Diabetes Mellitus, Type 2, Insulin Resistance
Conditions
Keywords
Circadian rhythm
Brief summary
This study will investigate the effect of exercise training on 24h rhythms in substrate metabolism in overweight subjects with impaired glucose tolerance. Subjects will perform exercise training for 12 weeks. Before and after the exercise period, they will be admitted to research facilities for 45 hours to assess 24h rhythms in substrate metabolism. In a single-arm longitudinal design, subjects will serve as their own control.
Detailed description
Recent evidence shows that pre-diabetes is characterized by marked alterations in 24h substrate metabolism, indicating metabolic inflexibility with an inability to fully switch to fat oxidation during the night. Whereas exercise has been shown to promote mitochondrial function and insulin sensitivity, it is unknown to if exercise training is able to restore 24h rhythmicity in overall substrate metabolism and muscle metabolism in human subjects with pre-diabetes. In this single-arm longitudinal design, subjects will serve as their own control. Subjects will perform high-intensity interval training for 12 weeks (3x times per week) on a cycle ergometer at the research facility. Pre and post exercise, subjects will stay in a metabolic chamber and adhere to a relatively normal life-style in order to standardize the main 24h measurement period. As the primary outcome, substrate metabolism will be measured with a ventilated hood system and by indirect calorimetry in the chambers. Muscle biopsies from the vastus lateralis and frequent blood samples will also be taken over the course of the 24h. Thereby, ex-vivo skeletal muscle mitochondrial function and muscle clock gene expression will serve as the main secondary outcomes.
Interventions
BEHAVIORALHigh-intensity interval training
3 times per week high-intensity interval training (HIIT) will be performed on a cycle ergometer for 12 weeks adding up to 36 HIIT sessions
Sponsors
Maastricht University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
40 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Caucasian * Healthy (as determined by dependent physician) * Overweight: BMI 25 - 35 kg/m2 * Prediabetic based on one or a combination of the following criteria: * Impaired Glucose Tolerance (IGT): plasma glucose values ≥ 7.8 mmol/l and ≤ 11.1 mmol/l 120 minutes after glucose drink consumption during OGTT in screening. * Impaired Fasting Glucose (IFG): Fasting plasma glucose ≥ 6.1 mmol/l and ≤ 6.9 mmol/l. * Insulin Resistance: glucose clearance rate ≤ 360ml/kg/min, as determined using the OGIS120 model. * HbA1c of 5.7-6.4%. * Regular sleeping time (normally 7 - 9h daily) * Stable dietary habits: no weight gain or loss \> 3kg in the last three months.
Exclusion criteria
* Use of anticoagulants * Previously diagnosed with type 2 diabetes * Current alcohol consumption \> 20 grams alcohol/day * Extreme early bird or extreme night person (score ≤ 30 or ≥ 70 on MEQ-SA questionnaire) * Heavily varying sleep-wake rhythm * Nightshift work during last 3 months * Travel across \> 1 time zone in the last 3 months * Significant food allergies/intolerance (seriously hampering study meals) * Using \> 400mg caffeine daily (more than 4 coffee or energy drink) * Smoking
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in 24 rhythm in whole-body energy metabolism (energy expenditure) | measured at 8:00, 13:00, 18:00, 23:00, 04:00 of the main test day before and after 12 weeks of exerise | Energy expenditure (kJ/min) measured by indirect calorimetry |
| Change in 24 rhythm in whole-body energy metabolism (glucose oxidation) | measured at 8:00, 13:00, 18:00, 23:00, 04:00 of the main test day before and after 12 weeks of exercise | Energy expenditure (kJ/min) measured by indirect calorimetry |
| Change in 24 rhythm in whole-body energy metabolism (fat oxidation) | measured at 8:00, 13:00, 18:00, 23:00, 04:00 of the main test day before and after 12 weeks of exercise | Energy expenditure (kJ/min) measured by indirect calorimetry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 24h rhythm in muscle DNA involved in molecular clock and mitochondrial metabolism. | measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise | Quantify DNA by micro-array |
| Change in 24h rhythm in muscle mRNA markers involved in molecular clock and mitochondrial metabolism | measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise | Quantify mRNA levels by micro array |
| Change in 24 rhythm of markers of normal 24h rhythm (cortisol) | every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise | Blood cortisol levels |
| Change in 24 rhythm of markers of normal 24h rhythm (melatonin) | every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise | Blood melatonin levels |
| Change in 24 rhythm of markers of normal 24h rhythm (core body temperature) | measured continuously for 24 hours on the main test day before and after 12 weeks of exercise | Core body temperature measured by an ingested telemetric pill |
| Change in 24 rhythm in skeletal muscle mitochondrial respiration | measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise | O2-flux (pmol/mg/s) measured with high resolution respirometry |
| Change in 24h rhythm in serum insulin | every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise | Serum insulin levels determined from venous blood draws |
| Change in 24h rhythm in serum free fatty acids (FFA) | every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise | Serum FFA levels determined from venous blood draws |
| Change in 24h rhythm in serum triglycerides | every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise | Serum triglycerides levels determined from venous blood draws |
| Change in 24h rhythm in serum cholesterol | every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise | Serum cholesterol levels determined from venous blood draws |
| Change in 24h rhythm in serum glucose | every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise | Serum glucose levels determined from venous blood draws |
| Change in 24h rhythm in muscle protein levels of markers involved in molecular clock and mitochondrial metabolism | measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise | Quantify protein levels by Western blots |
| Change in 24h rhythm in muscle DNA of markers involved in molecular clock and mitochondrial metabolism | measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise | Quantify DNA by qPCR |
Countries
Netherlands
Outcome results
None listed