Circadian Rhythm and Metabolic Effects of Exercise

Study Overview
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Brief Summary
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Physical exercise is efficacious in controlling blood glucose levels in individuals with Type 2 diabetes. An individual's exercise capacity and ability to utilize glucose as an energy source oscillates throughout the day. Hence, the beneficial effects of exercise on blood glucose levels may depend on the time of day when the exercise bout is performed. However, the time of day in which the most beneficial adaptations to exercise can be achieved remains unknown. This project aims to answer the following questions: Does time of day impact the beneficial effects of exercise on blood glucose? If so, when can the most beneficial effects of exercise be achieved? Which metabolic mechanisms links time of day, exercise and blood glucose control? To address these questions, individuals with or without Type 2 diabetes will perform an exercise session at two different times (09:00 and 16:00), and continuous glucose monitoring will be used to assess the effects of exercise on blood glucose. We will determine the specific metabolic processes which promote the most beneficial blood glucose response. To achieve this, we will measure which metabolic substrates (carbohydrates, lipids and proteins) are used and which metabolites produced in blood, skeletal muscle and adipose tissue in response to exercise at different times of the day.

Detailed Description
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Exercise has well-established metabolic benefits and is a preferred intervention for Type 2 diabetes prevention and management. Metabolic determinants of exercise such as skeletal muscle and whole-body substrate oxidation capacity, glucose tolerance and insulin sensitivity and adipose tissue fatty acid release all show circadian oscillations. These rhythms may promote substantially different responses depending on the time of day when exercise is performed. This is an exploratory study aiming to determine whether exercise at specific times of day can amplify the beneficial effects on glycemia and metabolism in twi groups of individuals: those with normal glucose tolerance (NGT) or Type 2 diabetes (n=40 per group). The primary objective is to determine the glycemic response to an exercise bout at two distinct times of day, measured by continuous glucose monitoring, in men and women with NGT or Type 2 diabetes. The secondary aim is to identify specific metabolites which facilitate the strongest glycemic response to exercise by examining the whole-body and peripheral tissue metabolomic response to an exercise bout. The primary goal of the study is to examine the glycemic and metabolic response to exercise within-group for participants with NGT or Type 2 diabetes. Further comparisons will be made between groups with NGT or Type 2 diabetes, across sexes, and by individual chronotype (determined by a standardized questionnaire) to examine the variation in the exercise response across these parameters.

Official Title
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Time of Day Specific Glycaemic and Metabolic Response to High-Intensity Interval Training

Conditions
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Diabetes Mellitus, Type 2, Circadian Rhythm, Glycemic Control

Intervention / Treatment
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* Behavioral: High-intensity Intermittent Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body Mass Index (BMI): 23 - 33 kg/m2 Participants diagnosed with Type 2 Diabetes (insulin independent) or Normal Glucose Tolerant (2h oral glucose tolerance test within normal range). Ability to provide informed consent Ability to complete the exercise regiment Exclusion Criteria: Medications: Insulin Current nicotine user (cigarettes, snus, nicotine gum) or past nicotine users less than 6 months before inclusion in the study Pre-existing cardiovascular condition (Angina pectoris, Cardiac arrhythmia, Cardiac infarction, Coronary stent / angiography, Cerebrovascular insult, Hypertension [> 160 mmHg systolic, or > 95 mmHg diastolic]) Pre-existing blood-borne disease (HIV, Hepatitis C, MRSA) Pre-existing systemic or localized rheumatic illness Malignant Disease Pre-existing psychiatric disorder Another pre-existing systemic disease

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 68 Years

Sexes Eligible for Study
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All

