title: Lack of insulin receptor substrate-2 causes progressive neointima formation in response to vessel injury.
abstract: 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.
  
  
  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.
authors.affiliation: Third Department of Internal Medicine, Toho University School of Medicine, Ohashi Hospital 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Masao
authors.initials: M
authors.lastname: Moroi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kamata
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Namiki
authors.forename: Shinichi
authors.initials: S
authors.lastname: Aizawa
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D006946:Hyperinsulinism / Q000097:blood / Q000235:genetics; D006949:Hyperlipidemias / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D017539:Tunica Intima / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D014654:Vascular Patency; D014664:Vasodilation / Q000235:genetics
chemical_list: D005230:Fatty Acids, Nonesterified; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D014280:Triglycerides