Ldlr-Deficient Mice with an Atherosclerosis-Resistant Background Develop Severe Hyperglycemia and Type 2 Diabetes on a Western-Type Diet

Apoe(-/-) and Ldlr(-/-) mice are two animal models extensively used for atherosclerosis research. We previously reported that Apoe(-/-) mice on certain genetic backgrounds, including C3H/HeJ (C3H), develop type 2 diabetes when fed a Western diet. We sought to characterize diabetes-related traits in C3H-Ldlr(-/-) mice through comparing with C3H-Apoe(-/-) mice. On a chow diet, Ldlr(-/-) mice had lower plasma total and non-HDL cholesterol levels but higher HDL levels than Apoe(-/-) mice. Fasting plasma glucose was much lower in Ldlr(-/-) than Apoe(-/-) mice (male: 122.5 ± 5.9 vs. 229.4 ± 17.5 mg/dL; female: 144.1 ± 12.4 vs. 232.7 ± 6.4 mg/dL). When fed a Western diet, Ldlr(-/-) and Apoe(-/-) mice developed severe hypercholesterolemia and also hyperglycemia with fasting plasma glucose levels exceeding 250 mg/dL. Both knockouts had similar non-HDL cholesterol and triglyceride levels, and their fasting glucose levels were also similar. Male Ldlr(-/-) mice exhibited greater glucose tolerance and insulin sensitivity compared to their Apoe(-/-) counterpart. Female mice showed similar glucose tolerance and insulin sensitivity though Ldlr(-/-) mice had higher non-fasting glucose levels. Male Ldlr(-/-) and Apoe(-/-) mice developed moderate obesity on the Western diet, but female mice did not. These results indicate that the Western diet and ensuing hyperlipidemia lead to the development of type 2 diabetes, irrespective of underlying genetic causes.