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
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The study will include a group of individuals with type 2 diabetes and a group of individuals with normal glucose tolerance. Each group of participants will complete either a morning (09:00) or an afternoon (16:00) exercise bout. After a one-week washout period, the participants will complete an additional exercise bout at the opposing time.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Morning First<br>Participants will complete a single bout of exercise at 09:00, and after at least a one-week washout perform another exercise bout at 16:00. | Behavioral: High-intensity Intermittent Exercise<br>* The participants will perform a low-volume, High-intensity Intermittent Exercise bout on a cycle ergometer. Peak exercise capacity of the study participants will be determined on a separate occasion using a ramp-up maximal oxygen consumption test (VO2peak). A single exercise bout will consist of a 7-minute warm-up on a cycle ergometer, followed by 6 1-minute intervals of cycling at individual maximal capacity and 75rpm (rotations per minute). These intervals will be interspersed with 1-min breaks of cycling at low resistance and 75rpm, and the session will conclude with a 3-minute cool-down interval (20 minutes in total).<br>|
| Experimental: Afternoon First<br>Participants will complete a single bout of exercise at 16:00, and after at least a one-week washout perform another exercise bout at 09:00. | Behavioral: High-intensity Intermittent Exercise<br>* The participants will perform a low-volume, High-intensity Intermittent Exercise bout on a cycle ergometer. Peak exercise capacity of the study participants will be determined on a separate occasion using a ramp-up maximal oxygen consumption test (VO2peak). A single exercise bout will consist of a 7-minute warm-up on a cycle ergometer, followed by 6 1-minute intervals of cycling at individual maximal capacity and 75rpm (rotations per minute). These intervals will be interspersed with 1-min breaks of cycling at low resistance and 75rpm, and the session will conclude with a 3-minute cool-down interval (20 minutes in total).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exercise-induced Changes in 24 Hour Interstitial Glucose Concentration | Glucose excursions will be charted using continuous interstitial glucose monitors. The day immediately before exercise will be used as baseline, the day of exercise to assess the acute response, and the day after exercise to assess lasting effects on glycemia. Exercise effects on glucose concentration will be primarily assessed by comparing 24-hour curves between conditions. | 3 days (1 day before to 1 day after exercise) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Exercise-induced Changes in Interstitial Glucose Concentration | Glucose will be charted using continuous glucose monitors. Acute response to exercise, during the exercise bout and during an additional 120 minutes will be compared between conditions. | 2 hours (0 minutes before to 120 minutes after exercise) | 
| Interstitial Glucose Concentration Response to a Meal | Glucose will be charted using continuous glucose monitors. Three standardized meals per day will be provided on each occasion for the day before, day of and day after exercise. The 120 minute glucose response to the standardized meal succeeding an exercise bout will be compared to the same meal on a baseline (no exercise) day and between the two exercise times. | 2 days (1 day before and day of exercise) | 
| Interstitial Glucose Concentration Variability | Glucose will be charted using continuous glucose monitors. The day immediately before exercise will be used as baseline, the day of exercise to assess the acute response, and the day after exercise to assess lasting effects on glucose concentration variability. | 3 days (1 day before to 1 day after exercise) | 
| Time Spent in Interstitial Glucose Concentration Range | Glucose will be charted using continuous glucose monitors. The day immediately before exercise will be used as baseline, the day of exercise to assess the acute response, and the day after exercise to assess lasting effects on glycemic variability. Daily time spent in low (<3.9mmol/L), high (>10mmol/L) and within target glycemic range (3.9-10mmol/L) will be calculated on each occasion. | 3 days (1 day before to 1 day after exercise) | 
| Nocturnal Interestitial Glucose Concentration | Glucose will be charted using continuous glucose monitors. The day immediately before exercise will be used as baseline, the day of exercise to assess the acute response, and the day after exercise to assess lasting effects on glycemic variability. Nocturnal glycemia (00:00-06:00) for each day will be compared on each exercise occasion. | 2 days (day of, and 1 day after exercise) | 
| Metabolic Response to Exercise | Changes in blood, skeletal muscle and subcutaneous adipose tissue metabolite levels will be assessed by broad-spectrum, untargeted metabolomics. Samples will be collected immediately before (-5 minutes) and after (+5 minutes) each exercise bout. An additional blood sample will be collected one hour after exercise completion (+60 minutes). | 1 hour (5 minutes before, 5 minutes after and 60 minutes after exercise) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, High-intensity Intermittent Exercise, Circadian Rhythm, Glycemic Control, Energy Metabolism