Clinical trial NCT03316690: The Interaction Between Metformin and Physical Training
Official title: The Interaction Between Metformin and Physical Training
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Impaired Glucose Tolerance
Diabetes Mellitus, Type 2
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: University of Copenhagen
First posted: 2017-10-20
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


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

Primary outcomes:
measure: Change in postprandial glycemic control as assessed by mean blood glucose concentration during a 4 hour mixed-meal tolerance test
timeFrame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
Secondary outcomes:
measure: Change in free-living glycemic control
timeFrame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in endogenous glucose production as assessed by rate of infused glucose tracer appearance in blood
timeFrame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in exogenous glucose uptake as assessed by rate of ingested glucose tracer appearance in blood
timeFrame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in peripheral glucose uptake as assessed by rate of glucose disappearance from blood
timeFrame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in maximal oxygen consumption
timeFrame: Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in body weight
timeFrame: Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in lean body mass
timeFrame: Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in total fat mass
timeFrame: Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in visceral fat mass
timeFrame: Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in AMPK activity in skeletal muscle
timeFrame: Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in skeletal muscle oxidative stress
timeFrame: Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Change in systemic oxidative stress
timeFrame: Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Maximal mitochondrial respiration
timeFrame: Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training)
measure: Training heart rate
timeFrame: Average heart rate during all training sessions (through study completion, [Day 101])
measure: Training rate of perceived exertion
timeFrame: Average rate of perceived exertion of all training sessions (through study completion, [Day 101])
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Center for aktiv sundhed
state: Copenhagen N
Study officials:
affiliation: Rigshospitalet, Denmark
name: Kristian Karstoft, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.