Gender-Specific Differences in a New ApoE-/-:Ins2+/Akita Mouse Model of Hyperglycemia-Induced Atherosclerosis

Abstract

People with diabetes mellitus have a 2- to 4-fold increased risk of cardiovascular disease (CVD). Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of CVD are unclear. To further our understanding of how diabetes promotes CVD, we have established and characterized a new model of hyperglycemia-induced atherosclerosis: the apoE-/-:Ins2+/Akita mouse. Ins2Akita is an autosomal dominant mutation (C96Y) that induces juvenile-onset hyperglycemia in the absence of obesity. Ins2+/Akita male mice were crossed to apoE-/- female mice, which spontaneously develop atherosclerosis. ApoE-/-:Ins2+/Akita mice were fed a standard chow diet and then examined from 5 to 25 weeks of age. Metabolic parameters including body weight, fat pad, blood glucose, cholesterol and triglycerides were monitored. The area of atherosclerotic lesions were quantified at the aortic sinus and aorta. Male apoE-/-:Ins2+/Akita developed persistent hyperglycemia. Mature atherosclerotic lesions were observed at 25 weeks of age. These lesions were 3 to 4 times larger than those observed in apoE-/- males. Enhanced hypercholesterolemia was observed from 15 weeks of age. Female apoE-/-:Ins2+/Akita presented transient hyperglycemia, which normalized by 15 weeks of age. Despite the transient hyperglycemia, larger atherosclerotic lesions were observed at 15 weeks of age compared to apoE-/- females. No plasma lipid changes were observed throughout the study. Ovariectomized female mice presented chronic hyperglycemia and accelerated atherosclerosis—similar to male mice. We have developed gender-specific models of chronic and transient hyperglycemia-induced atherosclerosis. Estrogen exerts a significant protective effect on functional insulin secretion in the apoE-/-:Ins2+/Akita mouse.