High-intensity Interval Training Prescriptions to Reduce the Risk of Complications Linked to Type 2 Diabetes: the Role of Interval Length on Clinical Benefits and on Physiological Mechanisms

Study Overview
=================
Brief Summary
-----------------
Type 2 diabetes (T2D) prevalence has steadily been rising in the past decades and its complications, including cardiovascular diseases (CVD), are a major public health concern. To lower CVD risk and to maintain an adequate glycemic control, Diabetes Canada recommends aerobic exercise of high-intensity interval training (HIIT). The leading hypothesis of this study is that longer intervals will favor an anti-inflammatory immune state, and that and that it will be correlated with reduced arterial stiffness and blood pressure.

Detailed Description
-----------------
Type 2 diabetes (T2D) prevalence has steadily been rising in the past decades and its complications, including cardiovascular diseases (CVD), are a major public health concern. Insulin resistance, an important component of T2D, is associated with vascular dysfunctions, which directly contributes to the pathogenesis of CVD, such as atherosclerosis, and hypertension, particularly with the elderly. It is also suggested that glucose variability, measured with continuous glucose monitors (CGM), is an independent risk factor of CVD in T2D individuals, exposing them to an increased risk of premature death. Moreover, in part because of immune dysregulation, women with T2D are at a heightened risk of developing CVD compared to males. Indeed, monocyte inflammatory profile is altered during the aging process and in women with T2D. This, in turn, causes vascular dysfunction which is associated with a pro-thrombotic state, and exacerbates atherosclerosis and arterial stiffening. To lower CVD risk and to maintain an adequate glycemic control, Diabetes Canada recommends aerobic exercise of high-intensity interval training (HIIT). However, this recommendation is solely based on the improvement of cardiorespiratory fitness in type 2 diabetes individuals (level of evidence: grade B, level 2). Furthermore, most of these studies use exercise protocols with ergocycles, which limit the ecological validity considering that the elderly population prefers to walk. Though, it is essential to evaluate the impact of different walking HIIT protocols on clinical targets such as arterial pressure, glycemic variability/control using ambulatory blood pressure monitors (ABPM) and CGM. The preliminary data collected in our laboratory shows that a low volume HIIIT program (6 × 1 min) is insufficient to improve glycemic control/variability and ambulatory blood pressure over 24 hours in elderly diabetic women, despite reducing inflammatory gene expression in monocytes. Interestingly, pro-inflammatory monocytes are linked with hyperglycemia and play a crucial role in the atherosclerotic process, while also being associated with arterial stiffening in individuals with kidney failure, a common T2D complication. These results raise several questions, including the role played by the length of HIIT intervals on clinical targets. While our preliminary results didn't impact ambulatory blood pressure over 24 hours with shorter intervals (6 × 1 min), other studied showed a reduction of this parameter with longer intervals (4 x 4 min). Therefore, the leading hypothesis of this study is that longer high intensity intervals (Wisløff protocol: 4 x 4 min) will reduce ambulatory blood pressure over 24 hours in a greater extent than shorter intervals (10 x 1 min). Indeed, reduced shear stress induced by shorter intervals could damper cellular and molecular responses to exercise bouts, thereby limiting the effects on arterial stiffness and blood pressure in the hours following exercise. Moreover, changes in gene expression do not guarantee changes at the protein level, and proteins are the real effectors of cellular response. Hence, proteomics will be useful to better understand monocyte response to different HIIT protocols and, possibly, the clinical benefits of this training method. Indeed, longer intervals could induce greater variations to the monocytes' proteome, favoring an anti-inflammatory phenotype, and those changes could be associated with reduced arterial stiffness and blood pressure. The primary objective of this study is therefore to compare the effect of two treadmill HIIT modalities (4x4 min vs. 10x1 min) on arterial stiffness, ambulatory blood pressure over 24 hours and on glycemic variability in elderly women with T2D. The secondary objective is to assess the proteomic changes in monocytes induced by the two HIIT modalities and to correlate them with changes in clinical parameters.

Official Title
-----------------
High-intensity Interval Training Prescriptions to Reduce the Risk of Complications Linked to Type 2 Diabetes: the Role of Interval Length on Clinical Benefits and on Physiological Mechanisms

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Other: High-intensity interval training (HIIT)-4
* Other: High-intensity interval training (HIIT)-10
* Other: Rest


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: With a diagnostic for type 2 diabetes Arterial hypertension (controlled at rest) Low or no alcohol consumption (≤ 7 alcoholic beverages/week) Non-smoking Physically active ( > 60 minutes of structured and scheduled physical activity/week for the previous 3 months) Exclusion Criteria: Insulin therapy Use of beta blockers Unstable medication in the past 6 months Stroke in the past 6 months, or with consequences limiting physical activity practice Coronary disease without revascularization, or peripheral artery disease Neuropathy, retinopathy of nephropathy diagnostics Orthopedic limitations, or medical counter-indication for physical activity practice Surgery scheduled during the study period

