Cardiorespiratory fitness, genetic susceptibility, inflammation and risk of incident type 2 diabetes: A population-based longitudinal study

Objective: To examine whether the association between cardiorespiratory fitness (CRF) and type 2 diabetes (T2D) is modified by genetic susceptibility and inflammation. Participants: The prospective study included 57,185 participants (40-70 years) who were free from T2D and received the CRF assessment at enrollment (2006-2010) in the UK biobank. CRF was examined through a submaximal cycle ergometer test and expressed in metabolic equivalent of tasks (METs), genetic susceptibility was quantified using a genetic risk score, and inflammation was assessed according to the concentration of C reactive protein. All these three factors were categorized into tertiles. Results: During a median follow-up of 10.4 years, 5477 (7.0%) cases of T2D were ascertained. CRF was inversely associated with the risk of T2D in a dose-response manner. The hazard ratio (HR) was 0.85 (95% confidence interval [CI]: 0.79-0.92) per 1 MET increment of CRF. There was a significant interaction between CRF and genetic susceptibility to T2D in relation to the risk of T2D (P for interaction = 0.03). Compared with participants with high CRF and low genetic susceptibility, the HR was 4.98 (95% CI: 3.17-7.82) for those with low CRF and high genetic susceptibility. A similar pattern was observed in participants with low CRF and high inflammation compared with those who had high CRF and low inflammation (HR = 2.53; 95% CI: 1.83-3.48), though the interaction between CRF and inflammation did not reach statistical significance. T2D risk declined progressively with increased CRF among different inflammation categories. Conclusion: Our study reveals that genetic susceptibility may modify the association between CRF and T2D, highlighting that risk of T2D associated with genetics could benefit most from interventions on improving CRF.