Abstract 17997: Metformin Prevents the Development of Cardiomyopathy and Cardiac Dysfunction in ‰Diabetogenic” Diet-fed BTBRob/+ Mice
Background: We recently have shown that, when fed a high-fat, high sucrose “diabetogenic” diet (DD) for 16 weeks, BTBR mice heterozygous for leptin deficiency (BTBRob/+) develop insulin resistance and a cardiomyopathy characterized by cardiac hypertrophy and both systolic and diastolic dysfunction. We investigated whether treatment with metformin for 6 weeks might prevent the development of cardiac hypertrophy and dysfunction in -fed BTBRob/ob mice.
Methods: At four weeks of age, female BTBRob/+ mice were placed on a “diabetogenic” diet consisting of 58% of calories from fat and 26% of calories from sucrose (“DD”, n=19). At 10 weeks on diet, mice were split into two groups, DD only (n=9) or DD plus Metformin (100 mg/kg/day) in drinking water (DD+Met, n=10) until sacrifice at 16 weeks on diet. Oral glucose tolerance tests (OGTTs) and fasting serum glucose levels were obtained every 4 weeks.
Results: At 16 weeks on diets, DD and DD+Met groups did not differ in the degree of glucose intolerance (P=0.39), fasting glucose (P=0.06), or body weight (P=0.21). Development of cardiac hypertrophy was substantially blunted by metformin, as demonstrated by a 10.4% ↓ in heart weight (P=0.019) at necropsy, and a 32% ↓ in LV mass index (P<0.0001) by echocardiography. Echocardiography also demonstrated that metformin treatment improved both systolic function (28% ↑ in fractional shortening, P<0.0001), and diastolic function (75% ↑ in Ea/Aa ratio, P<0.0001). Interestingly, cardiac fibrosis, as assessed by trichrome staining, was not significantly different in DD and DD+Met groups.
Conclusions: In BTBRob/+ mice with “diabetogenic” diet-induced impairments in glucose tolerance and fasting glucose, treatment with metformin for 6 weeks dramatically blunted the development of cardiac hypertrophy and improved both systolic and diastolic function, despite no significant effect of metformin on either glucose intolerance or elevated fasting glucose. Interestingly, the improvements in cardiac hypertrophy and function occurred in the absence of a beneficial effect of metformin on cardiac fibrosis, suggesting that the cardiac functional benefit of metformin was mediated at the level of cardiomyocytes.
- © 2012 by American Heart Association, Inc.