The Effects of Different Doses of Exercise on Pancreatic β-cell Function in Patients With Newly Diagnosed Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
This project will provide an exercise-based lifestyle intervention with the potential to reduce complications for patients with short standing type 2 diabetes (T2D). While exercise is widely accepted as a component of T2D management, little is known about the additive effect of exercise when combined with a diet on T2D pathophysiology and mechanisms believed to lead to micro- and macrovascular complications. Moreover, the necessary dose of exercise to revert the progression of T2D and the related complications has not been investigated. A large-scale randomized controlled trial (RCT) will be essential to document the effectiveness on reducing the risk of T2D complications. However, prior to conducting a large-scale RCT, we need to specify the exercise dose that efficiently compliments the diet. In a 4-armed randomized, clinical trial (N=80 T2D patients, T2D duration < than 7 years) we aim to investigate 1) the potential additive role of exercise on pancreatic β-cell function in patients with T2D when combined with a diet, 2) the causal relationship between lifestyle-induced reductions in glycaemic variability, oxidative stress and low-grade inflammation and, 3) the role of exercise in rescuing dysregulated muscle progenitor cells. The participants will be randomly allocated to either a) control, b) diet, c) diet and exercise 3 times/week or d) diet and exercise 6 times/week for 16 weeks. Prior to, during and following the interventions, all participants will undergo extensive testing.

Detailed Description
-----------------
A 4-armed, 16-week, parallel-group, assessor-blinded, randomized, clinical trial. Participants will be randomly allocated (1:1:1:1), stratified by sex Interventions: The lifestyle interventions will consist of two main components; 1) increased physical activity and structured exercise and/or 2) a dietary intervention aiming at a weight loss. Whereas there will be no differences in the dietary intervention between the lifestyle groups, the volume of physical activity and structured exercise will vary according to the frequencies of the structured exercise sessions. The study groups are prescribed: Control group (CON): No intervention Dietary control (DCON): Dietary intervention (see below) Moderate Exercise Dose (MED): Two aerobic training sessions per week of 45-60 min duration and one session per week with combined aerobic (30-35 min) and resistance (30 min) training and a dietary intervention (described below) High Exercise Dose (HED): Four aerobic training sessions per week of 45-60 min duration and two sessions per week with combined aerobic (30-35 min) and resistance (30 min) training and a dietary intervention (described below) Detailed description of the intervention components. Exercise: The training protocol will be adapted based on a previous study where the T2D participants were prescribed 6 weekly sessions of aerobic training alone or combined aerobic and resistance training (averaging 360-420 min of exercise per week). As previous analyses suggest that there may be an inverse dose-response relationship between reductions in HbA1c and aerobic exercise volume, this parameter will be used to adapt the training protocol. As the effect of exercise on HbA1c is closer related to the number of training sessions rather than intensity15, we will reduce the number of sessions by 50%, to three sessions/week in the moderate exercise dose group and maintain the original session frequency in the high dose exercise group (six sessions/week).Training will be supervised and monitored to ensure intensity and compliance. Dietary intervention and intended weight loss (DCON, MED and HED: The dietary intervention will be based on the recommendations from the American Diabetes Association (ADA) with increased focus on macronutrient quality. The macronutrient distributions are in line with the current guidelines from the national Diabetes Association and Canadian guidelines, where individualization in macronutrient distribution should lie within the range of 45-60 energy% carbohydrate, 15-20 energy% protein and 20-35 energy% fat. Thus, the dietary intervention emphasis will be on low glycemic index and low glycemic load in shape of non-processed foods and will aim at reducing saturated fat intake <7 energy%.

