Exercise Volume and Beta-cell Function in T2D The DOSE-EX Randomized Trial

Mathias Ried-Larsen82 enrolled

Overview

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: 1. Control group (CON): No intervention 2. Dietary control (DCON): Dietary intervention (see below) 3. 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) 4. 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%.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Secondary Outcomes

Pancreatic beta-cell function (Intention to treat)

As for per protocol

Time frame: 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

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Glucagon like peptide 1 sensitivity (glucagon)

Change in Glucagon like peptide 1 stimulated glucagon secretion

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Glucagon like peptide 1 sensitivity (insulin)

Change in Glucagon like peptide 1 stimulated insulin secretion

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Arginine sensitivity (insulin)

Change in Arginine stimulated insulin secretion

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Arginine sensitivity (c-peptide)

Change in Arginine stimulated C-peptide secretion

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Arginine sensitivity (glucagon)

Change in Arginine stimulated glucagon secretion

Time frame: 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

Time frame: 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

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Glucose clearance

Change in Rate of glucose clearance (stable isotope infusion) during steady state hyperglycemia

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Glucose appearance

Change in Rate of glucose appearance (stable isotope infusion) during steady state hyperglycemia

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: 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)

Time frame: 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)

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Time in hypoglycemia

Change in time in hypoglycaemia from min 3 days sensor glucose profiles

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Pancreatic fat

Change in Pancreatic fat

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Hepatic fat

Change in Hepatic fat

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Visceral fat

Change in visceral fat

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Total fat mass

Change in Total fat mass

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Total fat free mass

Change in Total fat free mass

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Total lean body mass

Change in Total lean body mass

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Android fat mass

Change in Android fat mass

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Gynoid fat mass

Change in gynoid fat mass

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Body weight

Change in body weight

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Body mass index

Change in body mass index

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Systemic oxidative stress (RNA)

Change in 8-oxo-guanosine

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

Systemic oxidative stress (DNA)

Change in 8-oxo-deoxoguonase

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

Advanced glycation end-products (AGE)

Change in AGE

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

The circulating receptor for advanced glycation end-products (sRAGE)

Change in sRAGE

Time frame: 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)

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

Glycated haemoglobin type 1AC (HbA1c)

Change in HbA1c

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

Total cholesterol

Change in total cholesterol

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

Total triglyceride

Change in total triglyceride

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

Low density lipoprotein (LDL)

Change in LDL

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

High density lipoprotein (HDL)

Change in HDL

Time frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)

Systolic blood pressure

Change systolic blood pressures

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Diastolic blood pressure

Change diastolic blood pressure

Time frame: 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

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Gastric emptying (AUC)

Change in the AUC (paracetamol) during a mixed meal tolerance test

Time frame: 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

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Physical fitness (VO2max)

Change in physical fitness (VO2) during a progressive maximal bicycle ergometer test

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Muscular 1 repetition max (strength)

Change in 1 repetition max

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Total physical activity

Change in objectively measured physical activity (counts per minute)

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Moderate and vigorous physical activity (MVPA)

Change in time spend on MVPA

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Sedentary time (SED)

Change in time spend on SED

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: From baseline (0 weeks) to follow-up (16 weeks)

Exercise Volume and Beta-cell Function in T2D The DOSE-EX Randomized Trial

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes