Lack of insulin receptor substrate-2 causes progressive neointima formation in response to vessel injury

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.