Morning exercise and pre-breakfast metformin interact to reduce glycaemia in people with Type 2 Diabetes: a randomized crossover trial

Abstract Exercise is recommended in the treatment of Type 2 Diabetes and can improve insulin sensitivity [1]. However, previous evidence suggests that exercise at different times of the day in people with type 2 diabetes may have opposing outcomes on glycaemia [2]. Metformin is the most commonly prescribed initial pharmacological intervention in Type 2 Diabetes, and may alter adaptions to exercise [3]. It is unknown if there is an interaction between metformin and diurnal exercise outcomes. We aimed to investigate glycaemic outcomes of moderate intensity morning vs. evening exercise in people with type 2 diabetes being prescribed metformin monotherapy. We hypothesised that evening exercise would be more efficacious than morning exercise at lowering glycaemia. In this study, nine male and nine females with type 2 diabetes undergoing metformin monotherapy (age 61±2 year, mean±SEM) completed a 16-week crossover trial including 2- week baseline recording, six weeks randomly assigned to a morning exercise (7-10am) or evening exercise (4-7pm), and a two-week wash-out period. Exercise arms consisted of 30 minutes of walking at 70% of estimated max-HR every other day. Glucose levels were measured with continuous glucose monitors and activity measured by wrist-worn monitors. Food-intake was recorded by 4-day food diaries during baseline, first and last 2 weeks of each exercise arm. There was no difference in exercise intensity, total caloric intake, or total physical activity between morning and evening arms. Acute glucose area under the curve (AUC), was lower ( p =0.02) after acute morning exercise (180.6±16.1 mmol/L) compared to baseline (210.3±18.0 mmol/L). Acute AUC glucose was significantly lower ( p =0.01) in participants taking metformin before breakfast (152.5±10.59 mmol/L) compared with participants taking metformin after breakfast (227.2±27.51 mmol/L) only during the morning exercise arm. During weeks 5-6 of the exercise protocol, AUC glucose was significantly lower (p=0.04) for participants taking metformin before breakfast (168.8±5.6), rather than after breakfast (224.5±21.2) only during morning exercise. Our data reveal morning moderate exercise acutely lowers glucose levels in people with type 2 diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. This beneficial effect upon glucose levels of combined morning exercise and pre-breakfast metformin persisted through the final two weeks of the trial. Our findings suggest that morning moderate intensity exercise combined with pre-breakfast metformin intake may benefit the management of glycaemia in people with type 2 diabetes. Research in Context What is already known about this subject? Exercise at different times of the day in people with Type 2 Diabetes has opposite outcomes on glycaemia. Metformin interferes with the glucose-lowering effect of acute exercise. It is unknown if there is an interaction between metformin intake timing and diurnal exercise outcomes. What is the key question? Is it possible to optimise timing of concomitant metformin and exercise in people with Type 2 Diabetes? What are the new findings? Morning moderate exercise acutely lowers glucose levels in people with Type 2 Diabetes being prescribed metformin. This difference appears to be driven by individuals that consumed metformin prior to breakfast rather than after breakfast. Morning exercise combined with pre-breakfast metformin persistently reduced glucose compared to morning exercise combined with post-breakfast metformin through the final week (week 6) of the intervention. How might this impact on clinical practice in the foreseeable future? Our study suggests it may be possible to make simple changes to the time that people with Type 2 Diabetes take metformin and perform exercise to improve their blood glucose.