Higher cardiorespiratory fitness is associated with higher insulin sensitivity and lower risk of type 2 diabetes, but until now it hasn’t been clear if the relationship is causal, and the biological mechanisms that underlie it were unknown. As a result cardiorespiratory fitness is rarely measured in people at risk of developing type 2 diabetes, and thus has not been given sufficient prominence in preventive interventions nor in clinical care.

A key question is if cardiorespiratory fitness is directly associated with a lower risk of type 2 diabetes, or if the apparent association is due to higher cardiorespiratory fitness being associated with lower body fat mass, which in turn has a well-established association with a lower risk of type 2 diabetes.

Creating a genetic score for cardiorespiratory fitness

In a paper published in Nature Communications last week, scientists at the MRC Epidemiology Unit report using a genetic risk score for fitness in a Mendelian randomization study to evaluate if cardiorespiratory fitness is causally linked to type 2 diabetes. Mendelian Randomization uses measured variation in genes of known to be associated with a modifiable trait – in this case cardiorespiratory fitness – to examine the causal effect of that trait on a disease such as type 2 diabetes. Since the genes a person has inherited are not affected by their behaviour, this approach reduces the risk of confounding and reverse causality in observational studies.

The authors first analysed the relationship between fitness and type 2 diabetes risk in 73,574 UK Biobank participants for whom exercise bike fitness test data was available, finding higher fitness was strongly associated with a lower risk of developing type 2 diabetes, in agreement with previous findings. They then undertook a genome-wide association study (GWAS) in 69,416 of these UK Biobank participants, and identified 14 genetic variations that were significantly associated with fitness.

In order to be able to analyse a larger sample size and identify more gene variants associated with cardiorespiratory fitness, the authors then made use of the fact that a lower resting heart rate is strongly correlated with higher fitness, and resting heart rate had been measured in most UK Biobank participants. Their GWAS in >450K UK Biobank participants of European ancestry they found that there is a strong genetic correlation between lower resting heart rate and fitness, and identified 148 resting heart rate variants which were also associated with fitness.

The team combined these 148 resting heart rate gene variants with the 14 gene variants for fitness they had identified earlier to create a genetic score based on 160 gene variants which had showed a consistent effect with fitness. This score was then independently validated in 9,512 Fenland Study participants for whom fitness data from a treadmill test was available.

Understanding the association between fitness and type 2 diabetes risk

This score was then used in a Mendelian Randomisation study in data from  >55K people with type 2 diabetes and >400K controls in the DIAMANTE consortium, finding that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of body fat mass.

To learn more about the underlying biology that might explain the independent association between cardiovascular fitness and type 2 diabetes, they examined the association between genetically predicted fitness and almost 5,000 proteins in more than 10,000 Fenland Study participants. This enabled then to identify several candidates as potential mediators of this relationship, including N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin.

Professor Nick Wareham, Director of the MRC Epidemiology Unit and senior author on this paper said:

Our genetic research provides strong evidence that the association of higher fitness with a lower risk of type 2 diabetes is independent of the amount of body fat. Improving fitness may be important to prevent and manage type 2 diabetes, and should be evaluated in future clinical trials”

Read more

• Cai , Gonzales T, Wheeler E, Kerrison N, Day F et al. Causal associations between cardiorespiratory fitness and type 2 diabetes. Nat Commun; 03 July 2023; DOI: 10.1038/s41467-023-38234-w