Background— Insulin resistance is associated with atherosclerosis, but its mechanism is unknown. It has been reported that insulin receptor substrate (IRS)-1 deficient (IRS-1^−/−) mice showed insulin resistance without type 2 diabetes, whereas the IRS-2 deficient (IRS-2^−/−) mice showed insulin resistance with type 2 diabetes.

Methods and Results— We investigated neointima formation in the IRS-1^−/− and IRS-2^−/− mice at 8 and 20 weeks. The IRS-2^−/− mice showed much greater neointima formation than the IRS-1^−/− and wild-type mice at 8 weeks. At 20 weeks, the IRS-2^−/− mice had greater neointima formation than the IRS-1^−/− mice, which showed more enhanced neointima formation than the wild-type mice. The IRS-1^−/− and IRS-2^−/− mice had dyslipidemia, hypertension, and insulin resistance. The IRS-2^−/− mice had more metabolic abnormalities than the IRS-1^−/− mice at 8 and 20 weeks. IRS-2 expression was detected, but IRS-1 expression was not detected in the vessels.

Conclusions— The neointima formation in the IRS-1^−/− and IRS-2^−/− mice appears to be related to abnormalities induced by the altered metabolic milieu in insulin-resistant states. Moreover, because neointima formation was much greater in the IRS-2^−/− mice than in the IRS-1^−/− mice at 8 and 20 weeks, it is suggested that a lack of IRS-2 renders the vasculature more susceptible to injury in the abnormal metabolic milieu, and IRS-2 may have a protective effect on neointima formation. We conclude that IRS-2 is protective and retards the development of neointima formation in insulin-resistant states.