Diabetes Mellitus, Type 2, Impaired Glucose Tolerance
Conditions
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.
Interventions
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
DRUGPlacebo 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
BEHAVIORALPhysical training
Twelve weeks of supervised physical training (4 times per week, 45 min per session, mean intensity at 70% of maximal oxygen consumption rate)
Sponsors
University of Copenhagen
Kristian Karstoft
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | Maximal oxygen uptake during an incremental bicycle test |
| Change in body weight | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | Body weight measured by standard procedures |
| Change in lean body mass | 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) |
| Change in total fat mass | 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) |
| Change in free-living glycemic control | Day 0 (before randomisation), 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | Blood HbA1c levels |
| Change in AMPK activity in skeletal muscle | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | AMPK activity measured via western blotting and activity assays |
| Change in skeletal muscle oxidative stress | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | Muscle mitochondrial oxidative stress measured via respirometry in muscle biopsies |
| Change in systemic oxidative stress | 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 |
| Maximal mitochondrial respiration | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | Maximal mitochondrial respiration measured via respirometry in muscle biopsies |
| Training heart rate | Average heart rate during all training sessions (through study completion, [Day 101]) | Heart rate will be measured continuously during all training sessions |
| Training rate of perceived exertion | 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 |
| Change in visceral fat mass | Day 17 (after initiation of metformin/placebo treatment), 101 (after 12 weeks of training) | Visceral fat mass evaluated via magnetic resonance imaging (MRI) scans |
Countries
Denmark
Outcome results
None listed