The prevalence of type 2 diabetes has been progressively increasing, worldwide, during the last few decades with serious complications and increased mortality among the vast number of people afflicted. As a model complex disease (or trait), it poses a classical problem for scientists. In their efforts to dissect its genetic components, they have created transgenic mice, hoping that elucidation of gene effect will help to unravel the complex pathophysiology of a disease whose manifestation is also influenced by environmental factors—especially diet and exercise. In ‘full-blown’diabetes, hyperglycaemia results from multiple defects in insulin action and glucose sensing. Insulin action on glucose uptake in muscle, glucose production by the liver and kidneys, and lipolysis in adipose tissue, is impaired, while the ability of glucose to stimulate insulin secretion, inhibit hepatic glucose production, and promote its own uptake in muscle is diminished1, 2. Insulin resistance does not cause overt hyperglycaemia as long as the pancreatic β-cell compensates by hyperplasia and increased insulin secretion (Fig. 1). When this compensation fails, diabetes occurs3. Thus, a variety of susceptibility traits, genetic modifiers, and environmental factors determine whether a primary defect in insulin action manifests as overt diabetes.