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Day-night Rhythm in Muscle Metabolism of Prediabetics

Primary Purpose

Diabetes Mellitus, Type 2, Insulin Resistance

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Standardized living protocol
Sponsored by
Maastricht University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes Mellitus, Type 2 focused on measuring Circadian Rhythm

Eligibility Criteria

40 Years - 75 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

  • Maastricht University

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Standardized living protocol

Arm Description

Subjects are kept at the research facility to adhere to a standardized living protocol, mimicking a normal daily living situation. During the study, multiple tests will be performed, including muscle biopsies, blood draws, MRS measurements and indirect calorimetry.

Outcomes

Primary Outcome Measures

Day-night rhythm in skeletal muscle mitochondrial respiration
O2-flux (pmol/mg/s) measured with high resolution respirometry

Secondary Outcome Measures

Day-night rhythm in whole-body energy metabolism (energy expenditure)
Energy expenditure (kJ/min) measured by indirect calorimetry
Day-night rhythm in whole-body energy metabolism (glucose oxidation)
glucose oxidation (g/min) measured by indirect calorimetry
Day-night rhythm in whole-body energy metabolism (fat oxidation)
fat oxidation (g/min) measured by indirect calorimetry
Day-night rhythm in muscle protein levels of markers involved in molecular clock and mitochondrial metabolism.
Quantify protein levels by Western blots
Day-night rhythm in muscle DNA of markers involved in molecular clock and mitochondrial metabolism.
Quantify DNA by qPCR
Day-night rhythm in muscle DNA involved in molecular clock and mitochondrial metabolism.
Quantify DNA by micro-array
Day-night rhythm in muscle mRNA markers involved in molecular clock and mitochondrial metabolism.
Quantify mRNA levels by micro array
Day-night rhythm of markers of normal day-night rhythm (cortisol)
Blood cortisol levels
Day-night rhythm of in markers of normal day-night rhythm (core body temperature)
Core body temperature measured by an ingested telemetric pill.
Day-night rhythm of in markers of normal day-night rhythm (melatonin)
Blood melatonin levels.
Day-night rhythm in serum glucose
Serum glucose levels determined from venous blood draws
Day-night rhythm in serum insulin
Serum insulin levels determined from venous blood draws
Day-night rhythm in serum free fatty acids (FFA)
Serum FFA levels determined from venous blood draws
Day-night rhythm in serum triglycerides
Serum triglyceride levels determined from venous blood draws
Day-night rhythm in serum cholesterol
Serum cholesterol levels determined from venous blood draws
Change in energy status of the heart between morning and evening
variation in phosphorus metabolites measured by Magnetic Resonance Imaging and - Spectroscopy (MRI/MRS)

Full Information

First Posted
September 19, 2018
Last Updated
August 15, 2019
Sponsor
Maastricht University
Collaborators
Maastricht University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03733743
Brief Title
Day-night Rhythm in Muscle Metabolism of Prediabetics
Official Title
Day-night Rhythm in Muscle Metabolism of Prediabetic Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
July 9, 2018 (Actual)
Primary Completion Date
March 20, 2019 (Actual)
Study Completion Date
March 29, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Maastricht University
Collaborators
Maastricht University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2, Insulin Resistance
Keywords
Circadian Rhythm

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
Standardized living protocol
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standardized living protocol
Arm Type
Other
Arm Description
Subjects are kept at the research facility to adhere to a standardized living protocol, mimicking a normal daily living situation. During the study, multiple tests will be performed, including muscle biopsies, blood draws, MRS measurements and indirect calorimetry.
Intervention Type
Other
Intervention Name(s)
Standardized living protocol
Intervention Description
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.
Primary Outcome Measure Information:
Title
Day-night rhythm in skeletal muscle mitochondrial respiration
Description
O2-flux (pmol/mg/s) measured with high resolution respirometry
Time Frame
measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Secondary Outcome Measure Information:
Title
Day-night rhythm in whole-body energy metabolism (energy expenditure)
Description
Energy expenditure (kJ/min) measured by indirect calorimetry
Time Frame
measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Title
Day-night rhythm in whole-body energy metabolism (glucose oxidation)
Description
glucose oxidation (g/min) measured by indirect calorimetry
Time Frame
measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Title
Day-night rhythm in whole-body energy metabolism (fat oxidation)
Description
fat oxidation (g/min) measured by indirect calorimetry
Time Frame
measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Title
Day-night rhythm in muscle protein levels of markers involved in molecular clock and mitochondrial metabolism.
Description
Quantify protein levels by Western blots
Time Frame
measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Title
Day-night rhythm in muscle DNA of markers involved in molecular clock and mitochondrial metabolism.
Description
Quantify DNA by qPCR
Time Frame
measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Title
Day-night rhythm in muscle DNA involved in molecular clock and mitochondrial metabolism.
Description
Quantify DNA by micro-array
Time Frame
measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Title
Day-night rhythm in muscle mRNA markers involved in molecular clock and mitochondrial metabolism.
Description
Quantify mRNA levels by micro array
Time Frame
measured on day two at 8:00, 13:00, 18:00, 23:00, 04:00
Title
Day-night rhythm of markers of normal day-night rhythm (cortisol)
Description
Blood cortisol levels
Time Frame
measured on day two, every two hours for 24 hours beginning at 08:00
Title
Day-night rhythm of in markers of normal day-night rhythm (core body temperature)
Description
Core body temperature measured by an ingested telemetric pill.
Time Frame
measured continuously for 24 hours on day two
Title
Day-night rhythm of in markers of normal day-night rhythm (melatonin)
Description
Blood melatonin levels.
Time Frame
measured on day two, every two hours for 24 hours beginning at 08:00
Title
Day-night rhythm in serum glucose
Description
Serum glucose levels determined from venous blood draws
Time Frame
measured on day two, every two hours for 24 hours beginning at 08:00
Title
Day-night rhythm in serum insulin
Description
Serum insulin levels determined from venous blood draws
Time Frame
measured on day two, every two hours for 24 hours beginning at 08:00
Title
Day-night rhythm in serum free fatty acids (FFA)
Description
Serum FFA levels determined from venous blood draws
Time Frame
measured on day two, every two hours for 24 hours beginning at 08:00
Title
Day-night rhythm in serum triglycerides
Description
Serum triglyceride levels determined from venous blood draws
Time Frame
measured on day two, every two hours for 24 hours beginning at 08:00
Title
Day-night rhythm in serum cholesterol
Description
Serum cholesterol levels determined from venous blood draws
Time Frame
measured on day two, every two hours for 24 hours beginning at 08:00
Title
Change in energy status of the heart between morning and evening
Description
variation in phosphorus metabolites measured by Magnetic Resonance Imaging and - Spectroscopy (MRI/MRS)
Time Frame
Measured on first study day 5:30 PM (duration 45 minutes), second study day 7:30 AM (duration 45 minutes)

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick Schrauwen, PhD
Organizational Affiliation
Maastricht University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Maastricht University
City
Maastricht
State/Province
Limburg
ZIP/Postal Code
6229 ER
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
32659272
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.
Results Reference
derived

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Day-night Rhythm in Muscle Metabolism of Prediabetics

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