Metformin improves vascular and metabolic insulin action in insulin resistant muscle

Insulin stimulates glucose disposal in skeletal muscle in part by increasing microvascular blood flow and this effect is blunted during insulin resistance. We aimed to determine whether metformin treatment improves insulin-mediated glucose disposal and vascular insulin responsiveness in skeletal muscle of insulin resistant rats. Sprague Dawley rats were fed a normal (ND) or high-fat (HFD) diet for four weeks. A separate HFD group was given metformin in drinking water (HFD+MF, 150 mg/kg/day) during the final two weeks. After the intervention, overnight-fasted (food and metformin removed) anaesthetised rats underwent a 2-hr euglycemic-hyperinsulinemic clamp (10 mU/min/kg) or saline infusion. Femoral artery blood flow, hindleg muscle microvascular blood flow, muscle glucose disposal and muscle signalling (Ser473-Akt and Thr172-AMPK phosphorylation) were measured. HFD rats had elevated body weight, epididymal fat pad weight, fasting plasma insulin and free fatty acid levels when compared to ND. HFD-fed animals displayed whole body and skeletal muscle insulin resistance and blunting of insulin-stimulated femoral artery blood flow, muscle microvascular blood flow and skeletal muscle insulin-stimulated Ser473-Akt phosphorylation. Metformin treatment of HFD rats reduced fasting insulin and non-esterified fatty acid concentrations and lowered body weight and adiposity. During hyperinsulinemic-euglycemic clamp, metformin-treated animals showed improved vascular responsiveness to insulin, improved insulin-stimulated muscle Ser473-Akt phosphorylation but only partially restored (60%) muscle glucose uptake. This occurred without any detectable levels of metformin in plasma or change in muscle Thr172-AMPK phosphorylation. We conclude that two-week metformin treatment is effective at improving vascular and metabolic insulin responsiveness in muscle of HFD-induced insulin resistant rats.