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

February 27, 2016 updated by: Bram Brouwers

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.

Study Overview

Study Type

Interventional

Enrollment (Actual)

81

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Limburg
      • Maastricht, Limburg, Netherlands, 6200MD
        • Maastricht University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Male

Description

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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
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
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
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention
Time Frame: 16 weeks
16 weeks
Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver
Time Frame: 16 weeks
16 weeks
13C-methionine breath test to measure hepatic mitochondrial function
Time Frame: 16 weeks
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.
16 weeks
Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility
Time Frame: 16 weeks
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.
16 weeks
Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise
Time Frame: 16 weeks
16 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.
Time Frame: 16 weeks
16 weeks
Echography of the heart to measure diastolic dysfunction
Time Frame: 16 weeks
16 weeks
Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention
Time Frame: 16 weeks
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
16 weeks
Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism
Time Frame: 16 weeks
. 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.
16 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Study Director: Patrick Schrauwen, PhD, Maastricht University
  • Principal Investigator: Bram MW Brouwers, M.S., Maastricht University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2011

Primary Completion (Actual)

November 1, 2015

Study Completion (Actual)

November 1, 2015

Study Registration Dates

First Submitted

March 16, 2011

First Submitted That Met QC Criteria

March 16, 2011

First Posted (Estimate)

March 17, 2011

Study Record Updates

Last Update Posted (Estimate)

March 1, 2016

Last Update Submitted That Met QC Criteria

February 27, 2016

Last Verified

February 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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