Optimizing the Beneficial Health Effects of Exercise for Diabetes: Focus on the Liver!

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by Maastricht University Medical Center
Sponsor:
Collaborator:
Dutch Diabetes Research Foundation
Information provided by (Responsible Party):
Bram Brouwers, Maastricht University Medical Center
ClinicalTrials.gov Identifier:
NCT01317576
First received: March 16, 2011
Last updated: October 23, 2013
Last verified: October 2013
  Purpose

Due to the western lifestyle, correlated with a high calorie intake and low physical activity, obesity is becoming a major health problem. All over the world obesity reaches epidemic proportions. Obesity is closely linked to type 2 diabetes, a multi-factorial disease that increases the presence of multiple health problems. Until now, exercise and dietary intervention seem to be the single most effective interventions to treat obesity and type 2 diabetes mellitus. In obesity and type 2 diabetes, not only fat accumulation in adipose tissue, but also fat accumulation in the peripheral tissues occurs. Fat accumulation in peripheral tissues has been associated with insulin resistance. Exercise seems to have a positive effect on the accumulation of fat in the peripheral tissue and on the insulin sensitivity in type 2 diabetic patients.

In this study we want to investigate if a prolonged exercise training program can lower the intrahepatic lipid content and can improve the metabolism of the liver in type 2 diabetic patients and patients with non-alcoholic fatty liver disease, and to examine if this leads to improvements in metabolic risk markers. To this end, we will include investigation of the effect of exercise on adipose tissue (inflammatory markers and adipocyte size) and skeletal muscle (ex vivo lipid metabolism) to incorporate the effect of exercise on liver, muscle and adipose tissue and to clarify the crosstalk between these tissues in the pathophysiology of type 2 diabetes.


Condition Intervention
Diabetes Mellitus, Type 2
Non-alcoholic Fatty Liver Disease
Obesity
Behavioral: Exercise intervention

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Optimizing the Beneficial Health Effects of Exercise for Diabetes: Focus on the Liver!

Resource links provided by NLM:


Further study details as provided by Maastricht University Medical Center:

Primary Outcome Measures:
  • Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • 13C-methionine breath test to measure hepatic mitochondrial function [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    Subjects will drink a solution of 200ml H2O with 13C-Methionine. The following 2 hours, every 10 minutes a breath sample will be taken and analysed to measure the concentration of 13C in the exhaled breath.

  • Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
    After taking fasting blood samples, a primed constant infusion of glucose is initiated. Plasma glucose levels are clamped at ~5 mmol/L by variable co-infusion of 20 % glucose. Every 5 minutes, blood is sampled for immediate determination of plasma glucose concentration. Glucose infusion rate is adjusted to obtain plasma glucose levels of ~5 mmol/L (euglycemia). A bolus of insulin is then infused. Before and during steady state, substrate oxidation is measured using an indirect calorimeter, which determines metabolic flexibility.

  • Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk. [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Echography of the heart to measure diastolic dysfunction [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
    A small amount of abdominal subcutaneous adipose tissue (~1g) will be collected under local anaesthesia (2% lidocain) using needle biopsy (with the needle connected to a vacuum syringe). Inflammatory markers in the adipose tissue (e.g. IL-6, IL-8, IL-1b, PAI-1, TNFa, CD68, CD163, CD11b, MCP-1, leptin, adiponectin mRNA expression) and adipocyte size will be analysed

  • Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
    . After local anaesthesia (2.0% Xylocain without adrenaline), a 5-mm diameter side-cutting needle will be passed through a 7-mm skin incision, according to the protocol of the Medical Ethical committee of the Academic Hospital and University of Maastricht. The muscle biopsy will be used to measure ex vivo lipid metabolism, muscle mitochondrial density and muscle mitochondrial function.


