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Exercise to Restore 24h Rhythms in Metabolism (RESTORE)

Primary Purpose

Diabetes Mellitus, Type 2, Insulin Resistance

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
High-intensity interval training
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

Experimental

Arm Label

Exercise training

Arm Description

12 week high-intensity interval training (3 sessions per week): Before and after exercise, 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 and indirect calorimetry.

Outcomes

Primary Outcome Measures

Change in 24 rhythm in whole-body energy metabolism (energy expenditure)
Energy expenditure (kJ/min) measured by indirect calorimetry
Change in 24 rhythm in whole-body energy metabolism (glucose oxidation)
Energy expenditure (kJ/min) measured by indirect calorimetry
Change in 24 rhythm in whole-body energy metabolism (fat oxidation)
Energy expenditure (kJ/min) measured by indirect calorimetry

Secondary Outcome Measures

Change in 24 rhythm in skeletal muscle mitochondrial respiration
O2-flux (pmol/mg/s) measured with high resolution respirometry
Change in 24h rhythm in muscle protein levels of markers involved in molecular clock and mitochondrial metabolism
Quantify protein levels by Western blots
Change in 24h rhythm in muscle DNA of markers involved in molecular clock and mitochondrial metabolism
Quantify DNA by qPCR
Change in 24h rhythm in muscle DNA involved in molecular clock and mitochondrial metabolism.
Quantify DNA by micro-array
Change in 24h rhythm in muscle mRNA markers involved in molecular clock and mitochondrial metabolism
Quantify mRNA levels by micro array
Change in 24 rhythm of markers of normal 24h rhythm (cortisol)
Blood cortisol levels
Change in 24 rhythm of markers of normal 24h rhythm (melatonin)
Blood melatonin levels
Change in 24 rhythm of markers of normal 24h rhythm (core body temperature)
Core body temperature measured by an ingested telemetric pill
Change in 24h rhythm in serum glucose
Serum glucose levels determined from venous blood draws
Change in 24h rhythm in serum insulin
Serum insulin levels determined from venous blood draws
Change in 24h rhythm in serum free fatty acids (FFA)
Serum FFA levels determined from venous blood draws
Change in 24h rhythm in serum triglycerides
Serum triglycerides levels determined from venous blood draws
Change in 24h rhythm in serum cholesterol
Serum cholesterol levels determined from venous blood draws

Full Information

First Posted
August 17, 2020
Last Updated
May 23, 2023
Sponsor
Maastricht University
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1. Study Identification

Unique Protocol Identification Number
NCT04565418
Brief Title
Exercise to Restore 24h Rhythms in Metabolism
Acronym
RESTORE
Official Title
Exercise to Restore 24h Rhythmicity in Substrate Metabolism of Prediabetes Subjects
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
January 26, 2021 (Actual)
Primary Completion Date
December 22, 2022 (Actual)
Study Completion Date
April 24, 2023 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

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

5. Study Description

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.

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
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Exercise training
Arm Type
Experimental
Arm Description
12 week high-intensity interval training (3 sessions per week): Before and after exercise, 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 and indirect calorimetry.
Intervention Type
Behavioral
Intervention Name(s)
High-intensity interval training
Intervention Description
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
Primary Outcome Measure Information:
Title
Change in 24 rhythm in whole-body energy metabolism (energy expenditure)
Description
Energy expenditure (kJ/min) measured by indirect calorimetry
Time Frame
measured at 8:00, 13:00, 18:00, 23:00, 04:00 of the main test day before and after 12 weeks of exerise
Title
Change in 24 rhythm in whole-body energy metabolism (glucose oxidation)
Description
Energy expenditure (kJ/min) measured by indirect calorimetry
Time Frame
measured at 8:00, 13:00, 18:00, 23:00, 04:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24 rhythm in whole-body energy metabolism (fat oxidation)
Description
Energy expenditure (kJ/min) measured by indirect calorimetry
Time Frame
measured at 8:00, 13:00, 18:00, 23:00, 04:00 of the main test day before and after 12 weeks of exercise
Secondary Outcome Measure Information:
Title
Change in 24 rhythm in skeletal muscle mitochondrial respiration
Description
O2-flux (pmol/mg/s) measured with high resolution respirometry
Time Frame
measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in muscle protein levels of markers involved in molecular clock and mitochondrial metabolism
Description
Quantify protein levels by Western blots
Time Frame
measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in muscle DNA of markers involved in molecular clock and mitochondrial metabolism
Description
Quantify DNA by qPCR
Time Frame
measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in muscle DNA involved in molecular clock and mitochondrial metabolism.
Description
Quantify DNA by micro-array
Time Frame
measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in muscle mRNA markers involved in molecular clock and mitochondrial metabolism
Description
Quantify mRNA levels by micro array
Time Frame
measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24 rhythm of markers of normal 24h rhythm (cortisol)
Description
Blood cortisol levels
Time Frame
every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24 rhythm of markers of normal 24h rhythm (melatonin)
Description
Blood melatonin levels
Time Frame
every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24 rhythm of markers of normal 24h rhythm (core body temperature)
Description
Core body temperature measured by an ingested telemetric pill
Time Frame
measured continuously for 24 hours on the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in serum glucose
Description
Serum glucose levels determined from venous blood draws
Time Frame
every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in serum insulin
Description
Serum insulin levels determined from venous blood draws
Time Frame
every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in serum free fatty acids (FFA)
Description
Serum FFA levels determined from venous blood draws
Time Frame
every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in serum triglycerides
Description
Serum triglycerides levels determined from venous blood draws
Time Frame
every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Title
Change in 24h rhythm in serum cholesterol
Description
Serum cholesterol levels determined from venous blood draws
Time Frame
every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise

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
Facility Information:
Facility Name
Maastricht University
City
Maastricht
Country
Netherlands

12. IPD Sharing Statement

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