Hyperoxic Exercise in Type 2 Diabetes.

Rationale:

Type 2 diabetes patients frequently suffer from physical deconditioning and vascular disease. Although the exact mechanisms are unclear, microvascular changes and endothelial dysfunction appear to inhibit the oxygen transport and uptake in peripheral skeletal muscle of type 2 diabetes patients. Hyperoxic-training has been shown a safe intervention to increase exercise capacity and energy expenditure and is now routinely used for athletes (‘live-high, train-low’) and COPD patients. Furthermore, in COPD patients normalisation of oxygen saturation improves insulin sensivity.



Objective:

This research project aims to investigate (1) whether hyperoxic interval training improves insulin resistance, endothelial dysfunction, cardiovascular fitness, lipid metabolism and glycemic control in the treatment of deconditioned non-insulin dependent type 2 diabetes patients (2) the pathophysiological role of endothelial dysfunction and insulin resistance on the adaptive response to exercise.



Study design:

Substudy 1 (dosefinding study): intervention study;
Substudy 2 (training intervention study): double-blind placebo controlled intervention study.



Study population:

48 deconditioned (non-)insulin dependent type 2 diabetes patients.



Intervention:

After inclusion, 12 patients will participate in the dosefinding study (substudy 1). The remaining 36 subjects will be randomised and blinded to 16 weeks of progressive 30-45 min cycle ergometer interval training, applied 3 times a week while breathing either hyperoxic (100%O2, 4-8 L/min) or normoxic (21%O2-79%N2, 4-8L/min) humidified air (=placebo) through a nasal tube.



Main study parameters/endpoints:

The main study parameter and end-point is the relative improvement in whole-body insulin sensitivity.
Secondary end-points are relative improvements in vascular function parameters using forearm plethysmography, cardiovascular fitness, systemic blood pressure, body composition, lipid metabolism, glycemic control, GLUT-4 expression in the muscle, mitochondrial enzymatic activity and muscle fiber morphologic characteristics.



Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Before inclusion subjects will undergo a physical examination and X-ECG to exclude cardiovascular disease and assess cardiorespiratory status. A group of 12 subjects will undergo a submaximal exercise test while obtaining arteriovenous blood samples to optimize oxygen flow during exercise (substudy 1). The other 36 participating subjects will be asked to attend a total of 48 supervised exercise sessions of 45 min (substudy 2). To minimize the risk for a hypoglycemic event during the first 2 weeks of the exercise intervention, capillary blood glucose will be measured following exercise. If necessary medication will be adjusted. Independent of oxygen concentration in the air mixture, patients are expected to improve their physical fitness and metabolic control. Beside the direct therapeutic effects, both interventions are expected to improve general health and well-being.

Although unlikely, in theory hyperoxic exercise training might worsen diabetes related retinopathy. Therefore, an experienced ophthalmologist will monitor and stage diabetic retinopathy before and after the 16 weeks training program. Dual energy x-ray absorptiometry will be used to assess changes in body composition. Frequently sampled intravenous and forearm venous occlusion plethysmography following intrabrachial infusions of methacholine and sodium nitroprusside will be applied. A muscle biopsy will be obtained from the non-dominant vastus lateralis muscle after local anesthesia in 24 subjects (12 from the control and 12 from the intervention group). To prevent bleeding complications patients using low molecular weight heparin derivates and oral anti-coagulants will be excluded. Furthermore a compressive bandage will be applied for 12 hours. The procedure will be performed under aseptic conditions to prevent infectious complications. Participating subjects will visit the clinical research unit 9 times over a 5 months time period, equivalent to a 22 hours time load. Over a period of 20 weeks multiple arterialised and venous blood samples (equivalent to 258 cc) will be drawn through an intravenous/arterial catheter.

Type 2 diabetes patients frequently suffer from physical deconditioning and vascular disease. Although the
exact mechanisms are unclear, microvascular changes and endothelial dysfunction appear to inhibit the
oxygen transport and uptake in peripheral skeletal muscle of type 2 diabetes patients. Hyperoxic-training has
been shown a safe intervention to increase exercise capacity and energy expenditure and is now routinely
used for athletes (‘live-high, train-low’) and COPD patients. Furthermore, in COPD patients normalisation of
oxygen saturation improves insulin sensivity.

All participants will receive:

1. Interview;

2. Clinical research and blood pressure measurements;

3. Food diary for three days;

4. Carry an activity monitor for seven days (Actigraph accelerationdevice);

5. Exercise ECG during cycle ergometer interval training;

6. Whole body DEXA measurement;

7. Fundus photography;

8. Frequently sampled intravenous glucose tolerance during three hours;

After inclusion, 12 patients will participate in the dosefinding study (substudy 1). The remaining 36 subjects will be randomised and blinded to 16 weeks of progressive 30-45 min cycle ergometer interval training, applied 3 times a week while breathing either hyperoxic (100%O2, 10-15 L/min) or normoxic (21%O2-79%N2, 10-15 L/min) humidified air (=placebo) through mask.