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: A semi-randomized (experimental conditions) crossover design will be used with a population of elderly women with T2D, and with three experimental conditions (1- rest, 2-HIIT-10: 10x 1 min, 3- HIIT-4: 4 x 4 min).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rest, HIIT-4, HIIT-10<br>Both arms start with the rest condition and the order of the two other conditions (HIIT-4 and HIIT-10) is determined at random. This arm's sequence of intervention is : 1-Rest; 2- HIIT-4 and 3- HIIT-10. | Other: High-intensity interval training (HIIT)-4<br>* 4 intervals of 4 minutes at 90% of maximum cardiac frequency, interspersed with 3-minute rests at 70% of maximum cardiac frequency. The session will last 32 minutes, including warm-up and cooldown.<br>Other: High-intensity interval training (HIIT)-10<br>* 10 intervals of 1 minutes at 90% of maximum cardiac frequency, interspersed with 1-minute rests at 70% of maximum cardiac frequency. The session will last 34 minutes, including warm-up and cooldown.<br>Other: Rest<br>* Participants are to stay seated for 30 minutes while reading or watching television.<br>|
| Experimental: Rest, HIIT-10, HIIT-4<br>Both arms start with the rest condition and the order of the two other conditions (HIIT-4 and HIIT-10) is determined at random. This arm's sequence of intervention is : 1- Rest; 2- HIIT-10 and 3- HIIT-4. | Other: High-intensity interval training (HIIT)-4<br>* 4 intervals of 4 minutes at 90% of maximum cardiac frequency, interspersed with 3-minute rests at 70% of maximum cardiac frequency. The session will last 32 minutes, including warm-up and cooldown.<br>Other: High-intensity interval training (HIIT)-10<br>* 10 intervals of 1 minutes at 90% of maximum cardiac frequency, interspersed with 1-minute rests at 70% of maximum cardiac frequency. The session will last 34 minutes, including warm-up and cooldown.<br>Other: Rest<br>* Participants are to stay seated for 30 minutes while reading or watching television.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ambulatory systolic and diastolic blood pressure | mmHg, measured with an ambulatory blood pressure monitor | During 24 hours after the three experimental conditions (Rest, HIIT-4 and HIIT-10) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in arterial stiffness | Estimated using pulse wave velocity (m/s), measured with an ambulatory blood pressure monitor | 30 min post-exercise (in lab measure) and during 24 hours after the three experimental conditions (Rest, HIIT-4 and HIIT-10) | 
| Change in post-exercise glucose levels | Measured with a continuous glucose monitor (mmol/L) | Every 5 min during 2 hours after each experimental condition (Rest, HIIT-4 and HIIT-10) | 
| Change in post-prandial glucose levels | Measured with a continuous glucose monitor and blood samples (mmol/L) | during the 2 hour-postprandial time (before and after standardized lunch, as well as at 7.5 , 15, 30 60, 90 and 120 min) for each experimental condition (Rest, HIIT-4, HIIT-10) | 
| Change in 24h glycemia | Measured with a continuous glucose monitor (mmol/L) | During 24 hours after the three experimental conditions (Rest, HIIT-4 and HIIT-10) | 
| Change in nocturnal glycemia | Measured with a continuous glucose monitor (mmol/L) | During the night, from 10 pm to 7 am following each the three experimental conditions (Rest, HIIT-4 and HIIT-10) | 
| Change in time passed in hyperglycemia (> 10 mmol/L) | Measured with a continuous glucose monitor (minutes) | During 24 hours after each experimental conditions (Rest, HIIT-4 and HIIT-10) | 
| Change in time passed in hypoglycemia (< 3.8 mmol/L) | Measured with a continuous glucose monitor (minutes) | During 24 hours after each experimental conditions (Rest, HIIT-4 and HIIT-10) | 
| Change in time spent in range (between 3.8 and 10 mmol/L) | Measured with a continuous glucose monitor (minutes) | During 24 hours after each experimental conditions (Rest, HIIT-4 and HIIT-10) | 
| Change in the proteome of blood monocytes | Use of proteomics to identify and quantify proteins in isolated peripheral blood monocytes | Before, right after the end and 1hour post exercise (HIIT-4 and HIIT-10) | 
| Change in the proportions of blood monocytes subtypes | Surface expression of CD14 and CD16, assessed by flow cytometry on isolated monocytes. | Before, right after the end and 1hour post exercise (HIIT-4 and HIIT-10) | 
| Resting systolic and diastolic blood pressure | Measured with a manual sphygmomanometer | During the preliminary visit, after 5 min of rest in sitting position | 
| Total body weight | Measured with an electric scale (kg) | At baseline, in fasted state | 
| Height | Measured with an mural stadiometer (m) | At baseline, in fasted state | 
| Change in monocyte-derived macrophages polarization | Surface expression of CD86 and CD206, assessed by flow cytometry on monocyte-derived macrophages differentiated 5 days in vitro. | Before and right after the end of exercise (HIIT-4 and HIIT-10) | 
| Change in monocyte-derived macrophages response to lipopolysaccharide (LPS) | Monocyte-derived macrophages differentiated 5 days in vitro will be treated or not with LPS for 24h. Culture media will be collected for cytokine secretion determination (Multiplex Luminex) | Before and right after the end of exercise conditions (HIIT-4 and HIIT-10) | 
| Change in plasma endothelial nitric oxide synthase (eNOS) | Enzyme-Linked Immunosorbent Assay (ELISA) to quantify the level of human eNOS in plasma (ng/mL). | Before, at the end of exercise and 1 hour post-exercise (HIIT-4 and HIIT-10) | 
| Change in plasma catecholamines | Enzyme-Linked Immunosorbent Assay (ELISA) to quantify the level of human epinephrine and norepinephrine in plasma (pg/mL). | Before, at the end of exercise and 1 hour post-exercise (HIIT-4 and HIIT-10) | 
| Change in plasma insulin | Dosage of plasma insulin (pmol/L) | during the 2 hour-postprandial time (before and after standardized lunch, as well as at 7.5, 15, 30 60, 90 and 120 min) for each experimental condition (Rest, HIIT-4, HIIT-10) | 
| Change in plasma C-peptide | Dosage of plasma C-peptide (ng/mL) | during the 2 hour-postprandial time (before and after standardized lunch, as well as at 7.5, 15, 30 60, 90 and 120 min) for each experimental condition (Rest, HIIT-4, HIIT-10) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Proteomics, Type 2 diabetes, Ambulatory blood pressure, Continous glucose monitoring, High-intensity interval training, Monocytes, Inflammation