title: Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions.
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 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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Renard
authors.forename: Farah
authors.initials: F
authors.lastname: Kramer
authors.forename: Fredrik
authors.initials: F
authors.lastname: Johansson
authors.forename: Najib
authors.initials: N
authors.lastname: Lamharzi
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Tannock
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
authors.forename: Karin E
authors.initials: KE
authors.lastname: Bornfeldt
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: D002791:Cholesterol, Dietary; D006442:Glycated Hemoglobin; D011973:Receptors, LDL