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Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions
Catherine B. Renard, … , Alan Chait, Karin E. Bornfeldt
Catherine B. Renard, … , Alan Chait, Karin E. Bornfeldt
Published September 1, 2004
Citation Information: J Clin Invest. 2004;114(5):659-668. https://doi.org/10.1172/JCI17867.
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Categories: Article Metabolism

Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions

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Abstract

Diabetes in humans accelerates cardiovascular disease caused by atherosclerosis. The relative contributions of hyperglycemia and dyslipidemia to atherosclerosis in patients with diabetes are not clear, largely because there is a lack of suitable animal models. We therefore have developed a transgenic mouse model that closely mimics atherosclerosis in humans with type 1 diabetes by breeding low-density lipoprotein receptor–deficient mice with transgenic mice in which type 1 diabetes can be induced at will. These mice express a viral protein under control of the insulin promoter and, when infected by the virus, develop an autoimmune attack on the insulin-producing β cells and subsequently develop type 1 diabetes. When these mice are fed a cholesterol-free diet, diabetes, in the absence of associated lipid abnormalities, causes both accelerated lesion initiation and increased arterial macrophage accumulation. When diabetic mice are fed cholesterol-rich diets, on the other hand, they develop severe hypertriglyceridemia and advanced lesions, characterized by extensive intralesional hemorrhage. This progression to advanced lesions is largely dependent on diabetes-induced dyslipidemia, because hyperlipidemic diabetic and nondiabetic mice with similar plasma cholesterol levels show a similar extent of atherosclerosis. Thus, diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions.

Authors

Catherine B. Renard, Farah Kramer, Fredrik Johansson, Najib Lamharzi, Lisa R. Tannock, Matthias G. von Herrath, Alan Chait, Karin E. Bornfeldt

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Figure 1

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Diabetic mice demonstrated hyperglycemia throughout the study, and their...
Diabetic mice demonstrated hyperglycemia throughout the study, and their metabolic control was improved by intense insulin therapy. Female LDLR–/–;GP littermate mice were injected with saline (nondiabetic) or LCMV (diabetic) 1 week prior to changing the diet at week 0. The diets contained 0%, 0.12%, or 0.5% cholesterol (see key). One group of diabetic mice was treated with an intense insulin therapy (intense insulin) and fed the cholesterol-free diet. Blood glucose was measured at the indicated times. The number of animals per group is indicated within parentheses. NS, nonsignificant versus nondiabetic mice fed the cholesterol-free diet. *P < 0.05, **P < 0.01, ***P < 0.001.
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