"The aim of this proposal is to make a major advance in understanding why some people develop diabetes despite relative leanness and why others maintain normal glucose levels despite obesity. My vision is that human genetics and the ability to study humans will provide a major leap in understanding disease mechanisms. We will use state of the art resources in genomics, metabolomics, and large human biobanks to study three stages in life that may influence predisposition to diabetes independently of obesity:in utero life: We will test the hypothesis that the in utero environment alters offspring glucose levels and metabolism. We will perform the most comprehensive analyses of the in utero environment using mass-spectrometry based metabolomics. We will use maternal genetic factors that influence glucose levels in pregnancy to test the causal effects of the in utero environment on offspring outcomes.“long-term” life: We will test the hypothesis that long-term exposure to altered metabolic and circulating factors influences glycaemia and metabolism. We will use the principle of Mendelian randomization to identify the subset of known and novel biomarkers that are likely to play a causal role in diabetes disease processes.“Pre-diabetes” life: We will test the hypothesis that non-diabetic individuals carrying different type 2 diabetes genetic risk factors will have different physiological characteristics. Little is known about the detailed physiology of individuals carrying the greatest number of genetic risk factors. We will perform detailed physiological studies in non-diabetic individuals predisposed to type 2 diabetes based on specific genetic risk factors. These characteristics may inform intervention and treatment strategies targeted at those at greatest genetic risk of diabetes."