A recent study published in Science Translational Medicine sheds light on the crucial role creatine kinase M2 (CKMT2) plays in mitochondrial dysfunction, a hallmark of type 2 diabetes. The study highlights the enzyme’s regulation of mitochondrial function and its potential as a therapeutic target for managing energy imbalances in diabetic patients.
CKMT2 and Its Role in Diabetes
In individuals with type 2 diabetes, insulin resistance leads to altered energy metabolism, limiting intracellular storage and transportation of adenosine triphosphate (ATP). Tissues with high energy demands, such as skeletal muscles and the brain, rely on creatine kinases to convert creatine into phosphocreatine, a critical component in cellular energy balance.
Creatine acts as an energy shuttle, facilitating ATP storage and transport across cell membranes. This process is closely tied to numerous physiological functions, including immune response regulation in macrophages. Dysfunctional phosphocreatine metabolism, particularly in white adipose tissue, has been linked to the proinflammatory conditions seen in obesity, a common precursor to diabetes. Studies have shown that increased plasma creatine levels in men correlate with a heightened risk of developing type 2 diabetes.
Alterations in creatine metabolism—whether through changes in the expression of creatine transporter proteins or the conversion of creatine to phosphocreatine—significantly impact the energy balance in diabetic patients. CKMT2, a sarcomeric mitochondrial enzyme localized in the mitochondrial intermembrane space, plays a vital role in phosphorylating creatine by working alongside the adenine nucleotide translocator (ANT). However, its exact function in skeletal muscle metabolism under diabetic conditions remains unclear.
Study Overview
The study sought to clarify CKMT2’s role in skeletal muscle function by analyzing creatine metabolism and gene expression in plasma and muscle biopsy samples from men with type 2 diabetes. The research also utilized mouse models to further investigate CKMT2’s impact on mitochondrial metabolism.
Researchers recruited 27 men with normal glucose tolerance and 25 men with type 2 diabetes. All participants with diabetes were receiving glucose-lowering medications, such as metformin or sulfonylurea, which were administered after collecting skeletal muscle biopsy samples.
Key Findings
The study revealed significantly higher circulating creatine levels in men with type 2 diabetes, which negatively correlated with the expression of the creatine transporter gene (SLC6A8) in skeletal muscle. Reduced levels of phosphocreatine, along with increased intramuscular creatine content, were also observed. These findings suggest a strong association between CKMT2 expression and impaired energy metabolism in skeletal muscle.
Reduced CKMT2 mRNA levels in skeletal muscle were linked to higher post-oral glucose tolerance test (OGTT) insulin levels in men with normal glucose tolerance. In patients with diabetes, CKMT2 expression correlated with elevated hemoglobin A1c (HbA1c) levels. Interestingly, CKMT2 expression also showed a positive correlation with hip diameter in men without diabetes.
The researchers observed that in high-fat diet-fed mice, creatine treatment partially reversed the downregulation of CKMT2 mRNA, leading to improvements in genes related to mitochondrial function and oxidative stress regulation. Creatine also enhanced basal glucose transport in the skeletal muscles of mice, particularly in those treated with a creatine analog, β-guanidinopropionic acid (β-GPA).
Experimental Insights
The study also utilized high-resolution respirometry assays to assess mitochondrial function in muscle cells. Silencing CKMT2 led to a reduction in mitochondrial respiration capacity and decreased mitochondrial membrane potential, as well as reduced levels of hydrogen peroxide. In contrast, overexpression of CKMT2 in skeletal muscle cells improved mitochondrial respiration, reduced metabolic stress caused by lipid exposure, and alleviated p38 mitogen-activated protein kinase (MAPK) activation.
Physical activity was shown to have a positive effect on CKMT2 levels, with 25 days of voluntary wheel running in mice increasing CKMT2 expression, independent of mitochondrial biogenesis.
Conclusion
This study provides valuable insights into CKMT2’s crucial role in maintaining mitochondrial health and regulating energy metabolism, particularly in the context of type 2 diabetes. Reduced CKMT2 expression was linked to several key indicators of mitochondrial dysfunction, such as impaired glucose metabolism and increased oxidative stress in skeletal muscle. These findings point to CKMT2 as a potential therapeutic target for improving metabolic health and managing type 2 diabetes.
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