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

• Published in: The Journal of clinical investigation 2004-09, Vol.114 (5), p.659-668
• Main Authors: Renard, Catherine B, Kramer, Farah, Johansson, Fredrik, Lamharzi, Najib, Tannock, Lisa R, von Herrath, Matthias G, Chait, Alan, Bornfeldt, Karin E
• Format: Article
• Language: English
• Subjects: Animals; Arteriosclerosis - etiology; Arteriosclerosis - metabolism; Atherosclerosis; Biomedical research; Cholesterol; Cholesterol, Dietary - administration & dosage; Diabetes; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diet; Glucose; Glycated Hemoglobin A - metabolism; Glycoproteins; Hemoglobin; Hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - metabolism; Insulin; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Lipid Metabolism; Lipids; Low density lipoprotein receptors; Metabolic disorders; Mice; Mice, Transgenic; Receptors, LDL - deficiency; Receptors, LDL - genetics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci200417867

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 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.