Exercise to Restore 24h Rhythms in Metabolism (RESTORE)

Exercise to Restore 24h Rhythmicity in Substrate Metabolism of Prediabetes Subjects

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Insulin Resistance
• Intervention / Treatment: Behavioral: High-intensity interval training

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Patrick Schrauwen, PhD; Phone Number: +31(0)43 3881502; Email: p.schrauwen@maastrichtuniversity.nl

Study Locations

• Netherlands
  • Maastricht, Netherlands
    • Maastricht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise training; 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.	Behavioral: High-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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 24 rhythm in whole-body energy metabolism (energy expenditure)	Energy expenditure (kJ/min) measured by indirect calorimetry	measured at 8:00, 13:00, 18:00, 23:00, 04:00 of the main test day before and after 12 weeks of exerise
Change in 24 rhythm in whole-body energy metabolism (glucose oxidation)	Energy expenditure (kJ/min) measured by indirect calorimetry	measured at 8:00, 13:00, 18:00, 23:00, 04:00 of the main test day before and after 12 weeks of exercise
Change in 24 rhythm in whole-body energy metabolism (fat oxidation)	Energy expenditure (kJ/min) measured by indirect calorimetry	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 Measures

Outcome Measure	Measure Description	Time Frame
Change in 24 rhythm in skeletal muscle mitochondrial respiration	O2-flux (pmol/mg/s) measured with high resolution respirometry	measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Change in 24h rhythm in muscle protein levels of markers involved in molecular clock and mitochondrial metabolism	Quantify protein levels by Western blots	measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Change in 24h rhythm in muscle DNA of markers involved in molecular clock and mitochondrial metabolism	Quantify DNA by qPCR	measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Change in 24h rhythm in muscle DNA involved in molecular clock and mitochondrial metabolism.	Quantify DNA by micro-array	measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Change in 24h rhythm in muscle mRNA markers involved in molecular clock and mitochondrial metabolism	Quantify mRNA levels by micro array	measured at 8:00, 13:00, 23:00 of the main test day before and after 12 weeks of exercise
Change in 24 rhythm of markers of normal 24h rhythm (cortisol)	Blood cortisol levels	every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Change in 24 rhythm of markers of normal 24h rhythm (melatonin)	Blood melatonin levels	every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Change in 24 rhythm of markers of normal 24h rhythm (core body temperature)	Core body temperature measured by an ingested telemetric pill	measured continuously for 24 hours on the main test day before and after 12 weeks of exercise
Change in 24h rhythm in serum glucose	Serum glucose levels determined from venous blood draws	every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Change in 24h rhythm in serum insulin	Serum insulin levels determined from venous blood draws	every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Change in 24h rhythm in serum free fatty acids (FFA)	Serum FFA levels determined from venous blood draws	every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Change in 24h rhythm in serum triglycerides	Serum triglycerides levels determined from venous blood draws	every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise
Change in 24h rhythm in serum cholesterol	Serum cholesterol levels determined from venous blood draws	every two hours for 24 hours beginning at 08:00 of the main test day before and after 12 weeks of exercise

Collaborators and Investigators

• Sponsor: Maastricht University

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2021
• Primary Completion (Actual): December 22, 2022
• Study Completion (Actual): April 24, 2023

Study Registration Dates

• First Submitted: August 17, 2020
• First Submitted That Met QC Criteria: September 21, 2020
• First Posted (Actual): September 25, 2020

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 23, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Circadian rhythm
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperinsulinism; Diabetes Mellitus, Type 2; Insulin Resistance
• Other Study ID Numbers: NL73834.068.20

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No