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

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

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

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.

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%.

Exercise, Physical Activity, Type 2 diabetes, Pancreatic beta-cell function, Insulin sensitivity, Dose finding, lifestyle

Upon completion of the study and prior to breaking the allocation code, a data-collection form is generated by a statistician and the principal investigator. The data-analyst breaks the allocation code and labels the participants according to the assigned treatment and analyzes the outcomes. Following the analyses, group allocation will be concealed in all data outputs and the N per group and present the data to the writing committee in a blinded fashion. Then the writing committee will provide their blinded interpretations.

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

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)

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)

The participants will undergo diet or combined diet and exercise. The exercise will be provided at different volumes

The change in the late-phase disposition index (DI) during the final 30 minutes of hyperglycemic phase of the hyperglycemic clamp.

Change in 1st phase C-peptide secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp

Change in 1st phase insulin secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp

Change in Mean amplitude of glycemic excursions (MAGE - calculated based on min 3 days sensor glucose profiles)

Change in Coefficient of variation defined as (mean glucose/the standard deviation (SD)) of min 3 days sensor glucose profiles

Change in inflammatory markers (e.g. high sensitive C-reactive protein, interferon-ϒ, interleukin-10, interleukin-8, interleukin-6, interleukin-1, TNFα)

Change incremental and total area under the curve (glucose, c-peptide, insulin) during a mixed meal tolerance test

Change in physical well being (Based on the physical dimension score from short-form 36, range 0-100)

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

Lyngbaek MPP, Legaard GE, Bennetsen SL, Feineis CS, Rasmussen V, Moegelberg N, Brinklov CF, Nielsen AB, Kofoed KS, Lauridsen CA, Ewertsen C, Poulsen HE, Christensen R, Van Hall G, Karstoft K, Solomon TPJ, Ellingsgaard H, Almdal TP, Pedersen BK, Ried-Larsen M. The effects of different doses of exercise on pancreatic beta-cell function in patients with newly diagnosed type 2 diabetes: study protocol for and rationale behind the "DOSE-EX" multi-arm parallel-group randomised clinical trial. Trials. 2021 Apr 1;22(1):244. doi: 10.1186/s13063-021-05207-7.