Exercise to Restore 24h Rhythms in Metabolism

Diabetes Mellitus, Type 2 Clinical Trial

— RESTORE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04565418
• Other study ID #: NL73834.068.20
• Status: Completed
• Phase: N/A
• Start date: January 26, 2021
• Est. completion date: April 24, 2023

Study information

• Verified date: May 2023
• Source: Maastricht University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: April 24, 2023
• Est. primary completion date: December 22, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 40 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Insulin Resistance

Intervention

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

Locations

Country	Name	City	State
Netherlands	Maastricht University	Maastricht

Sponsors (1)

Lead Sponsor	Collaborator
Maastricht University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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