The incretin hormones (GLP-1 and GIP) are secreted from the gut in response to food intake and their primary role is to amplify nutrient-induced insulin release. Most of this effect is lost in obesity and type 2 diabetes. Glucagon acts as a counter-regulatory hormone to insulin and may therefore also be essential in type 2 diabetes pathophysiology. My objective is to carry out a unique combination of state-of-the-art phenotyping and genotyping in a large, well-characterized cohort of people at key stages of increased diabetes risk. I will genotype a large panel of more than 500,000 genetic markers in 2,082 individuals with varying levels of glucose tolerance, either normal glucose tolerance, impaired fasting glycaemia, impaired glucose tolerance or type 2 diabetes. In addition, I will measure plasma levels of GLP-1, GIP and glucagon at 0, 30 and 120 minutes during an oral glucose tolerance test in the same individuals. I will then examine the effect of these genetic markers on incretin and glucagon levels during the oral glucose challenge. The results of the association study will be followed up in an additional cohort consisting of ~8,200 individuals from Sweden and Finland. The knowledge generated about the complex interplay of mechanisms driving the earliest stages of diabetes will allow identification of new potential targets for individualized prevention and treatment of type 2 diabetes. The epidemiological scale of the study will enable a direct translation of the findings to the real-life setting of population-wide general practice-based diabetes screening and tailored prevention.