Genome-wide association study and functional characterisation identifies candidate genes for insulin-stimulated glucose uptake

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 hours after a glucose challenge in >55,000 participants from three ancestry groups. We identified 10 novel loci (P<5x10(-8)) not previously associated with post-challenge insulin resistance, 8 of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified 9 candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on post-prandial insulin resistance, we highlight mechanisms of action at T2D loci that are not adequately captured by studies of fasting glycaemic traits.