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

Diabetes Mellitus, Type 2 Clinical Trial

— DOSE-EX  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03769883
• Other study ID #: H-18038298
• Status: Recruiting
• Phase: N/A
• Start date: December 12, 2018
• Est. completion date: August 2021

Study information

• Verified date: December 2018
• Source: Rigshospitalet, Denmark
• Contact: Inge Holm
• Phone: +45 35 45 76 41
• Email: inge.holm[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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%.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: August 2021
• Est. primary completion date: August 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus
• Type2 Diabetes
• Type2 Diabetes Mellitus

Intervention

Behavioral:
• Exercise and diet
The participants will undergo diet or combined diet and exercise. The exercise will be provided at different volumes
• Diet
Dietary intervention

Locations

Country	Name	City	State
Denmark	Center for Physical Activity Research, Copenhagen University Hospital	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Mathias Ried-Larsen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Muscular metabolic function	Change in metabolic function (Based on muscle biopsies in a subset of participants, N=16-32))	From baseline (0 weeks) to follow-up (16 weeks)
Other	Fat tissue metabolic function	Change in metabolic function (Based on muscle biopsies in a subset of participants, N=16-32)	From baseline (0 weeks) to follow-up (16 weeks)
Primary	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	Pancreatic beta-cell function (Intention to treat)	As for per protocol	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	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)
Secondary	Glucagon like peptide 1 sensitivity (glucagon)	Change in Glucagon like peptide 1 stimulated glucagon secretion	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Glucagon like peptide 1 sensitivity (insulin)	Change in Glucagon like peptide 1 stimulated insulin secretion	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Arginine sensitivity (insulin)	Change in Arginine stimulated insulin secretion	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Arginine sensitivity (c-peptide)	Change in Arginine stimulated C-peptide secretion	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Arginine sensitivity (glucagon)	Change in Arginine stimulated glucagon secretion	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	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)
Secondary	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)
Secondary	Glucose clearance	Change in Rate of glucose clearance (stable isotope infusion) during steady state hyperglycemia	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Glucose appearance	Change in Rate of glucose appearance (stable isotope infusion) during steady state hyperglycemia	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Time in hypoglycemia	Change in time in hypoglycaemia from min 3 days sensor glucose profiles	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Pancreatic fat	Change in Pancreatic fat	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Hepatic fat	Change in Hepatic fat	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Visceral fat	Change in visceral fat	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Total fat mass	Change in Total fat mass	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Total fat free mass	Change in Total fat free mass	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Total lean body mass	Change in Total lean body mass	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Android fat mass	Change in Android fat mass	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Gynoid fat mass	Change in gynoid fat mass	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Body weight	Change in body weight	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Body mass index	Change in body mass index	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Systemic oxidative stress (RNA)	Change in 8-oxo-guanosine	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	Systemic oxidative stress (DNA)	Change in 8-oxo-deoxoguonase	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	Advanced glycation end-products (AGE)	Change in AGE	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	The circulating receptor for advanced glycation end-products (sRAGE)	Change in sRAGE	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	Markers of low-grade inflammation	Change in inflammatory markers (e.g. high sensitive C-reactive protein, interferon-?, interleukin-10, interleukin-8, interleukin-6, interleukin-1, TNFa)	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	Glycated haemoglobin type 1AC (HbA1c)	Change in HbA1c	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	Total cholesterol	Change in total cholesterol	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	Total triglyceride	Change in total triglyceride	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	Low density lipoprotein (LDL)	Change in LDL	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	High density lipoprotein (HDL)	Change in HDL	From baseline (0 weeks) to follow-up (4, 12 and 16 weeks)
Secondary	Systolic blood pressure	Change systolic blood pressures	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Diastolic blood pressure	Change diastolic blood pressure	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	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)
Secondary	Gastric emptying (AUC)	Change in the AUC (paracetamol) during a mixed meal tolerance test	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	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)
Secondary	Physical fitness (VO2max)	Change in physical fitness (VO2) during a progressive maximal bicycle ergometer test	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Muscular 1 repetition max (strength)	Change in 1 repetition max	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Total physical activity	Change in objectively measured physical activity (counts per minute)	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Moderate and vigorous physical activity (MVPA)	Change in time spend on MVPA	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	Sedentary time (SED)	Change in time spend on SED	From baseline (0 weeks) to follow-up (16 weeks)
Secondary	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)
Secondary	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)
Secondary	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)