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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Impaired Glucose Tolerance
• Intervention / Treatment: Drug: Metformin treatment; Behavioral: Physical training; Drug: Placebo treatment

• Study Type: Interventional
• Enrollment (Actual): 34
• 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 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo treatment	Behavioral: Physical training; Twelve weeks of supervised physical training (4 times per week, 45 min per session, mean intensity at 70% of maximal oxygen consumption rate); Drug: Placebo treatment; 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
EXPERIMENTAL: Metformin treatment	Drug: Metformin treatment; 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; Behavioral: Physical training; Twelve weeks of supervised physical training (4 times per week, 45 min per session, mean intensity at 70% of maximal oxygen consumption rate)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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])

Collaborators and Investigators

• Sponsor: Kristian Karstoft
• Collaborators: University of Copenhagen

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.
• Pilmark NS, Lyngbaek M, Oberholzer L, Elkjaer I, Petersen-Bonding C, Kofoed K, Siebenmann C, Kellenberger K, van Hall G, Abildgaard J, Ellingsgaard H, Lauridsen C, Ried-Larsen M, Pedersen BK, Hansen KB, Karstoft K. The interaction between metformin and physical activity on postprandial glucose and glucose kinetics: a randomised, clinical trial. Diabetologia. 2021 Feb;64(2):397-409. doi: 10.1007/s00125-020-05282-6. Epub 2020 Sep 26.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 20, 2017
• Primary Completion (ACTUAL): October 1, 2018
• Study Completion (ACTUAL): October 1, 2018

Study Registration Dates

• First Submitted: October 3, 2017
• First Submitted That Met QC Criteria: October 17, 2017
• First Posted (ACTUAL): October 20, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 9, 2018
• Last Update Submitted That Met QC Criteria: November 7, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Diabetes Mellitus, Type 2; Glucose Intolerance; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: H-17012307

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No