Clinical trial NCT03769883: Exercise Volume and Beta-cell Function in T2D The DOSE-EX Randomized Trial
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Type 2 Diabetes Mellitus
Type2 Diabetes
Diabetes Mellitus, Type 2
Type2 Diabetes Mellitus
Keywords: Exercise
Physical Activity
Type 2 diabetes
Pancreatic beta-cell function
Insulin sensitivity
Dose finding
lifestyle
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2018-12-10
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

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 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

Primary outcomes:
measure: Pancreatic beta-cell function (Per protocol)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
Secondary outcomes:
measure: Pancreatic beta-cell function (Intention to treat)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Glucagon like peptide 1 sensitivity (c-peptide)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Glucagon like peptide 1 sensitivity (glucagon)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Glucagon like peptide 1 sensitivity (insulin)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Arginine sensitivity (insulin)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Arginine sensitivity (c-peptide)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Arginine sensitivity (glucagon)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Early phase disposition index (c-peptide)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Early phase disposition index (insulin)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Glucose clearance
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Glucose appearance
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Insulin sensitivity
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Mean amplitude of glycemic excursions
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Coefficient of glucose variation
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Mean glucose levels
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Time in hyperglycemia
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Time in hypoglycemia
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Pancreatic fat
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Hepatic fat
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Visceral fat
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Total fat mass
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Total fat free mass
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Total lean body mass
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Android fat mass
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Gynoid fat mass
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Body weight
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Body mass index
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Systemic oxidative stress (RNA)
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: Systemic oxidative stress (DNA)
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: Advanced glycation end-products (AGE)
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: The circulating receptor for advanced glycation end-products (sRAGE)
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: Markers of low-grade inflammation
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: Glycated haemoglobin type 1AC (HbA1c)
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: Total cholesterol
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: Total triglyceride
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: Low density lipoprotein (LDL)
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: High density lipoprotein (HDL)
timeFrame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
measure: Systolic blood pressure
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Diastolic blood pressure
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Glucose tolerance
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Gastric emptying (AUC)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Gastric emptying (Rate of appearance)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Physical fitness (VO2max)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Muscular 1 repetition max (strength)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Total physical activity
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Moderate and vigorous physical activity (MVPA)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Sedentary time (SED)
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Physical well being
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Mental well being
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Satiety
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
Other outcomes:
measure: Muscular metabolic function
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
measure: Fat tissue metabolic function
timeFrame: From baseline (0 weeks) to follow-up (16 weeks)
Locations:
city: Copenhagen
country: Denmark
facility: Center for Physical Activity Research, Copenhagen University Hospital
Study officials:
affiliation: Centre for Physical Activity Research, Righospitalet
name: Mathias Ried-Larsen, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Legaard GE, Lyngbaek MPP, Almdal TP, Karstoft K, Bennetsen SL, Feineis CS, Nielsen NS, Durrer CG, Liebetrau B, Nystrup U, Ostergaard M, Thomsen K, Trinh B, Solomon TPJ, Van Hall G, Brond JC, Holst JJ, Hartmann B, Christensen R, Pedersen BK, Ried-Larsen M. Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial. Nat Metab. 2023 May;5(5):880-895. doi: 10.1038/s42255-023-00799-7. Epub 2023 May 1.
citation: Legaard GE, Lyngbaek MPP, Almdal TP, Durrer CG, Nystrup U, Larsen EL, Poulsen HE, Karstoft K, Pedersen BK, Ried-Larsen M. Effects of different doses of exercise in adjunct to diet-induced weight loss on the AGE-RAGE axis in patients with short standing type 2 diabetes: Secondary analysis of the DOSE-EX multi-arm, parallel-group, randomised trial. Free Radic Biol Med. 2023 Nov 1;208:52-61. doi: 10.1016/j.freeradbiomed.2023.07.031. Epub 2023 Jul 31.