Clinical trial NCT03733743: Day-night Rhythm in Muscle Metabolism of Prediabetics
Official title: Day-night Rhythm in Muscle Metabolism of Prediabetic Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Insulin Resistance
Keywords: Circadian Rhythm
Lead sponsor: Maastricht University
Sponsor class: OTHER
Collaborators: name: Maastricht University Medical Center
First posted: 2018-11-07
Enrollment: 12
Sex: MALE
Minimum age (years): 40
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Standardized living protocol
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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

Primary outcomes:
measure: Day-night rhythm in skeletal muscle mitochondrial respiration
timeFrame: measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Secondary outcomes:
measure: Day-night rhythm in whole-body energy metabolism (energy expenditure)
timeFrame: measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
measure: Day-night rhythm in whole-body energy metabolism (glucose oxidation)
timeFrame: measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
measure: Day-night rhythm in whole-body energy metabolism (fat oxidation)
timeFrame: measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
measure: Day-night rhythm in muscle protein levels of markers involved in molecular clock and mitochondrial metabolism.
timeFrame: measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
measure: Day-night rhythm in muscle DNA of markers involved in molecular clock and mitochondrial metabolism.
timeFrame: measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
measure: Day-night rhythm in muscle DNA involved in molecular clock and mitochondrial metabolism.
timeFrame: measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
measure: Day-night rhythm in muscle mRNA markers involved in molecular clock and mitochondrial metabolism.
timeFrame: measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
measure: Day-night rhythm of markers of normal day-night rhythm (cortisol)
timeFrame: measured on day two, every two hours for 24 hours beginning at 08:00
measure: Day-night rhythm of in markers of normal day-night rhythm (core body temperature)
timeFrame: measured continuously for 24 hours on day two
measure: Day-night rhythm of in markers of normal day-night rhythm (melatonin)
timeFrame: measured on day two, every two hours for 24 hours beginning at 08:00
measure: Day-night rhythm in serum glucose
timeFrame: measured on day two, every two hours for 24 hours beginning at 08:00
measure: Day-night rhythm in serum insulin
timeFrame: measured on day two, every two hours for 24 hours beginning at 08:00
measure: Day-night rhythm in serum free fatty acids (FFA)
timeFrame: measured on day two, every two hours for 24 hours beginning at 08:00
measure: Day-night rhythm in serum triglycerides
timeFrame: measured on day two, every two hours for 24 hours beginning at 08:00
measure: Day-night rhythm in serum cholesterol
timeFrame: measured on day two, every two hours for 24 hours beginning at 08:00
measure: Change in energy status of the heart between morning and evening
timeFrame: Measured on first study day 5:30 PM (duration 45 minutes), second study day 7:30 AM (duration 45 minutes)
Other outcomes:
Locations:
city: Maastricht
country: Netherlands
facility: Maastricht University
state: Limburg
Study officials:
affiliation: Maastricht University
name: Patrick Schrauwen, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wefers J, Connell NJ, Fealy CE, Andriessen C, de Wit V, van Moorsel D, Moonen-Kornips E, Jorgensen JA, Hesselink MKC, Havekes B, Hoeks J, Schrauwen P. Day-night rhythm of skeletal muscle metabolism is disturbed in older, metabolically compromised individuals. Mol Metab. 2020 Nov;41:101050. doi: 10.1016/j.molmet.2020.101050. Epub 2020 Jul 11.