Official Title
-----------------
The Effects of Different Doses of Exercise on Pancreatic ß-cell Function in Patients With Newly Diagnosed Type 2 Diabetes (DOSE-EX): A Randomized Clinical Trial

Conditions
-----------------
Type 2 Diabetes Mellitus, Type2 Diabetes, Diabetes Mellitus, Type 2, Type2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Behavioral: Exercise and diet
* Behavioral: Diet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with diabetes type 2 and/or HbA1c ≥ 48 mmol/mol if no treatment with anti-diabetic medication and/or use of antidiabetic medication Caucasian No diagnose of Type 1 diabetes, mature onset diabetes of the young, Latent autoimmune diabetes of adults T2D 0-6 years of duration No treatment with insulin Body Mass Index (BMI) >27 kg/m2 and <40 kg/m2 No known or signs of intermediate or severe microvascular complications to diabetes (retino-, neuro- or nephropathy) No known cancer No Known lung disease No known cardiovascular disease No known thyroid disease No known liver disease No known autoimmune disease No other endocrine disorder causing obesity No current treatment with anti-obesity medication No current treatment with anti-inflammatory medication No weight loss of > 5kg within the last 6 months No diagnose of depression or treatment with anti-depressive medication, ongoing or within the last three months before enrolment No diagnose of psychiatric disorder or treatment with anti-psychotic medication No history of suicidal behavior or ideations within the last three months before enrolment No previous surgical treatment for obesity (excluding liposuction > 1 year prior to enrolment) Not pregnant/considering pregnancy No functional impairments that prevents the performance of intensive exercise Accept of medical regulation by the U-TURN endocrinologist Inactivity, defined as < 1,5 hours of structured physical activity pr. week at moderate intensity and cycling < 30 minutes/5 km pr. day at moderate intensity (moderate intensity = out of breath but able to speak) No participation in other research intervention studies Exclusion Criteria: HbA1c: >=75 mmol/mol with no glucose lowering medications HbA1c: >=64 mmol/mol with mono glucose lowering therapy (if compliant with the prescription) HbA1c: >=57 mmol/mol with >=dual glucose lowering therapy (if compliant with the prescription) estimated glomerular filtration rate<60 mL/min Protein or glucose in the urine at pre-screening No biochemical sign of other major diseases Presence of circulating glutamate-decarboxylase anti body (GAD) 65 Objective findings that contraindicates participation in intensive exercise Anamnestic findings that contraindicates participation in the study Unable to allocate the needed time to fulfill the intervention Language barrier, mental incapacity, unwillingness or inability to understand and be able to complete the interventions

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dietary control (DCON)<br>The macro-nutrient distributions are in line with the current guidelines from the national Diabetes Association and Canadian guidelines, where individualization in macronutrient distribution should lie within the range of 45-60E% carbohydrate, 15-20E% protein and 20-35E% fat. The dietary plan will aim at reducing saturated fat intake <7E% aiming at a caloric deficit of 500 kilo calories/day | Behavioral: Diet<br>* Dietary intervention<br>|
| Experimental: Moderate Exercise Dose (MED)<br>Two aerobic training sessions per week of 45-60 min duration and one session per week with combined aerobic (30-35 min) and resistance (30 min) training and a dietary intervention (as above) | Behavioral: Exercise and diet<br>* The participants will undergo diet or combined diet and exercise. The exercise will be provided at different volumes<br>|
| Experimental: High Exercise Dose (HED)<br>Four aerobic training sessions per week of 45-60 min duration and two sessions per week with combined aerobic (30-35 min) and resistance (30 min) training and a dietary intervention (as above) | Behavioral: Exercise and diet<br>* The participants will undergo diet or combined diet and exercise. The exercise will be provided at different volumes<br>|
| No Intervention: Control<br>No intervention | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pancreatic beta-cell function (Per protocol) | The change in the late-phase disposition index (DI) during the final 30 minutes of hyperglycemic phase of the hyperglycemic clamp. | From baseline (0 weeks) to follow-up (16 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pancreatic beta-cell function (Intention to treat) | As for per protocol | From baseline (0 weeks) to follow-up (16 weeks) | 
| Glucagon like peptide 1 sensitivity (c-peptide) | Change in Glucagon like peptide 1 stimulated C-peptide secretion | From baseline (0 weeks) to follow-up (16 weeks) | 
| Glucagon like peptide 1 sensitivity (glucagon) | Change in Glucagon like peptide 1 stimulated glucagon secretion | From baseline (0 weeks) to follow-up (16 weeks) | 
| Glucagon like peptide 1 sensitivity (insulin) | Change in Glucagon like peptide 1 stimulated insulin secretion | From baseline (0 weeks) to follow-up (16 weeks) | 
| Arginine sensitivity (insulin) | Change in Arginine stimulated insulin secretion | From baseline (0 weeks) to follow-up (16 weeks) | 
| Arginine sensitivity (c-peptide) | Change in Arginine stimulated C-peptide secretion | From baseline (0 weeks) to follow-up (16 weeks) | 
| Arginine sensitivity (glucagon) | Change in Arginine stimulated glucagon secretion | From baseline (0 weeks) to follow-up (16 weeks) | 
| Early phase disposition index (c-peptide) | Change in 1st phase C-peptide secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp | From baseline (0 weeks) to follow-up (16 weeks) | 
