は、2型糖尿病においてインスリンとは無関係に骨格筋のミトコンドリア機能を障害する Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes
David Rizo-Roca, Dimitrius Santiago P. S. F. Guimarães, Logan A. Pendergrast, Nicolas Di Leo, […], and Anna Krook
Science Translational medicine Published:9 Oct 2024
DOI:https://doi.org/10.1126/scitranslmed.ado3022
Editor’s summary
Increased plasma creatine is associated with type 2 diabetes, but causation has not been established. Rizo-Roca et al. show that men with type 2 diabetes had increased plasma creatine and decreased muscle phosphocreatine, which was associated with poor glucose handling. In myotubes in vitro, silencing the mitochondria-associated sarcomeric mitochondrial creatine kinase 2 (Ckmt2) gene resulted in impaired mitochondrial functions. In mice fed a high-fat diet, creatine supplementation had no effect on glucose handling, but overexpression of Ckmt2 in muscle improved mitochondrial functions. Data from humans and mice showed that exercise increased CKMT2 and metrics of mitochondrial functions. These results suggest that creatine changes are a consequence rather than a cause of insulin resistance in type 2 diabetes. —Brandon Berry
Abstract
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.
