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Fit to beat diabetes: mendelian randomization study confirms the power of exercise


Fitness is linked to lower T2D risk; however, the causality of the association remains unclear.

The United Kingdom Biobank (UKBB) data analysis showed that genes are linked to fitness. However, interpreting these findings is challenging due to skewed risk-stratified sub-maximal bike test data estimations.

About the study

In the present genome-wide association study (GWAS), researchers examined causal associations between fitness and T2D using genetic risk scores for cardiorespiratory fitness as variables in Mendelian randomization (MR).

The UKBB cohort of 450k Europeans was used to devise an optimized genomic instrument for cardiorespiratory fitness. The study identified 160 fitness-associated loci, validated in the Fenland trial comprising 10,707 individuals.

The instrument was applied to determine causality between cardiorespiratory fitness, T2D risk, and physiological risk parameters using inverse variance weighted-type (IVW) MR methods. The team assessed whether genetically predicted fitness was causally associated with glycemic traits or adiposity.

Fitness was defined as the maximum oxygen intake (VO2max) determined using sub-maximal ramped bicycle ergometer test data.

Logistic regression modeling was performed to determine the odds ratios (OR) for incident T2D according to fitness level in the UKBB, adjusting for age, sex, ethnicity, hypertension, anti-hypertensive medications, smoking, employment, area deprivation index, adiposity, history of stroke, heart failure, heart disease, atrial fibrillation, chronic obstructive pulmonary disease, or cancer, and intake of alcohol, meat, oily fish, fruits, and vegetables.

Non-European individuals, those without available genotype data, those without resting heart rate (RHR) measurements, and those taking β-blockers for pre-existing heart conditions were excluded from the analysis.

The subsample having bike test results were obtained from a previous UKBB cohort, and the results were triangulated with a GWAS of RHR to devise an optimized genomic instrument for cardiorespiratory fitness.

The genetic overlap between fitness measured by RHR and an exercise test was leveraged to determine the genetic determinants of cardiorespiratory fitness.

The findings were validated in the Fenland study cohort of 10,707 individuals. Further, the team explored the associations between genomically estimated cardiorespiratory fitness and serological proteins and conducted bioinformatic tests to provide insights into the underlying biological mechanisms.

The team investigated whether genomically estimated fitness had causal relationships with fasting glucose, fasting insulin, two-hour post-prandial oral glucose loads, and glycated hemoglobin (HbA1c)] or adiposity [determined using the body mass index (BMI) values].


As observed in the Fenland trial, increased fitness was strongly inversely and linearly related to the likelihood of having T2D in the present study, which included 73,574 participants with fitness measures over ten years.

The proteomic analysis findings indicated N-terminal pro-B-type natriuretic peptide, hepatocyte growth factor-like protein, and sex hormone-binding globulin as potential mediators of the association.

After adjusting for age, gender, adiposity, and other possible confounders, every one ml O2 per minute per kg of fat-free mass (FFM) increase in fitness was related to a 3.0% decreased chance of developing T2D.

In addition, 14 genome-level significant fitness-related single-nucleotide polymorphisms (SNPs) were identified among 69,416 Europeans in the UKBB study. An inverse genetic correlation was observed between fitness and RHR.

The radial-filtering approach identified 148 variants that showed a consistent effect on fitness. A difference of 3.60 ml O2 per minute per kg of FFM was observed in the average fitness level between the study participants in the highest and lowest deciles of the 160-variant optimized fitness instrument.

In the MR analysis, after filtering, for 126 variants, a significant and directionally consistent causal relationship between cardiorespiratory fitness and T2D was observed: odds ratio 0.97 for every unit higher genomically estimated fitness, expressed as ml O2 per minute per kg of FFM), and one standard deviation (SD) higher genomically predicted cardiorespiratory fitness was linked to an 11.0% lower T2D risk without heterogeneity.

The team found a statistically significant. Bonferroni-corrected relationship between genetically estimated fitness and fasting insulin levels, but not for other parameters.

Several genes [sodium voltage-gated channel alpha subunit 10 (SCN10A), calcium voltage-gated channel subunit alpha1 c (CACNA1C), and myosin heavy chain (MYH)-6 and 11] enriched in biological processes related to cardiac muscle development and muscle contractility were related to cellular muscle differentiation in muscles, development of organs, and enhanced contractility of heart muscles.

The findings were underpinned by those obtained from the Multi-marker Analysis of GenoMic Annotation (MAGMA) and the Functional Mapping and Annotation of Genome-Wide Association Studies (FUMA) pipelines.


Overall, the study findings showed a strong linear inverse association between exercise-measured cardiorespiratory fitness and the risk of developing T2D. Fasting insulin, an indicator of insulin resistance associated with fitness, was most likely the cause of the relationship.

Since both have similar physiological functions with the oxidative ability of skeletal muscles, the link between cardiorespiratory fitness and insulin sensitivity is scientifically feasible.

On the other hand, the immediate impact of cardiorespiratory fitness on T2D risk was only marginally reduced, indicating that other mechanisms may be involved.

The researchers found several genes that code for proteins essential for smooth and cardiac muscle function and growth, supporting the relationship between cardiorespiratory fitness and T2D risk.

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