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

To examine whether the association between cardiorespiratory fitness (CRF) and type 2 diabetes (T2D) is modified by genetic susceptibility and inflammation.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.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.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.