Estimated Enrollment: 114
Study Start Date: March 2011
Estimated Study Completion Date: March 2014
Estimated Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Healthy control
This group will exist of healthy obese that are matched for BMI and age with the type 2 diabetes group and non-alcoholic fatty liver disease group.
Behavioral: Exercise intervention
Subjects will be training for 12 week, 3 times a week. Two times a week they will perform a 30 minutes bicycle training. Once a week they will perform a 30 minutes resistance training.
Experimental: Non-alcoholic fatty liver disease
This group will exist of people that suffer from non-alcoholic fatty liver disease. They will be matched for BMI and age according to the Type 2 diabetes group
Behavioral: Exercise intervention
Subjects will be training for 12 week, 3 times a week. Two times a week they will perform a 30 minutes bicycle training. Once a week they will perform a 30 minutes resistance training.
Experimental: Type 2 diabetes patients
This group will exist of patients that suffer from type 2 diabetes
Behavioral: Exercise intervention
Subjects will be training for 12 week, 3 times a week. Two times a week they will perform a 30 minutes bicycle training. Once a week they will perform a 30 minutes resistance training.

  Eligibility

Ages Eligible for Study:   40 Years to 70 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. All subjects:

    • Male sex
    • Age 40-70 years
    • BMI 27-35 kg/m2
    • Stable dietary habits
    • Sedentary: No participation in any kind of sports for at least 2 years.
  2. For diabetic patients only:

    • Must be on sulphonylurea or metformin therapy for at least 6 months with constant dose for at least 2 months, or on a dietary treatment for at least 6 months
    • Well-controlled diabetes: fasting plasma glucose concentration ≥ 7.0 mmol/l and < 10.0 mmol/l at the time of screening.
  3. For subjects with non-alcoholic fatty liver disease:

    • Liver fat content ≥ 5,56%, based on the formula of Kotronen et al. and confirmed with MRS.
    • Fasting plasma glucose concentration must be < 7.0 mmol/l
  4. For control subjects:

    • Liver fat content < 5,56%, based on the formula of Kotronen et al. and confirmed with MRS.
    • Normoglycemic according to the WHO criteria (OGTT)

Exclusion Criteria:

  1. All subjects:

    • Female sex
    • Unstable body weight (weight gain or loss > 3 kg in the past three months)
    • Participation in an intensive weight-loss program or in vigorous exercise program during the last year before the start of the study.
    • Active cardiovascular disease. (This will be determined by questionnaires and by screening on medication. Furthermore, all subjects will undergo a physical examination by a medical doctor).
    • Chronic renal dysfunction (creatinine > 2 increased (normal values: 64-104 µmol/l))
    • Use of Thiazolidines (glitazone/rosiglitazone/pioglitazone/troglitazone)
    • Systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg
    • Haemoglobin < 7.5 mmol/l (anaemia)
    • Blood donor
    • Use of medication known to interfere with glucose homeostasis (i.e. corticosteroids), except for diabetic patients.
    • Use of anti-thrombotic medication
    • Claustrophobia and contra-indications for MRI
    • Abuse of alcohol(> 3 units (1unit = 10 gram ethanol) per day)
    • Abuse of drugs
    • Participation in another biomedical study within 1 month before the first screening visit
  2. For diabetics:

    • Severe diabetes which requires application of insulin or patients with diabetes-related complications
  3. For controls:

    • Liver disease or liver dysfunction (ALAT > 2.5 x increased)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01317576

Contacts
Contact: Bram MW Brouwers, M.S. 31433884258 b.brouwers@maastrichtuniversity.nl

Locations
Netherlands
Maastricht University Recruiting
Maastricht, Limburg, Netherlands, 6200MD
Contact: Bram MW Brouwers, M.S.    31433884258    b.brouwers@maastrichtuniversity.nl   
Principal Investigator: Bram Brouwers, M.S.         
Sub-Investigator: Vera Schrauwen-Hinderling, PhD         
Sponsors and Collaborators
Bram Brouwers
Dutch Diabetes Research Foundation
Investigators
Study Director: Patrick Schrauwen, PhD Maastricht University
Principal Investigator: Bram MW Brouwers, M.S. Maastricht University
  More Information

Publications:
Responsible Party: Bram Brouwers, Drs, Maastricht University Medical Center
ClinicalTrials.gov Identifier: NCT01317576     History of Changes
Other Study ID Numbers: MEC 11-3-002
Study First Received: March 16, 2011
Last Updated: October 23, 2013
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Maastricht University Medical Center:
Magnetic Resonance Spectroscopy
Exercise

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

ClinicalTrials.gov processed this record on October 30, 2014