Systematic assessment of the genetic architecture of type 2 diabetes (T2D) has allowed the identification of hundreds of genetic loci contributing to T2D risk. However, understanding how these loci contribute to the aetiological complexity of T2D has been more challenging. Using an interdisciplinary approach this thesis aimed to investigate the genetic contribution to T2D, and related metabolic subphenotypes, to further the understanding of disease aetiology. This incorporated large-scale population genetic analyses of T2D and fine-scale intermediate traits, with targeted in vitro functional follow up of genes and variants of interest. Focused in vitro and genetic investigation of a single gene, MC3R, of which loss of function was previously thought to result in obesity and metabolic dysfunction, revealed that this was not the case. Combining functional assessment of coding variants in MC3R and association analyses at population-scale revealed a key role of MC3R in relaying nutritional cues to the timing of puberty, accrual of lean mass and height. At the other end of the spectrum, hypothesis-free genome-wide approaches examining traits intermediate to T2D, in combination with in vitro follow up, also have great utility in understanding T2D aetiology. A genetic discovery including > 55,000 individuals was conducted for insulin resistance after a glucose challenge (post-challenge insulin resistance) to approximate insulin resistance specifically in the post-prandial state, a key but understudied contributor to T2D onset. This revealed ten novel genetic loci for post-challenge insulin resistance (P<5x10^-8), including an association at SLC2A4, encoding the key insulin-stimulated glucose transporter GLUT4. Most of these post-challenge insulin resistance loci are shared with T2D, suggesting potential mechanisms behind these disease associations. Functional follow up using cell-based assays identified 9 novel candidate genes involved in insulin-stimulated glucose uptake and GLUT4 trafficking. Finally, integration of information of T2D genetic risk, T2D incidence, and untargeted plasma metabolomics identified distinct metabolomic signatures of specific T2D genetic endophenotypes associated with T2D development, which together with mediation analyses prioritised a subset of potential causal pathways. This work demonstrates the power of integrating population genetic analyses, refined traits intermediate to disease, and tailored in vitro follow up in prioritising key genes and pathways involved in T2D aetiology, and additionally highlights several candidates for further investigation.