Type 2 diabetes is a complex disease characterized by insulin resistance in target tissues and a reduced capacity to produce compensatory levels of insulin in pancreatic-cells (1). Not surprisingly, a single molecular defect causing type 2 diabetes has been difficult to identify. A considerable body of evidence suggests that several genetic factors contribute to the pathogenesis of type 2 diabetes, given its familial clustering and prevalence in certain ethnic groups (2, 3). Mutations in several genes have been linked to rare monogenic forms of type 2 diabetes, including those encoding insulin, the insulin receptor, glucokinase, hepatocyte nuclear factors, insulin-promoting factor 1 (IPF-1, also known as IDX-1 and STF-1), and some mitochondrial proteins (4–8). In addition, genetic variations have been found in the sequence of insulin receptor substrate (IRS)-1 in a small percentage of patients with type 2 diabetes (9–12). Disruption of IRS-1 in mice causes insulin resistance, but does not impair the compensatory insulin production (13). In fact, islets are larger in IRS1 (–/–) mice, suggesting that the increased requirement for insulin is accommodated, at least partially, by an increased number of-cells (14). Thus, dysfunction of IRS-1 alone is unlikely to cause type 2 diabetes.

R ecently, we found that homozygous disruption of the mirs 2 gene causes peripheral insulin resistance and relative-cell failure (14). Consequently, IRS2 (–/–) mice display progressive deterioration of glucose homeostasis culminating with profound fasting hyperglycemia between 8 and 10 weeks of age. These results suggest that dysfunction of IRS-2 may contribute to the pathophysiology of type 2 diabetes. To establish a genetic basis for this hypothesis in humans, we cloned the human IRS-2 gene and characterized it in normal individuals and patients with type 2 diabetes.