The Interaction Between Metformin and Acute Exercise

Physical activity is a first line treatment for patients with type 2 diabetes (T2D), however, the vast majority of patients with T2D do not achieve satisfying glycemic control with physical activity alone, which is why pharmacological treatment with metformin is most often initiated. It is known that metformin and exercise both activates 5' adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle and liver, and the activation of AMPK results in many different metabolic effects, including improvements in glycemic control. Because of this similarity in mechanism of action, an interaction between metformin and exercise is plausible, but knowledge in the area is sparse. Thus, the aim of this study is to assess the effects of acute physical activity with and without concomitant metformin treatment, in order to investigate whether an interaction between the two occur. Subjects with impaired glucose tolerance will be randomized (1:1) to metformin/placebo treatment in a double-blinded way. Following a treatment run-in period of 17 days, two experimental days (one with acute exercise and one without acute exercise), separated by one week, will be performed in each subject. This registration concerns a sub-study of another study which has previously been registrered at ClinicalTrials.gov (Unique Protocol ID: H-17012307). The specific outcomes in this registration have not previously been registered.

Daily treatment with metformin tablets for 24 days according to the following scheme: Day 1-4: Metformin tablet 500 mg x 2 Day 5-8: Metformin tablet 1000 + 500 mg Day 9-24: Metformin tablet 1000 mg x 2

Daily treatment with placebo tablets for 24 days according to the following scheme: Day 1-4: Placebo tablet 500 mg x 2 Day 5-8: Placebo tablet 1000 + 500 mg Day 9-24: Placebo tablet 1000 mg x 2

Difference in postprandial glycemic control as assessed by mean blood glucose concentration during a 4 hour mixed-meal tolerance test

Difference in endogenous glucose production as assessed by rate of infused glucose tracer appearance in blood

Difference in exogenous glucose uptake as assessed by rate of ingested glucose tracer appearance in blood

Inclusion Criteria: Glucose-lowering-medication naïve T2D and/or subjects with impaired glucose tolerance defined as: 2-h plasma glucose (PG) in the 75-g OGTT (7.8-11.0 mmol/L) and/or HbA1c (39-47 mmol/mol) Caucasian BMI > 25 but < 40 kg/m2 Low to moderate physically active (≤90 min of structured physical activity/week) Exclusion Criteria: Pregnancy Smoking Glucose-lowering treatment Treatment with steroids and other immunomodulating drugs Contraindication to increased levels of physical activity Liver disease (ALAT elevated more than 3 times above upper normal limit, or reduced levels of the liver function markers albumin and KF II+VII+X) Renal insufficiency (eGFR<60 ml/min) Prior history of lactic acidosis HbA1c >55 mmol/mol and/or 2-hPG in the 75-g OGTT > 15 mmol/L