Exercise to Restore 24h Rhythms in Metabolism

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Diabetes Mellitus, Type 2, Insulin Resistance

Intervention / Treatment
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* Behavioral: High-intensity interval training


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise training<br>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<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Circadian rhythm