Aims/hypothesis The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals.

Methods Glucose-intolerant (2 h OGTT glucose of 7.8-11.0 mmol/l and/or HbA(1c) of 39-47 mmol/mol [5.7-6.5%] or glucose-lowering-medication naive type 2 diabetes), overweight/obese (BMI 25-42 kg/m(2)) individuals were randomly allocated to a placebo study group (PLA,n = 15) or a metformin study group (MET,n = 14), and underwent 3 experimental days: BASELINE (before randomisation), MEDICATION (after 3 weeks of metformin [2 g/day] or placebo treatment) and TRAINING (after 12 weeks of exercise training in combination with metformin/placebo treatment). Training consisted of supervised bicycle interval sessions with a mean intensity of 64% of Watt(max)for 45 min, 4 times/week. The primary outcome was postprandial glucose (mean glucose concentration) during a mixed meal tolerance test (MMTT), which was assessed on each experimental day. For within-group differences, a group x time interaction was assessed using two-way repeated measures ANOVA. Between-group changes of the outcomes at different timepoints were compared using unpaired two-tailed Student'sttests.

Results Postprandial glucose improved from BASELINE to TRAINING in both the PLA group and the MET group ( increment PLA: -0.7 [95% CI -1.4, 0.0] mmol/l,p = 0.05 and increment MET: -0.7 [-1.5, -0.0] mmol/l,p = 0.03), with no between-group difference (p = 0.92). In PLA, the entire reduction was seen from MEDICATION to TRAINING (-0.8 [-1.3, -0.1] mmol/l,p = 0.01). Conversely, in MET, the entire reduction was observed from BASELINE to MEDICATION (-0.9 [-1.6, -0.2] mmol/l,p = 0.01). The reductions in mean glucose concentration during the MMTT from BASELINE to TRAINING were dependent on differential time effects: in the PLA group, a decrease was observed at timepoint (t) = 120 min (p = 0.009), whereas in the MET group, a reduction occurred at t = 30 min (p <0.001). (V) over dotO(2peak)increased 15% (4.6 [3.3, 5.9] ml kg(-1) min(-1),p <0.0001) from MEDICATION to TRAINING and body weight decreased (-4.0 [-5.2, -2.7] kg,p <0.0001) from BASELINE to TRAINING, with no between-group differences (p = 0.7 andp = 0.5, respectively).

Conclusions/interpretation Metformin plus exercise training was not superior to exercise training alone in improving postprandial glucose. The differential time effects during the MMTT suggest an interaction between the two modalities.