Diabetes Mellitus, Type 2, Insulin Resistance
Conditions
Keywords
Circadian Rhythm
Brief summary
This study evaluates the existence of a day-night rhythm in skeletal muscle energy metabolism in prediabetic subjects. Subjects will stay at the research facility for 44 hours with a standardized living protocol during which several measurements of skeletal muscle and whole body energy metabolism will be performed.
Detailed description
Recent evidence from both observational and experimental studies indicates that disobedience of a normal day-night rhythm negatively influences metabolic and cardiovascular health, possibly leading to obesity and type 2 diabetes mellitus (T2DM). An important hallmark of obesity and T2DM is a decreased skeletal muscle mitochondrial function. Interestingly, recent research indicates that also skeletal muscle mitochondrial function is under the influence of a day-night rhythm. In this study, the presence of a day-night rhythm in skeletal muscle energy metabolism (in particular mitochondrial function) of overweight prediabetic participants will be investigated. During this study, subjects will stay at the research unit for 44 hours, with standardized meals and sleeping time. Five muscle biopsies (v. lateralis) and frequent blood draws will be taken. In addition, indirect calorimetry measurements will be performed.
Interventions
Subjects stay at the research facility for 44 hours and adhere to a standard sleeping, eating and activity protocol. During this protocol, multiple measurements will be performed including skeletal muscle biopsies (m. vastus lateralis), blood draws, indirect calorimetry and MRS measurements.
Sponsors
Maastricht University Medical Center
Maastricht University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Standardized living protocol
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 |
|---|---|---|
| Day-night rhythm in skeletal muscle mitochondrial respiration | measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00 | O2-flux (pmol/mg/s) measured with high resolution respirometry |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Day-night rhythm in whole-body energy metabolism (glucose oxidation) | measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00 | glucose oxidation (g/min) measured by indirect calorimetry |
| Day-night rhythm in whole-body energy metabolism (fat oxidation) | measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00 | fat oxidation (g/min) measured by indirect calorimetry |
| Day-night rhythm in muscle protein levels of markers involved in molecular clock and mitochondrial metabolism. | measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00 | Quantify protein levels by Western blots |
| Day-night rhythm in muscle DNA of markers involved in molecular clock and mitochondrial metabolism. | measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00 | Quantify DNA by qPCR |
| Day-night rhythm in muscle DNA involved in molecular clock and mitochondrial metabolism. | measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00 | Quantify DNA by micro-array |
| Day-night rhythm in muscle mRNA markers involved in molecular clock and mitochondrial metabolism. | measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00 | Quantify mRNA levels by micro array |
| Day-night rhythm of markers of normal day-night rhythm (cortisol) | measured on day two, every two hours for 24 hours beginning at 08:00 | Blood cortisol levels |
| Day-night rhythm in whole-body energy metabolism (energy expenditure) | measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00 | Energy expenditure (kJ/min) measured by indirect calorimetry |
| Day-night rhythm of in markers of normal day-night rhythm (melatonin) | measured on day two, every two hours for 24 hours beginning at 08:00 | Blood melatonin levels. |
| Day-night rhythm in serum glucose | measured on day two, every two hours for 24 hours beginning at 08:00 | Serum glucose levels determined from venous blood draws |
| Day-night rhythm in serum insulin | measured on day two, every two hours for 24 hours beginning at 08:00 | Serum insulin levels determined from venous blood draws |
| Day-night rhythm in serum free fatty acids (FFA) | measured on day two, every two hours for 24 hours beginning at 08:00 | Serum FFA levels determined from venous blood draws |
| Day-night rhythm in serum triglycerides | measured on day two, every two hours for 24 hours beginning at 08:00 | Serum triglyceride levels determined from venous blood draws |
| Day-night rhythm in serum cholesterol | measured on day two, every two hours for 24 hours beginning at 08:00 | Serum cholesterol levels determined from venous blood draws |
| Change in energy status of the heart between morning and evening | Measured on first study day 5:30 PM (duration 45 minutes), second study day 7:30 AM (duration 45 minutes) | variation in phosphorus metabolites measured by Magnetic Resonance Imaging and - Spectroscopy (MRI/MRS) |
| Day-night rhythm of in markers of normal day-night rhythm (core body temperature) | measured continuously for 24 hours on day two | Core body temperature measured by an ingested telemetric pill. |
Countries
Netherlands
Outcome results
None listed