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NCT Number: NCT01317576

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

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.

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Key information

Conditions

Diabetes Mellitus, Type 2 Behavior Body Weight Diabetes Mellitus Digestive System Diseases Endocrine System Diseases Fatty Liver Glucose Metabolism Disorders Liver Diseases Metabolic Diseases Motor Activity Non-Alcoholic Fatty Liver Disease Nutrition Disorders Nutritional and Metabolic Diseases Obesity Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

40 year–70 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

Maastricht University

Maastricht, Limburg, 6200MD, Netherlands

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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.
  • 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.
  • 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
  • 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

  • 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
  • For diabetics:
  • Severe diabetes which requires application of insulin or patients with diabetes-related complications
  • For controls:
  • Liver disease or liver dysfunction (ALAT > 2.5 x increased)

Treatment and study plan

Exercise Intervention

Behavioral

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.

Primary outcomes

  1. Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention

    Time frame: 16 weeks

  2. Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver

    Time frame: 16 weeks

  3. 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.

  4. 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.

  5. Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise

    Time frame: 16 weeks

Secondary outcomes

  1. Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.

    Time frame: 16 weeks

  2. Echography of the heart to measure diastolic dysfunction

    Time frame: 16 weeks

  3. 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

  4. 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.

Sponsors and collaborators

Lead sponsor

Bram Brouwers

Other

Collaborators

  • Dutch Diabetes Research Foundation

Registry information

Important dates

Study start
2011
Primary completion
2015
Study completion
2015
First posted
Mar 17, 2011
Registry last updated
Mar 1, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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