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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
81
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.
Maastricht University
Maastricht, Limburg, Netherlands
Proton Magnetic resonance spectroscopy to measure the reduction in liver fat content after a training intervention
Time frame: 16 weeks
Magnetic resonance spectroscopy to measure the ATP and Pi concentrations in the liver
Time frame: 16 weeks
13C-methionine breath test to measure hepatic mitochondrial function
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.
Time frame: 16 weeks
Euglycemic-hyperinsulinemic clamp for measurement of insulin sensitivity and metabolic flexibility
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.
Time frame: 16 weeks
Blood sampling to determine the concentration of cardiovascular risk factors in the blood before and after exercise
Time frame: 16 weeks
Peripheral arterial tonometry to measure endothelial function, as a marker for cardiovascular risk.
Time frame: 16 weeks
Echography of the heart to measure diastolic dysfunction
Time frame: 16 weeks
Fat biopsy to measure adipose tissue inflammatory markers and adipocyte size before and after training intervention
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
Time frame: 16 weeks
Muscle biopsy to measure muscle mitochondrial density, muscle mitochondrial function and muscle lipid metabolism
. 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.
Time frame: 16 weeks
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