Supplemental oxygen to improve the efficiency of exercise training therapy in type 2 diabetes patients.

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 and
(2) the pathophysiological role of endothelial dysfunction and insulin.
resistance on the adaptive response to exercise.


Study design:
double-blind placebo controlled intervention study.
Study population:
36 deconditioned non-insulin dependent type 2 diabetes
patients.


Intervention:
After inclusion, 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 and glycemic control.


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 subgroup of 12 subjects will undergo a
submaximal exercise test while obtaining arteriovenous blood samples to
optimize oxygen flow during exercise. All 36 participating subjects will be
asked to attend a total of 48 supervised exercise sessions of 45 min. 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. 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.

This research project hypothesises that hyperoxic interval training improves whole body insulin resistance, endothelial dysfunction, cardiovascular fitness, lipid metabolism and glycemic control in the treatment of deconditioned non-insulin dependent type 2 diabetes patients.

1. Baseline measurements aftrer inclusion;

2. Endpoint measurements after 16 weeks.

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 (substudy 2).