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

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ClinicalTrials.gov Identifier: NCT03769883
Recruitment Status : Recruiting
First Posted : December 10, 2018
Last Update Posted : December 13, 2018
Sponsor:
Information provided by (Responsible Party):
Mathias Ried-Larsen, Rigshospitalet, Denmark

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.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Mellitus Type2 Diabetes Diabetes Mellitus, Type 2 Type2 Diabetes Mellitus Behavioral: Exercise and diet Behavioral: Diet Not Applicable

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%.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description: 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.
Primary Purpose: Treatment
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
Actual Study Start Date : December 12, 2018
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dietary control (DCON)
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
Dietary intervention

Experimental: 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 (as above)
Behavioral: Exercise and diet
The participants will undergo diet or combined diet and exercise. The exercise will be provided at different volumes

Experimental: 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 (as above)
Behavioral: Exercise and diet
The participants will undergo diet or combined diet and exercise. The exercise will be provided at different volumes

No Intervention: Control
No intervention



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


Secondary Outcome Measures :
  1. Pancreatic beta-cell function (Intention to treat) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    As for per protocol

  2. Glucagon like peptide 1 sensitivity (c-peptide) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Glucagon like peptide 1 stimulated C-peptide secretion

  3. Glucagon like peptide 1 sensitivity (glucagon) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Glucagon like peptide 1 stimulated glucagon secretion

  4. Glucagon like peptide 1 sensitivity (insulin) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Glucagon like peptide 1 stimulated insulin secretion

  5. Arginine sensitivity (insulin) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Arginine stimulated insulin secretion

  6. Arginine sensitivity (c-peptide) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Arginine stimulated C-peptide secretion

  7. Arginine sensitivity (glucagon) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Arginine stimulated glucagon secretion

  8. Early phase disposition index (c-peptide) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in 1st phase C-peptide secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp

  9. Early phase disposition index (insulin) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in 1st phase insulin secretion defined as the peak concentration during the initial 10 minutes of the hyperglycaemic clamp

  10. Glucose clearance [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Rate of glucose clearance (stable isotope infusion) during steady state hyperglycemia

  11. Glucose appearance [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Rate of glucose appearance (stable isotope infusion) during steady state hyperglycemia

  12. Insulin sensitivity [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in mean Glucose infusion rate over last 30 min of clamp phase/(mean insulin×glucose

  13. Mean amplitude of glycemic excursions [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Mean amplitude of glycemic excursions (MAGE - calculated based on min 3 days sensor glucose profiles)

  14. Coefficient of glucose variation [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Coefficient of variation defined as (mean glucose/the standard deviation (SD)) of min 3 days sensor glucose profiles

  15. Mean glucose levels [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in the mean glucose levels (calculated based on min 3 days sensor glucose profiles)

  16. Time in hyperglycemia [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in time in hyperglycaemia (calculated based on min 3 days sensor glucose profiles)

  17. Time in hypoglycemia [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in time in hypoglycaemia from min 3 days sensor glucose profiles

  18. Pancreatic fat [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Pancreatic fat

  19. Hepatic fat [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Hepatic fat

  20. Visceral fat [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in visceral fat

  21. Total fat mass [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Total fat mass

  22. Total fat free mass [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Total fat free mass

  23. Total lean body mass [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Total lean body mass

  24. Android fat mass [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in Android fat mass

  25. Gynoid fat mass [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in gynoid fat mass

  26. Body weight [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in body weight

  27. Body mass index [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in body mass index

  28. Systemic oxidative stress (RNA) [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in 8-oxo-guanosine

  29. Systemic oxidative stress (DNA) [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in 8-oxo-deoxoguonase

  30. Advanced glycation end-products (AGE) [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in AGE

  31. The circulating receptor for advanced glycation end-products (sRAGE) [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in sRAGE

  32. Markers of low-grade inflammation [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in inflammatory markers (e.g. high sensitive C-reactive protein, interferon-ϒ, interleukin-10, interleukin-8, interleukin-6, interleukin-1, TNFα)

  33. Glycated haemoglobin type 1AC (HbA1c) [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in HbA1c

  34. Total cholesterol [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in total cholesterol

  35. Total triglyceride [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in total triglyceride

  36. Low density lipoprotein (LDL) [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in LDL

  37. High density lipoprotein (HDL) [ Time Frame: From baseline (0 weeks) to follow-up (4, 12 and 16 weeks) ]
    Change in HDL

  38. Systolic blood pressure [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change systolic blood pressures

  39. Diastolic blood pressure [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change diastolic blood pressure

  40. Glucose tolerance [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change incremental and total area under the curve (glucose, c-peptide, insulin) during a mixed meal tolerance test

  41. Gastric emptying (AUC) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in the AUC (paracetamol) during a mixed meal tolerance test

  42. Gastric emptying (Rate of appearance) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in rate of appearance of paracetamol during a mixed meal tolerance test

  43. Physical fitness (VO2max) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in physical fitness (VO2) during a progressive maximal bicycle ergometer test

  44. Muscular 1 repetition max (strength) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in 1 repetition max

  45. Total physical activity [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in objectively measured physical activity (counts per minute)

  46. Moderate and vigorous physical activity (MVPA) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in time spend on MVPA

  47. Sedentary time (SED) [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in time spend on SED

  48. Physical well being [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in physical well being (Based on the physical dimension score from short-form 36, range 0-100)

  49. Mental well being [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in mental well being (Based on the mental dimension score from Short-form 36) (range 0-100)

  50. Satiety [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in self-reported satiety (VAS) during a mixed meal tolerance test (range 0-10)


Other Outcome Measures:
  1. Muscular metabolic function [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in metabolic function (Based on muscle biopsies in a subset of participants, N=16-32))

  2. Fat tissue metabolic function [ Time Frame: From baseline (0 weeks) to follow-up (16 weeks) ]
    Change in metabolic function (Based on muscle biopsies in a subset of participants, N=16-32)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03769883


Contacts
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Contact: Inge Holm +45 35 45 76 41 inge.holm@regionh.dk
Contact: Bente K Pedersen, Dr Med +45 35 45 76 41 inge.holm@regionh.dk

Locations
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Denmark
Center for Physical Activity Research, Copenhagen University Hospital Recruiting
Copenhagen, Denmark, 2100
Contact: Mathias Ried-larsen, PhD    0045 35 45 06 99    mathias.ried-larsen@regionh.dk   
Contact: Inge Holm    0045 35 45 76 21    inge.holm@regionh.dk   
Sponsors and Collaborators
Mathias Ried-Larsen
Investigators
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Principal Investigator: Mathias Ried-Larsen, PhD Centre for Physical Activity Research, Righospitalet

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Responsible Party: Mathias Ried-Larsen, Principal investigator, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT03769883     History of Changes
Other Study ID Numbers: H-18038298
First Posted: December 10, 2018    Key Record Dates
Last Update Posted: December 13, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: If the data can be fully anonymized the data can be shared.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mathias Ried-Larsen, Rigshospitalet, Denmark:
Exercise
Physical Activity
Type 2 diabetes
Pancreatic beta-cell function
Insulin sensitivity
Dose finding
lifestyle

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases