Examining treatment modality interactions

OBJECTIVE—To determine the effect of metformin on the acute metabolic response to sub-maximalexercise,theeffectofexerciseonplasmametforminconcentrations,andtheinteractionbetween metformin and exercise on the subsequent response to a standardized meal.RESEARCH DESIGN AND METHODS—Ten participants with type 2 diabetes wererecruited for this randomized crossover study. Metformin or placebo was given for 28 days,followedbythealternateconditionfor28days.Onthelast2daysofeachcondition,participantswere assessed during a nonexercise and a subsequent exercise day. Exercise took place in themorning and involved a total of 35 min performed at three different submaximal intensities.RESULTS—Metforminincreasedheartrateandplasmalactateduringexercise(bothP#0.01)but lowered respiratory exchange ratio (P = 0.03) without affecting total energy expenditure,whichsuggestsincreasedfatoxidation.Metforminplasmaconcentrationsweregreateratseveral,but not all, time points on the exercise day compared with the nonexercise day. The glycemicresponse to a standardized meal was reduced by metformin, but the reduction was attenuatedwhen exercise was added (metformin 3 exercise interaction, P = 0.05). Glucagon levels werehighest in the combined exercise and metformin condition.CONCLUSIONS—This study reveals several ways by which metformin and exercise thera-pies can affect each other. By increasing heart rate, metformin could lead to the prescription oflowerexerciseworkloads.Furthermore,underthetestedconditions,exerciseinterferedwiththeglucose-lowering effect of metformin.Diabetes Care 34:1469–1474, 2011