Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 114, Issue 5, Pages 659-668Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200417867
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Funding
- NHLBI NIH HHS [HL62887, R01 HL076719, HL076719, R01 HL062887, 32HL07820, T32 HL007820] Funding Source: Medline
- NIA NIH HHS [AG04342, P01 AG004342] Funding Source: Medline
- NIDDK NIH HHS [R29 DK051091, DK035816, P30 DK017047, DK02456, P30 DK035816, R01 DK051091, P01 DK002456, DK51091, P30 DK17047] Funding Source: Medline
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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 I 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 beta 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.
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