Diabetes Mellitus, Type 2, Non-alcoholic Fatty Liver Disease, Obesity
Conditions
Keywords
Magnetic Resonance Spectroscopy, Exercise
Brief summary
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.
Interventions
BEHAVIORALExercise 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.
Sponsors
Dutch Diabetes Research Foundation
Bram Brouwers
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
40 Years to 70 Years
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise | 16 weeks | — |
| Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention | 16 weeks | — |
| Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver | 16 weeks | — |
| 13C-methionine breath test to measure hepatic mitochondrial function | 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. |
| Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Echography of the heart to measure diastolic dysfunction | 16 weeks | — |
| Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention | 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 |
| Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism | 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. |
| Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk. | 16 weeks | — |
Countries
Netherlands
Outcome results
None listed