New Insights on the Relationship between Cardiorespiratory Fitness and Type 2 Diabetes

Researchers from various institutions, including Lina Cai, Tomas Gonzales, Eleanor Wheeler, Nicola D. Kerrison, Felix R. Day, Claudia Langenberg, John R. B. Perry, Soren Brage, and Nicholas J. Wareham, have conducted a study to investigate the causal associations between cardiorespiratory fitness and type 2 diabetes. Their findings, published in the journal Nature Communications, shed light on the genetic determinants of fitness, its impact on diabetes risk, and potential biological mechanisms underlying this relationship.

Cardiorespiratory fitness refers to the ability of the circulatory and respiratory systems to supply oxygen to working muscles during prolonged exercise. It is a complex trait influenced by both genetic and environmental factors. Previous research has shown that higher fitness is associated with a lower risk of type 2 diabetes, but the causality of this relationship and the underlying biological mechanisms have remained unclear.

To explore the genetic basis of fitness and its association with type 2 diabetes, the researchers analyzed data from 450,000 individuals of European ancestry in the UK Biobank. They leveraged the genetic overlap between fitness, measured by an exercise test, and resting heart rate to identify fitness-associated loci. The study identified 160 genetic loci associated with fitness, which were validated in an independent cohort, the Fenland study.

Gene-based analyses prioritized candidate genes involved in biological processes related to cardiac muscle development and muscle contractility, such as CACNA1C, SCN10A, MYH11, and MYH6. These genes provide insights into the biological mechanisms underlying cardiorespiratory fitness.

Using a Mendelian Randomization framework, the researchers demonstrated that higher genetically predicted fitness is causally associated with a lower risk of type 2 diabetes, independent of adiposity (body fatness). This approach helps establish a causal link between fitness and diabetes risk, reducing confounding and reverse causality issues that can affect observational studies.

The study also investigated potential mediators of the relationship between fitness and diabetes risk. Integration with proteomic data identified several proteins, including N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein, and sex hormone-binding globulin, as potential mediators. These proteins may play a role in the biological pathways linking fitness to diabetes risk.

The findings highlight the importance of improving fitness for diabetes prevention and provide valuable insights into the biological mechanisms underlying cardiorespiratory fitness. By uncovering the genetic determinants of fitness and its causal association with diabetes risk, this research contributes to our understanding of the complex interplay between physical fitness and metabolic health.