Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory β-cell hyperplasia

To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2(-/-) mice) had a body weight similar to wildtype mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2(-/-) mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of beta -cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of beta -cells in IRS-1-deficient mice (IRS-1(-/-) mice) to compensate for insulin resistance. Thus, IRS-2 plays a crucial role in the regulation of beta -cell mass. On the other hand, insulin secretion by the same number of cells in response to glucose measured ex vivo was significantly increased in IRS-2(-/-) mice compared with wild-type mice but was decreased in IRS-1(-/-) mice. These results suggest that IRS-1 and IRS-S may play different roles in the regulation of beta -cell mass and the function of individual beta -cells.