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(Circulation Research. 2007;101:1058.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Increased Atherosclerotic Lesion Calcification in a Novel Mouse Model Combining Insulin Resistance, Hyperglycemia, and Hypercholesterolemia

Suvi E. Heinonen, Pia Leppänen, Ivana Kholová, Henri Lumivuori, Sanna-Kaisa Häkkinen, Fatima Bosch, Markku Laakso, Seppo Ylä-Herttuala

From the Department of Biotechnology and Molecular Medicine (S.E.H., P.L., I.K., H.L., S.-K.H., S.Y.-H.), A.I. Virtanen Institute, University of Kuopio, Finland; the Center of Animal Biotechnology and Gene Therapy (F.B.), Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain; the Department of Biochemistry and Molecular Biology (F.B.), School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain; and the Departments of Medicine (M.L., S.Y.-H.) and the Gene Therapy Unit (S.Y.-H.), Kuopio University Hospital, Kuopio, Finland.

Correspondence to Seppo Ylä-Herttuala, MD, PhD, FESC, Professor of Molecular Medicine, A.I. Virtanen Institute, University of Kuopio, PO Box 1627, FI-70211, Kuopio, Finland. E-mail Seppo.Ylaherttuala{at}uku.fi

No mouse model is currently available where the induction of type 2 diabetes on an atherosclerotic background could be achieved without significant concomitant changes in plasma lipid levels. We crossbred 2 genetically modified mouse strains to achieve a model expressing both atherosclerosis and characteristics of type 2 diabetes. For atherosclerotic background we used low-density lipoprotein receptor–deficient mice synthetizing only apolipoprotein B100 (LDLR^–/– ApoB^100/100). Diabetic background was obtained from transgenic mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells. Thorough phenotypic characterization was performed in 6- and 15-month-old mice on both normal and high-fat Western diet. Results indicated that IGF-II transgenic LDLR^–/–ApoB^100/100 mice demonstrated insulin resistance, hyperglycemia, and mild hyperinsulinemia compared with hypercholesterolemic LDLR^–/–ApoB^100/100 controls. In addition, old IGF-II/LDLR^–/–ApoB^100/100 mice displayed significantly increased lesion calcification, which was more related to insulin resistance than glucose levels, and significantly higher baseline expression in aorta of several genes related to calcification and inflammation. Lipid levels of IGF-II/LDLR^–/–ApoB^100/100 mice did not differ from LDLR^–/–ApoB^100/100 controls at any time. In conclusion, type 2 diabetic factors induce increased calcification and lesion progression without any lipid changes in a new mouse model of diabetic macroangiopathy.

Key Words: type 2 diabetes • atherosclerosis • insulin resistance • mouse model • hypercholesterolemia

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