Hyperglycemic Ins2 Akita Ldlr -/- mice show severely elevated lipid levels and
increased atherosclerosis: a model of type 1 diabetic macrovascular disease.
Authors Zhou C, Pridgen B, King N, Xu J, Breslow JL
Submitted By Richard McIndoe on 2/22/2012
Status Published
Journal Journal of lipid research
Year 2011
Date Published 8/1/2011
Volume : Pages 52 : 1483 - 1493
PubMed Reference 21606463
Abstract Accelerated atherosclerosis is the leading cause of death in type 1 diabetes,
but the mechanism of type 1 diabetes-accelerated atherosclerosis is not well
understood, in part due to the lack of a good animal model for the long-term
studies required. In an attempt to create a model for studying diabetic
macrovascular disease, we have generated type 1 diabetic Akita mice lacking the
low density lipoprotein receptor (Ins2(Akita)Ldlr?/?). Ins2(Akita)Ldlr?/? mice
were severely hyperglycemic with impaired glucose tolerance. Compared with
Ldlr?/? mice, 20-week-old Ins2(Akita)Ldlr?/? mice fed a 0.02% cholesterol AIN76a
diet showed increased plasma triglyceride and cholesterol levels, and increased
aortic root cross-sectional atherosclerotic lesion area [224% (P < 0.001) in
males and 30% (P < 0.05) in females]. Microarray and quantitative PCR analyses
of livers from Ins2(Akita)Ldlr?/? mice revealed altered expression of lipid
homeostatic genes, including sterol-regulatory element binding protein (Srebp)1,
liver X receptor (Lxr)a, Abca1, Cyp7b1, Cyp27a1, and Lpl, along with increased
expression of pro-inflammatory cytokine genes, including interleukin (Il)1a,
Il1ß, Il2, tumor necrosis factor (Tnf)a, and Mcp1. Immunofluorescence staining
showed that the expression levels of Mcp1, Tnfa, and Il1ß were also increased in
the atherosclerotic lesions and artery walls of Ins2(Akita)Ldlr?/? mice. Thus,
the Ins2(Akita)Ldlr?/? mouse appears to be a promising model for mechanistic
studies of type 1 diabetes-accelerated atherosclerosis.