Abstract
The factors underlying cardiovascular risk in patients with diabetes have not been clearly elucidated. Efforts to study this in mice have been hindered because the usual atherogenic diets that contain fat and cholesterol also lead to obesity and insulin resistance. We compared plasma glucose, insulin, and atherosclerotic lesion formation in LDL receptor knockout (Ldlr(-/-)) mice fed diets with varying fat and cholesterol content that induced similar lipoprotein profiles. Ldlr(-/-) mice fed a high-fat diet developed obesity, mild hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Quantitative and qualitative assessments of atherosclerosis were unchanged in diabetic Ldlr(-/-) mice fed a high-fat diet compared with lean nondiabetic control mice after 20 weeks of diet. Although one group of mice fed diets for 40 weeks had larger lesions at the aortic root, this was associated with a more atherogenic lipoprotein profile. The presence of a human aldose reductase transgene had no effect on atherosclerosis in fat-fed Ldlr(-/-) mice with mild diabetes. Our data suggest that when lipoprotein profiles are similar, addition of fat to a cholesterol-rich diet does not increase atherosclerotic lesion formation in Ldlr(-/-) mice.
Highlights
The factors underlying cardiovascular risk in patients with diabetes have not been clearly elucidated
Our current study demonstrates that mild hyperglycemia, obesity, and insulin resistance had little if any effect on atherosclerosis in Ldlr2/2 mice
After 20 weeks, mice fed high-fat diet 1- (HF1) developed a metabolic syndrome-like phenotype characterized by elevated body weight, mild hyperglycemia, and increased plasma insulin (Table 2)
Summary
The factors underlying cardiovascular risk in patients with diabetes have not been clearly elucidated Efforts to study this in mice have been hindered because the usual atherogenic diets that contain fat and cholesterol lead to obesity and insulin resistance. Insulin, and atherosclerotic lesion formation in LDL receptor knockout (Ldlr2/2) mice fed diets with varying fat and cholesterol content that induced similar lipoprotein profiles. The presence of a human aldose reductase transgene had no effect on atherosclerosis in fat-fed Ldlr2/2 mice with mild diabetes. Addition of dietary fat to cholesterol in the diets of LDL receptor knockout mice: effects on plasma insulin, lipoproteins, and atherosclerosis. Our current study demonstrates that mild hyperglycemia, obesity, and insulin resistance had little if any effect on atherosclerosis in Ldlr2/2 mice. In the setting of the mild dietary hyperglycemia in the present study, this transgene had no effect on atherosclerosis
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