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Completed

NCT Number: NCT03316690

The Interaction Between Metformin and Physical Training

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.

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Key information

Conditions

Impaired Glucose Tolerance Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Intolerance Glucose Metabolism Disorders Hyperglycemia Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Center for aktiv sundhed

Copenhagen, Copenhagen N, 2200, Denmark

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Metformin treatment

Drug

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 treatment

Drug

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 training

Behavioral

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

Primary outcomes

  1. 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

  1. Change in free-living glycemic control

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

    Blood HbA1c levels

  2. 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)

  3. 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)

  4. 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)

  5. Change in maximal oxygen consumption

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

    Maximal oxygen uptake during an incremental bicycle test

  6. Change in body weight

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

    Body weight measured by standard procedures

  7. Change in lean body mass

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

    Lean body mass evaluated via Dual energy x-ray absorptiometry (Dxa)

  8. Change in total fat mass

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

    Total body fat mass evaluated via Dual energy x-ray absorptiometry (Dxa)

  9. Change in visceral fat mass

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

    Visceral fat mass evaluated via magnetic resonance imaging (MRI) scans

  10. Change in AMPK activity in skeletal muscle

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

    AMPK activity measured via western blotting and activity assays

  11. Change in skeletal muscle oxidative stress

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

    Muscle mitochondrial oxidative stress measured via respirometry in muscle biopsies

  12. Change in systemic oxidative stress

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

    Systemic oxidative stress measured via RNA/DNA oxidation products in urine

  13. Maximal mitochondrial respiration

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

    Maximal mitochondrial respiration measured via respirometry in muscle biopsies

  14. Training heart rate

    Time frame: Average heart rate during all training sessions (through study completion, [Day 101])

    Heart rate will be measured continuously during all training sessions

  15. Training rate of perceived exertion

    Time frame: Average rate of perceived exertion of all training sessions (through study completion, [Day 101])

    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

Sponsors and collaborators

Lead sponsor

Kristian Karstoft

Other

Collaborators

  • University of Copenhagen

Registry information

Important dates

Study start
2017
Primary completion
2018
Study completion
2018
First posted
Oct 20, 2017
Registry last updated
Nov 9, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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