The Interaction Between Metformin and Physical Training

Kristian Karstoft34 enrolled

Overview

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 training with and without concomitant metformin treatment, in order to investigate whether an interaction between the two occur. Subjects with impaired glucose tolerance will all undergo 12 weeks of training but will be randomized (1:1) to concomitant metformin/placebo treatment in a double-blinded way. Experimental days will be performed before randomisation (before initiation of metformin/placebo treatment), before initiation of the training period and after the training period.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Enrollment

Conditions

Impaired Glucose Tolerance Diabetes Mellitus, Type 2

Interventions

Metformin treatmentDRUG

Daily treatment with metformin tablets for 101 days according to the following scheme: Day 1-4: Metformin tablet 500 mg x 2 Day 5-8: Metformin tablet 1000 + 500 mg Day 9-101: Metformin tablet 1000 mg x 2

Placebo treatmentDRUG

Daily treatment with placebo tablets for 101 days according to the following scheme: Day 1-4: Placebo tablet 500 mg x 2 Day 5-8: Placebo tablet 1000 + 500 mg Day 9-101: Placebo tablet 1000 mg x 2

Physical trainingBEHAVIORAL

Twelve weeks of supervised physical training (4 times per week, 45 min per session, mean intensity at 70% of maximal oxygen consumption rate)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 YearsHealthy volunteers:

Medical Language ↔ Plain English

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 reduce 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

Locations (1)

Center for aktiv sundhed

Copenhagen, Copenhagen N, Denmark

Outcomes

Primary Outcomes

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

Time frame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)

Secondary Outcomes

Change in free-living glycemic control

Blood HbA1c levels

Time frame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)

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

Time frame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)

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

Time frame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)

Change in peripheral glucose uptake as assessed by rate of glucose disappearance from blood

Time frame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)

Change in maximal oxygen consumption

Maximal oxygen uptake during an incremental bicycle test