Implications of genome wide association studies for the understanding of type 2 diabetes pathophysiology

The rapid rise in prevalence of type 2 diabetes mellitus (T2DM) has been driven by changes in environmental factors - primarily increased caloric intake and reduced energy expenditure - resulting in reduced whole body insulin sensitivity (often termed insulin resistance). Insulin resistance has been proposed to be a major driver of progression to T2DM. However, of 38 individual susceptibility loci for T2DM recently identified by genome wide association studies, by far the majority code for proteins involved in β-cell function. In this review, we discuss the possible reasons for the paucity of insulin resistance genes and ask whether the new genetic susceptibility data should focus attention on β-cell targets in the development of therapies for T2DM.