Abstract
One of the major causes of non-insulin dependent diabetes mellitus is insulin resistance in the
skeletal muscle. Insulin resistant individuals experience skeletal muscle capillary rarefaction and
present a blunted exercise-induced angiogenic response. Furthermore, levels of VEGF (an
important mediator of angiogenesis) are reduced in insulin resistant individuals. Exercise training
can improve skeletal muscle capillarization and the angiogenic potential and physical activity has
also been proven to enhance muscle insulin sensitivity. Increased skeletal muscle capillarization is
associated with improved glucose tolerance and insulin sensitivity however a direct causal
relationship has not previously been established.
The main hypothesis of this thesis was that skeletal muscle capillarization is important for
skeletal muscle glucose uptake and thereby whole-body insulin sensitivity and that an increase in
the number of capillaries in the muscle tissue will improve skeletal muscle glucose uptake.
To test this hypothesis, capillarization was experimentally increased in skeletal muscle of rodents
and humans by use of an α1-adrenergic antagonist (prazosin or terazosin; study I and III) or by
overexpression of VEGF-A in the tibialis anterior muscle (transfection; study II) and the effect
of the increased muscle capillarization on muscle insulin sensitivity was examined.
In study I skeletal muscle specific angiogenesis was induced by administering an α1-adrenergic
antagonist (prazosin) to healthy Sprague-Dawley rats. Whole-body insulin sensitivity was measured
in conscious, unrestrained rats by hyperinsulinemic euglycemic clamp. Tissue-specific insulin
sensitivity was assessed by administration of 2-deoxy-[3H] glucose during the plateau phase of the
clamp. There was a significant increase in skeletal muscle capillarization (17.0±2.0%; EDL and
20.1±2.4%; soleus muscle) and whole-body insulin sensitivity increased by 24.0±5.0%.
In study II obese Zucker rats were transfected with a VEGF-A overexpression vector. The rats
were then subjected to 30 days of swim training (over a period of 6 weeks). After the
intervention period, insulin sensitivity was measured as in study I. VEGF-A transfection caused
a normalization of the VEGF levels in the muscle. VEGF transfection in combination with
training resulted in an increased capillarization (20.7±4.3%) and insulin-stimulated glucose
uptake (124±14%) in the tibialis anterior muscle.
In study III, inactive, overweight human subjects with insulin resistance received an oral dose of
the α1-adrenergic antagonist, terazosin, for 4 weeks. Before and after the intervention, insulin
sensitivity was measured by using a hyperinsulinemic euglycemic clamp. After terazosin
treatment, the capillary to fiber ratio was increased by 12.1±5.2% and whole-body insulin
sensitivity was significantly improved by 23.1±9.8%.
Neither of the three studies, showed enhanced insulin signaling suggesting that the improvement in
insulin-stimulated muscle glucose uptake could be due to improved diffusion conditions for glucose
in the muscle.
The results of this PhD project show that treatment with an α1-adrenergic antagonist increases
capillarization and whole-body insulin sensitivity in both rodents and humans. In addition, the
combination of VEGF-A electrotransfer and training result in increased muscle capillarization
and increased insulin-stimulated glucose disposal in rodent muscle. Combined, the results from
this thesis strongly suggest that an increased capillarization in skeletal muscle improves insulin
sensitivity and point towards the importance of increasing skeletal muscle capillarization for
prevention and treatment of type 2 diabetes.
skeletal muscle. Insulin resistant individuals experience skeletal muscle capillary rarefaction and
present a blunted exercise-induced angiogenic response. Furthermore, levels of VEGF (an
important mediator of angiogenesis) are reduced in insulin resistant individuals. Exercise training
can improve skeletal muscle capillarization and the angiogenic potential and physical activity has
also been proven to enhance muscle insulin sensitivity. Increased skeletal muscle capillarization is
associated with improved glucose tolerance and insulin sensitivity however a direct causal
relationship has not previously been established.
The main hypothesis of this thesis was that skeletal muscle capillarization is important for
skeletal muscle glucose uptake and thereby whole-body insulin sensitivity and that an increase in
the number of capillaries in the muscle tissue will improve skeletal muscle glucose uptake.
To test this hypothesis, capillarization was experimentally increased in skeletal muscle of rodents
and humans by use of an α1-adrenergic antagonist (prazosin or terazosin; study I and III) or by
overexpression of VEGF-A in the tibialis anterior muscle (transfection; study II) and the effect
of the increased muscle capillarization on muscle insulin sensitivity was examined.
In study I skeletal muscle specific angiogenesis was induced by administering an α1-adrenergic
antagonist (prazosin) to healthy Sprague-Dawley rats. Whole-body insulin sensitivity was measured
in conscious, unrestrained rats by hyperinsulinemic euglycemic clamp. Tissue-specific insulin
sensitivity was assessed by administration of 2-deoxy-[3H] glucose during the plateau phase of the
clamp. There was a significant increase in skeletal muscle capillarization (17.0±2.0%; EDL and
20.1±2.4%; soleus muscle) and whole-body insulin sensitivity increased by 24.0±5.0%.
In study II obese Zucker rats were transfected with a VEGF-A overexpression vector. The rats
were then subjected to 30 days of swim training (over a period of 6 weeks). After the
intervention period, insulin sensitivity was measured as in study I. VEGF-A transfection caused
a normalization of the VEGF levels in the muscle. VEGF transfection in combination with
training resulted in an increased capillarization (20.7±4.3%) and insulin-stimulated glucose
uptake (124±14%) in the tibialis anterior muscle.
In study III, inactive, overweight human subjects with insulin resistance received an oral dose of
the α1-adrenergic antagonist, terazosin, for 4 weeks. Before and after the intervention, insulin
sensitivity was measured by using a hyperinsulinemic euglycemic clamp. After terazosin
treatment, the capillary to fiber ratio was increased by 12.1±5.2% and whole-body insulin
sensitivity was significantly improved by 23.1±9.8%.
Neither of the three studies, showed enhanced insulin signaling suggesting that the improvement in
insulin-stimulated muscle glucose uptake could be due to improved diffusion conditions for glucose
in the muscle.
The results of this PhD project show that treatment with an α1-adrenergic antagonist increases
capillarization and whole-body insulin sensitivity in both rodents and humans. In addition, the
combination of VEGF-A electrotransfer and training result in increased muscle capillarization
and increased insulin-stimulated glucose disposal in rodent muscle. Combined, the results from
this thesis strongly suggest that an increased capillarization in skeletal muscle improves insulin
sensitivity and point towards the importance of increasing skeletal muscle capillarization for
prevention and treatment of type 2 diabetes.
| Originalsprog | Engelsk |
|---|
| Udgivelsessted | Copenhagen |
|---|---|
| Forlag | Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen |
| Antal sider | 80 |
| ISBN (Trykt) | 978-87-93476-79-0 |
| Status | Udgivet - 2016 |
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