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.


Eligibility 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)