Metformin severely impairs in vivo muscle oxidative capacity in a rat model of type 2 diabetes

Objective: To investigate the effects of metformin on in vivo and in vitro skeletal muscle mitochondrial function in Zucker diabetic fatty (ZDF) rats using 31P magnetic resonance spectroscopy (MRS) and high-resolution respirometry (HRR), respectively. Methods: 12-week old healthy (fa/+) and diabetic (fa/fa) ZDF rats were treated with metformin (0, 30, 100 or 300 mg/kg body weight/day) for 15 days by oral gavage. At day 14, in vivo31P MRS was performed on the tibialis anterior (TA) muscle to measure PCr recovery. At day 15, animals were killed and TA muscles were excised for in vitro HRR measurements. Results: Metformin treatment decreased PCr recovery rates in a dose-dependent manner in both healthy fa/+ and diabetic fa/fa rats. Whereas, the clinical dose of 30 mg/kg/day had no significant effect, PCr recovery rates were ~22% and ~47% decreased at 100 and 300 mg/kg/day. HRR measurements showed a similar, but less pronounced effect of metformin on in vitro mitochondrial function.