The Interaction Between Metformin and Physical Training

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
The Interaction Between Metformin and Physical Training

Conditions
-----------------
Impaired Glucose Tolerance, Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: Metformin treatment
* Drug: Placebo treatment
* Behavioral: Physical training


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin treatment<br> | Drug: Metformin treatment<br>* 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<br>Behavioral: Physical training<br>* Twelve weeks of supervised physical training (4 times per week, 45 min per session, mean intensity at 70% of maximal oxygen consumption rate)<br>|
| Placebo Comparator: Placebo treatment<br> | Drug: Placebo treatment<br>* 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<br>Behavioral: Physical training<br>* Twelve weeks of supervised physical training (4 times per week, 45 min per session, mean intensity at 70% of maximal oxygen consumption rate)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in postprandial glycemic control as assessed by mean blood glucose concentration during a 4 hour mixed-meal tolerance test |  | Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in free-living glycemic control | Blood HbA1c levels | 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 |  | 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 |  | 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 |  | 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 | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Change in body weight | Body weight measured by standard procedures | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Change in lean body mass | Lean body mass evaluated via Dual energy x-ray absorptiometry (Dxa) | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Change in total fat mass | Total body fat mass evaluated via Dual energy x-ray absorptiometry (Dxa) | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Change in visceral fat mass | Visceral fat mass evaluated via magnetic resonance imaging (MRI) scans | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Change in AMPK activity in skeletal muscle | AMPK activity measured via western blotting and activity assays | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Change in skeletal muscle oxidative stress | Muscle mitochondrial oxidative stress measured via respirometry in muscle biopsies | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Change in systemic oxidative stress | Systemic oxidative stress measured via RNA/DNA oxidation products in urine | Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Maximal mitochondrial respiration | Maximal mitochondrial respiration measured via respirometry in muscle biopsies | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | 
| Training heart rate | Heart rate will be measured continuously during all training sessions | Average heart rate during all training sessions (through study completion, [Day 101]) | 
| Training rate of perceived exertion | Rate of perceived exertion measured via a Borg scale (range 6-20 where higher values indicate higher rate of perceived exertion) will be assessed for each training session | Average rate of perceived exertion of all training sessions (through study completion, [Day 101]) |