The Effects of Metformin on Self-selected Exercise Intensity, Physical Fitness and Exercise-induced AMPK-activation

The purpose of this study is to evaluate the potential interaction between metformin and exercise in order to optimize clinical guidelines for treatment of T2D.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Metformin; Other: Placebo

Detailed Description

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 AMPK, which results in many different metabolic effects. Because of this similarity, an interaction between metformin and exercise is plausible, but knowledge in the area is sparse. With this study the investigators aim to look at the individual and combined effects of metformin and exercise in order to investigate whether an interaction occur. An Interaction will have tremendous clinical importance for patients with T2D given current guidelines where the vast majority of these patients are recommended both exercise and metformin treatment.

The investigators hypothesize that metformin treatment reduces self-selected exercise intensity, which may be explained via decreased mitochondrial complex 1 function, increased blood lactate levels, heart rate and RPE during exercise. Furthermore exercise-induced AMPK-activation is reduced with metformin treatment.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen N
    • Copenhagen, Copenhagen N, Denmark, 2200
      • Center for aktiv sundhed

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• male
• HbA1c < 39 mmol/l
• BMI < 25
• structured physical activity < = 150 min/week
• apparently healthy

Exclusion Criteria:

• smoking
• daily pharmaceutical treatment
• contraindication to increased levels of physical activity
• ALAT/ASAT elevated 3 times above upper normal values
• renal insufficiency (eGFR < 60 ml/min)
• prior history of lactic acidosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; 17 days metformin treatment	Drug: Metformin; 17 days treatment with metformin
Placebo Comparator: Placebo; 17 days placebo treatment	Other: Placebo; 17 days treatment with placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall aerobic work performed during an exercise bout with self-selected intensity	Total oxygen consumption (L O2) during a 45 min ergometer cycling bout with self-selected intensity

Secondary Outcome Measures

Outcome Measure	Time Frame
External work performed during an exercise bout with self-selected intensity	Total work produced (kJ) during a 45 min ergometer cycling bout with self-selected intensity
Rate of perceived exertion during an exercise bout with fixed intensity	Mean rate of perceived exertion (Borg scale) during a 45 min ergometer cycling bout with fixed intensity
blood lactate during an exercise bout with fixed intensity	Mean blood lactate (mmol/l) during a 45 min ergometer cycling bout with fixed intensity
Heartrate during an exercise bout with fixed intensity	Mean heart rate (bpm) during a 45 min ergometer cycling bout with fixed intensity
Respiratory exchange ratio during an exercise bout with fixed intensity	Mean VCO2/VO2 during a 45 min ergometer cycling bout with fixed intensity
Physical fitness (VO2max)	maximal oxygen consumption (L/min) during a VO2 max test

Other Outcome Measures

Outcome Measure	Time Frame
AMPK-activation in skeletal muscle during an exercise bout with fixed intensity	change in exercise induced AMPK-activation after compared to before a 45 min ergometer cycling bout with self-selected intensity
Oxidative phosphorylation in skeletal muscle fibers	Mitochondrial Complex I respiration in skeletal muscle tissue after 17 days of metformin/placebo treatment

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: University of Copenhagen
• Investigators: Principal Investigator: Kristian Karstoft, MD, PhD, Center for aktiv sundhed, Rigshospitalet

Publications and helpful links

General Publications

• Pilmark NS, Oberholzer L, Halling JF, Kristensen JM, Bonding CP, Elkjaer I, Lyngbaek M, Elster G, Siebenmann C, Holm NFR, Birk JB, Larsen EL, Lundby AM, Wojtaszewski J, Pilegaard H, Poulsen HE, Pedersen BK, Hansen KB, Karstoft K. Skeletal muscle adaptations to exercise are not influenced by metformin treatment in humans: secondary analyses of 2 randomized, clinical trials. Appl Physiol Nutr Metab. 2022 Mar;47(3):309-320. doi: 10.1139/apnm-2021-0194. Epub 2021 Nov 16.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2016
• Primary Completion (Actual): April 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: October 27, 2016
• First Submitted That Met QC Criteria: October 31, 2016
• First Posted (Estimate): November 1, 2016

Study Record Updates

• Last Update Posted (Actual): September 27, 2017
• Last Update Submitted That Met QC Criteria: September 26, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: H- 16032037

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED