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Open Access Original investigation

The protective effect and underlying mechanism of metformin on neointima formation in fructose-induced insulin resistant rats

Jianxin Lu12, Jingzhang Ji12, Howard Meng3, David Wang3, Bo Jiang4, Lixin Liu4, Edward Randell5, Khosrow Adeli3 and Qing H Meng12*

Author Affiliations

1 Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine, Wenzhou Medical College, Wenzhou, China

2 Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada

3 Department of Laboratory Medicine and Pathobiology (D.W., H. M., K. A.), University of Toronto, Toronto, Canada

4 Department of Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada

5 Laboratory Medicine, Faculty of Medicine, Memorial University, St. John’s, NL, Canada

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Cardiovascular Diabetology 2013, 12:58  doi:10.1186/1475-2840-12-58

Published: 5 April 2013

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.

Conclusion

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.

Keywords:
Neointimal hyperplasia; Insulin resistance; Methylglyoxal; Metformin; Rat