Metformin attenuates metabolic insulin sensitivity and insulin‐stimulated carbohydrate oxidation after high‐intensity exercise training in adults at risk for metabolic syndrome

Abstract Aims Mixed evidence exists on whether metformin adds to or attenuates the insulin‐sensitising effects of exercise. To date, no studies have tested whether metformin differentially impacts exercise training intensity–mediated insulin sensitivity. We tested the hypothesis that metformin would blunt metabolic insulin sensitivity and carbohydrate oxidation in an intensity‐based manner among adults with metabolic syndrome (MetS) risk. Materials and methods In a double‐blind, placebo‐controlled trial, participants were randomised to low‐intensity exercise plus placebo (~55% VO 2 max 5 days/week, LoEx + PL, n = 22) or metformin (2000 mg/day, LoEx + Met, n = 21) and high‐intensity exercise plus placebo (~85% VO 2 max 5 days/week, HiEx + PL, n = 24) or metformin (HiEx + Met, n = 24) for 16 weeks. A 120‐min euglycaemic–hyperinsulinemic clamp (40 mU/m 2 /min, 90 mg/dL) was conducted pre‐ and post‐treatment to assess metabolic insulin sensitivity (M‐value/insulin). Fasting and insulin‐stimulated carbohydrate oxidation was also assessed using indirect calorimetry. Adipokines (leptin, high molecular weight (HWM), and total adiponectin) were measured at 0 and 120 min of the clamp. Aerobic fitness (VO 2 max) and body composition (DXA) were also analysed. Results HiEx + PL increased metabolic insulin sensitivity ( p = 0.017) while HiEx + Met, LoEx + PL, or LoEx + Met did not. HiEx + PL also raised insulin‐stimulated carbohydrate oxidation and decreased fat oxidation compared with LoEx + Met (both, p = 0.008). Increased metabolic insulin sensitivity related to reductions in fasting glucose ( r = −0.41, p = 0.025), VO 2 max ( r = 0.55, p = 0.002), fasting leptin ( r = −0.54, p = 0.01), and weight loss ( r = −0.60, p < 0.001) after exercise and placebo, but not exercise and metformin. Conclusions Metformin attenuated metabolic insulin sensitivity and insulin‐stimulated carbohydrate oxidation after high‐intensity exercise training in adults at risk for MetS.