Abstract 18296: A Murine Model of Diet-Induced Insulin Resistance and Cardiomyopathy

Abstract

Background: Diabetes is associated with a 2- to 3-fold ↑ in risk for congestive heart failure (CHF), due primarily to cardiac hypertrophy and fibrosis. We recently have shown that leptin-deficient, female BTBR mice (BTBR ob/ob ) develop cardiomyopathy, with a 24-25% ↑ in heart weight and a 5-fold ↑ in fibrosis. We investigated whether the cardiomyopathy phenotype might be replicated with diet-induced obesity in wild-type, BTBR mice. Methods: At 4 weeks of age, male and female BTBR mice (n=7-8/group) were placed on one of three diets: 1) standard rodent chow (“Chow”), 2) a “diabetogenic” diet, with 58% of calories from fat and 14% of calories from sucrose (“DD”), or 3) the “diabetogenic” diet with 0.15% cholesterol added (“DDC”). Oral glucose tolerance tests were performed at 8 and 16 weeks on diets. Mice were sacrificed after 16 weeks on diets for determination of heart weights and fibrosis. Results: By 8 weeks on DD or DDC, both female and male BTBR mice had normal fasting glucose, but glucose tolerance (as judged by area under the glucose excursion curve) was significantly impaired vs. Chow-fed controls. Prior to sacrifice at 16 weeks, as compared to Chow, mice on DD or DDC had similar blood pressures and fasting glucose levels. However, necropsy heart weights were 17-18% higher (P<0.01 vs. Chow for both DD and DDC for both genders). In addition, Masson's trichrome stain demonstrated significant increases in fibrosis vs. Chow for BTBR mice fed either DD (P=0.015) or DDC (P=0.029). Conclusions: Thus, in both genders, 16 weeks feeding of high-fat, high-sucrose diets to wild-type BTBR mice results in a 2-fold ↑ in fibrosis, and achieves >60% of the cardiac hypertrophy seen in BTBR ob/ob females by age 16 weeks. These findings suggest that diabetogenic diet feeding in BTBR mice may represent an efficient model for studying the pathogenic mechanisms underlying cardiomyopathy in insulin resistance and diabetes.