Type 2 diabetes (T2D) is a complex chronic disease which is associated with micro- and macro-vascular complications and premature mortality. This multifactorial disease originates from a complex interplay between genetic, behavioural and environmental risk factors, the underlying mechanisms of which are unclear. The goal of this thesis was to investigate the contributions of genetic, metabolic and behavioural risk factors in the aetiology of T2D by studying large-scale population studies, in order to provide insights for the development of T2D prevention and intervention strategies. I first conducted a genome-wide association study on T2D in a large prospective cohort study for T2D, the EPIC-InterAct study. This work provides a valuable resource for the research community to conduct in-depth genetic investigations on T2D. The strongest T2D-associated genetic variant was at the established TCF7L2 locus. I then used the profiling of behavioural factors in the EPIC-InterAct study to show that there was no interaction between TCF7L2 genetic variants and an index of the number of health behaviour goals achieved, a measure that was strongly associated with diabetes risk. In a meta-analysis of three randomised controlled trials designed to investigate the effect of lifestyle intervention on the risk of developing T2D, I showed that there was no overall interaction between TCF7L2 and allocation to the intervention rather than the control arm. However, there was an interaction in one trial, which focused more on physical activity and dietary change than on weight change. In an analysis of a detailed quantitative metabolic trait study, I demonstrated a specific interaction between TCF7L2 and physical activity energy expenditure (PAEE). These data suggest that genetic targeting could have additive effects with health behaviour interventions and may be more valuable for personalised prevention if linked to very specific behaviours. To build on this observation and explore the potential mechanisms through which physical activity may affect the risk of T2D in different genetic subgroups, I undertook a systematic investigation of interaction effects between PAEE and genetic risk scores for glycaemic traits in the Fenland study. I did not find any significant interaction. Alternatively, using an agnostic approach, I searched for potential interactions with PAEE across the genome. Preliminary analyses detected three variants showing genome-wide significant interaction effects, although the mechanisms were unclear. As obesity is a strong risk factor for T2D and a previous study had reported that BMI modifies the effect of LAMA1 gene on T2D risk, I undertook an in-depth analysis of this potential interaction in the large-scale UKBB and EPIC-InterAct studies. I showed and confirmed that LAMA1 has a stronger effect on T2D among lean individuals compared with obese individuals in independent studies. Observational studies suggest that low cardiovascular fitness (CRF) is an independent T2D risk factor. However, it is unclear whether the association is causal or is due to confounding. I performed the largest genetic discovery of cardiorespiratory fitness in the UKBB study and developed a genetic risk score for CRF. In Mendelian randomisation analyses, I showed that the associations of this score with T2D and hyperinsulinaemia were compatible with underlying causal relationships. High-throughput metabolomics based on large-scale population studies offers a great opportunity for providing direct biological insights and identifying physiological alterations linking risk factors to T2D. I characterised the metabolic profiles of physical activity and cardiorespiratory fitness and identified shared and distinct signatures highlighting the roles of branched-chain amino acid metabolism and fatty acid oxidation. Overall, my PhD work contributes towards 1) a wider understanding of interpersonal differences for diabetes risk in response to behavioural factors based on variable genetic make-up and its implication in population-level diabetes prevention and intervention strategies 2) the discovery of the genetic basis of cardiorespiratory fitness and the provision of strong evidence supporting its causal role for T2D; 3) the characterisation of metabolic profiles of physical activity and cardiorespiratory fitness and the generation of hypotheses for potential biological pathways and physiological mechanisms underlying their influences on diabetes development.