title: The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats.
abstract: BACKGROUND
  Insulin resistance is strongly associated with the development of type 2 diabetes and cardiovascular disease. However, the underlying mechanisms linking insulin resistance and the development of atherosclerosis have not been fully elucidated. Moreover, the protective effect of antihyperglycemic agent, metformin, is not fully understood. This study investigated the protective effects and underlying mechanisms of metformin in balloon-injury induced stenosis in insulin resistant rats.
  
  
  METHODS
  After 4 weeks high fructose diet, rats received balloon catheter injury on carotid arteries and were sacrificed at 1 and 4 weeks post injury. Biochemical, histological, and molecular changes were investigated.
  
  
  RESULTS
  Plasma levels of glucose, insulin, total cholesterol, triglyceride, free fatty acids, and methylglyoxal were highly increased in fructose-induced insulin resistant rats and treatment with metformin significantly improved this metabolic profile. The neointimal formation of the carotid arteries was enhanced, and treatment with metformin markedly attenuated neointimal hyperplasia. A significant reduction in BrdU-positive cells in the neointima was observed in the metformin-treated group (P<0.01). Insulin signaling pathways were inhibited in insulin resistant rats while treatment with metformin enhanced the expression of insulin signaling pathways. Increased expression of JNK and NFKB was suppressed following metformin treatment. Vasoreactivity was impaired while treatment with metformin attenuated phenylephrine-induced vasoconstriction and enhanced methacholine-induced vasorelaxation of the balloon injured carotid arteries in insulin resistant rats.
  
  
  CONCLUSIONS
  The balloon-injury induced neointimal formation of the carotid arteries is enhanced by insulin resistance. Treatment with metformin significantly attenuates neointimal hyperplasia through inhibition of smooth muscle cell proliferation, migration, and inflammation as well as by improvement of the insulin signaling pathway.
authors.affiliation: Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine, Wenzhou Medical College, Wenzhou, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.forename: Jingzhang
authors.initials: J
authors.lastname: Ji
authors.forename: Howard
authors.initials: H
authors.lastname: Meng
authors.forename: David
authors.initials: D
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Lixin
authors.initials: L
authors.lastname: Liu
authors.forename: Edward
authors.initials: E
authors.lastname: Randell
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
authors.forename: Qing H
authors.initials: QH
authors.lastname: Meng
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D020212:Carotid Artery Injuries; D016893:Carotid Stenosis; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005632:Fructose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D058426:Neointima / Q000473:pathology*; D020011:Protective Agents / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood; D062666:Vascular Access Devices; D014945:Wound Healing / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D020011:Protective Agents; D014280:Triglycerides; D005632:Fructose; D011765:Pyruvaldehyde; D008687:Metformin; D002784:Cholesterol
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