| Early phase disposition index (insulin) | Change in 1st phase insulin secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp | From baseline (0 weeks) to follow-up (16 weeks) | 
| Glucose clearance | Change in Rate of glucose clearance (stable isotope infusion) during steady state hyperglycemia | From baseline (0 weeks) to follow-up (16 weeks) | 
| Glucose appearance | Change in Rate of glucose appearance (stable isotope infusion) during steady state hyperglycemia | From baseline (0 weeks) to follow-up (16 weeks) | 
| Insulin sensitivity | Change in mean Glucose infusion rate over last 30 min of clamp phase/(mean insulin×glucose | From baseline (0 weeks) to follow-up (16 weeks) | 
| Mean amplitude of glycemic excursions | Change in Mean amplitude of glycemic excursions (MAGE - calculated based on min 3 days sensor glucose profiles) | From baseline (0 weeks) to follow-up (16 weeks) | 
| Coefficient of glucose variation | Change in Coefficient of variation defined as (mean glucose/the standard deviation (SD)) of min 3 days sensor glucose profiles | From baseline (0 weeks) to follow-up (16 weeks) | 
| Mean glucose levels | Change in the mean glucose levels (calculated based on min 3 days sensor glucose profiles) | From baseline (0 weeks) to follow-up (16 weeks) | 
| Time in hyperglycemia | Change in time in hyperglycaemia (calculated based on min 3 days sensor glucose profiles) | From baseline (0 weeks) to follow-up (16 weeks) | 
| Time in hypoglycemia | Change in time in hypoglycaemia from min 3 days sensor glucose profiles | From baseline (0 weeks) to follow-up (16 weeks) | 
| Pancreatic fat | Change in Pancreatic fat | From baseline (0 weeks) to follow-up (16 weeks) | 
| Hepatic fat | Change in Hepatic fat | From baseline (0 weeks) to follow-up (16 weeks) | 
| Visceral fat | Change in visceral fat | From baseline (0 weeks) to follow-up (16 weeks) | 
| Total fat mass | Change in Total fat mass | From baseline (0 weeks) to follow-up (16 weeks) | 
| Total fat free mass | Change in Total fat free mass | From baseline (0 weeks) to follow-up (16 weeks) | 
| Total lean body mass | Change in Total lean body mass | From baseline (0 weeks) to follow-up (16 weeks) | 
| Android fat mass | Change in Android fat mass | From baseline (0 weeks) to follow-up (16 weeks) | 
| Gynoid fat mass | Change in gynoid fat mass | From baseline (0 weeks) to follow-up (16 weeks) | 
| Body weight | Change in body weight | From baseline (0 weeks) to follow-up (16 weeks) | 
| Body mass index | Change in body mass index | From baseline (0 weeks) to follow-up (16 weeks) | 
| Systemic oxidative stress (RNA) | Change in 8-oxo-guanosine | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| Systemic oxidative stress (DNA) | Change in 8-oxo-deoxoguonase | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| Advanced glycation end-products (AGE) | Change in AGE | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| The circulating receptor for advanced glycation end-products (sRAGE) | Change in sRAGE | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| Markers of low-grade inflammation | Change in inflammatory markers (e.g. high sensitive C-reactive protein, interferon-ϒ, interleukin-10, interleukin-8, interleukin-6, interleukin-1, TNFα) | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| Glycated haemoglobin type 1AC (HbA1c) | Change in HbA1c | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| Total cholesterol | Change in total cholesterol | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| Total triglyceride | Change in total triglyceride | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| Low density lipoprotein (LDL) | Change in LDL | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| High density lipoprotein (HDL) | Change in HDL | From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) | 
| Systolic blood pressure | Change systolic blood pressures | From baseline (0 weeks) to follow-up (16 weeks) | 
| Diastolic blood pressure | Change diastolic blood pressure | From baseline (0 weeks) to follow-up (16 weeks) | 
| Glucose tolerance | Change incremental and total area under the curve (glucose, c-peptide, insulin) during a mixed meal tolerance test | From baseline (0 weeks) to follow-up (16 weeks) | 
| Gastric emptying (AUC) | Change in the AUC (paracetamol) during a mixed meal tolerance test | From baseline (0 weeks) to follow-up (16 weeks) | 
| Gastric emptying (Rate of appearance) | Change in rate of appearance of paracetamol during a mixed meal tolerance test | From baseline (0 weeks) to follow-up (16 weeks) | 
| Physical fitness (VO2max) | Change in physical fitness (VO2) during a progressive maximal bicycle ergometer test | From baseline (0 weeks) to follow-up (16 weeks) | 
| Muscular 1 repetition max (strength) | Change in 1 repetition max | From baseline (0 weeks) to follow-up (16 weeks) | 
| Total physical activity | Change in objectively measured physical activity (counts per minute) | From baseline (0 weeks) to follow-up (16 weeks) | 
| Moderate and vigorous physical activity (MVPA) | Change in time spend on MVPA | From baseline (0 weeks) to follow-up (16 weeks) | 
| Sedentary time (SED) | Change in time spend on SED | From baseline (0 weeks) to follow-up (16 weeks) | 
| Physical well being | Change in physical well being (Based on the physical dimension score from short-form 36, range 0-100) | From baseline (0 weeks) to follow-up (16 weeks) | 
| Mental well being | Change in mental well being (Based on the mental dimension score from Short-form 36) (range 0-100) | From baseline (0 weeks) to follow-up (16 weeks) | 
| Satiety | Change in self-reported satiety (VAS) during a mixed meal tolerance test (range 0-10) | From baseline (0 weeks) to follow-up (16 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Exercise, Physical Activity, Type 2 diabetes, Pancreatic beta-cell function, Insulin sensitivity, Dose finding, lifestyle