Metformin alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy

The first line therapy for managing type 2 diabetes (T2D), metformin, has been shown to be cardioprotective in humans and several preclinical models of cardiovascular disease. However, there has been limited interrogation into metformin's effects on diastolic function, a hallmark characteristic of diabetic cardiomyopathy (DbCM), which is becoming increasingly prevalent in people with pre- and early-stage T2D. Accordingly, we aimed to determine the effects of metformin on the pathogenesis of DbCM and hypothesized that treatment with metformin would alleviate diastolic dysfunction in mice with T2D. To induce experimental T2D and DbCM, male C57BL/6J mice were fed a high-fat diet for 12.5 weeks, in combination with a single, low-dose injection of streptozotocin (75 mg/kg) at week 4.5. The animals' drinking water was randomized to include either vehicle control or metformin (3.0 g/L) during the final 7.5 weeks. As expected, metformin treatment improved glycemia with a trend towards a reduction in adiposity in mice with T2D. Using ultrasound echocardiography, we observed that metformin improved diastolic function in mice with T2D as reflected by an increase and a decrease in the e'/a' and E/e' ratios, respectively. Furthermore, wheat-germ agglutinin staining indicated that treatment with metformin decreased cardiomyocyte hypertrophy in mice with T2D. However, mice with T2D treated with metformin did not exhibit increases in myocardial adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Thus, our findings suggest that metformin has salutary actions against DbCM and its associated diastolic dysfunction, which may be independent of its ability to increase AMPK activity.