New research from Karolinska Institutet reveals that reduced levels of creatine kinase in muscle cells may explain energy production deficiencies in type 2 diabetes, offering potential new therapeutic targets for metabolic disorders.
Photo: Johannes Frandsén
Understanding the creatine connection
Scientists have long observed that individuals with type 2 diabetes (T2D) exhibit impaired energy metabolism in their muscles, but the underlying mechanisms have remained unclear. Now, a groundbreaking study published in Science Translational Medicine (9 October 2024) [1] has identified a crucial protein deficiency that may explain this metabolic dysfunction.
The research team, led by Professor Anna Krook from the Department of Physiology and Pharmacology at Karolinska Institutet, discovered that people with T2D have significantly lower levels of creatine kinase in their muscles. This protein plays a vital role in metabolising and converting creatine, a natural compound essential for muscle energy production.
Consequence rather than cause of disease
The findings help resolve a longstanding puzzle in diabetes research. Previous studies had identified elevated blood creatine levels as a potential risk factor for T2D, raising concerns about creatine supplementation – a popular practice among athletes and fitness enthusiasts. However, this new research suggests that high blood creatine levels are a consequence rather than a cause of the disease.
“The findings indicate that impaired creatine metabolism is a consequence of type 2 diabetes, rather than a cause of the disease,” explains Prof. Krook in the study announcement.
Impact on cellular powerhouses
Through detailed investigations using both human and mouse models, the researchers demonstrated that reduced creatine kinase levels have far-reaching effects on cellular energy production. The study revealed that low levels of this protein impair the function of mitochondria – the cellular structures responsible for energy generation.
These compromised mitochondria exhibited both reduced energy production capacity and increased cellular stress, consistent with the metabolic inefficiencies commonly observed in T2D patients.
Unexpected findings
The research yielded an unexpected discovery about the relationship between creatine kinase and mitochondrial function. The team found that alterations in creatine kinase levels affected both the structural appearance and energy-producing capabilities of mitochondria, independent of available creatine levels.
“This suggests that although the main role of creatine kinase is to process creatine, it affects mitochondrial function in other ways,” notes Dr David Rizo-Roca, the study’s first author. The team is now investigating the molecular mechanisms underlying these effects.
Therapeutic implications
The identification of creatine kinase’s role in T2D opens new avenues for therapeutic intervention. Prof. Krook suggests that regulating creatine kinase could potentially become part of the treatment strategy for metabolic diseases, including obesity and diabetes.
The research represents a significant advance in understanding the relationship between creatine metabolism and diabetes. It suggests that previous concerns about creatine supplementation may need to be re-evaluated in light of the finding that creatine accumulation appears to be a marker of metabolic dysfunction rather than its cause.
The study was conducted in collaboration with Danderyd Hospital and Karolinska University Hospital Huddinge, with funding from several prestigious organisations including the European Association for the Study of Diabetes (EASD), the Knut and Alice Wallenberg Foundation, and the Novo Nordisk Foundation.
Reference
- Rizo-Roca D., Guimarães, D. S. P. F., Pendergrast, L. A., et. al. (2024). Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.ado3022
