Abstract
Diabetes mellitus is associated with an increased risk of microvascular and
macrovascular complications, such as retinopathy, nephropathy, neuropathy and
atherosclerosis, which account for the increased morbidity and mortality associated
with this disease. There is considerable evidence that these complications are the
result of vascular dysfunction, which is closely related to poor glycaemic control.
This thesis studied the hypothesis that the vascular abnormalities in diabetes are the
consequence of exposure to elevated blood glucose concentrations.
To date the majority of studies of vascular function in diabetes have been performed
using animal models. However, results from such studies have produced conflicting
results and are difficult to relate to the human condition. Therefore, it would be
advantageous if vascular function could be studied in vessels isolated from a human
source. Due to the irregular and unpredictable nature of obtaining human vessels it
was first necessary to develop protocols using animal vessels. Vessel structure was
studied using a combination of histological and immunological techniques and this
was complemented by functional studies using small vessel myography. Preliminary
data demonstrated that storing vessels in a physiological salt solution at 4°C did not
alter endothelial or vascular smooth muscle cell function and therefore human
vessels could be stored for subsequent functional analysis in the knowledge that this
does not adversely affect vascular function. Exposure of rat mesenteric resistance
arteries to elevated glucose had no adverse effect on endothelium-dependent
relaxation. However, a selective attenuation of endothelin-1 (ET-l)-induced
contraction was demonstrated, perhaps indicating alterations in ET-1 receptors.
Relatively few studies have investigated vascular function in human subcutaneous
resistance arteries, hence it was necessary to develop techniques to characterise these
vessels. This investigation demonstrated the existence of three distinct vessel types,
large and small resistance arteries and veins, which can be distinguished on the basis
of physical appearance, differences in response to transmural stretch and functional
reactivity. Furthermore, endothelium-dependent relaxation in human subcutaneous
resistance arteries was shown to be predominately mediated by an endotheliumderived
hyperpolarising factor (EDHF), with little or no contribution from nitric
oxide (NO) or prostacyclin (PGI2). Functional investigations in resistance arteries
isolated from Type 1 and Type 2 diabetic patients demonstrated unaltered
endothelium-dependent and endothelium-independent relaxation. However, there
was a selective alteration in contractile function which was related to the type of
diabetes.
In conclusion, this study has shown that although diabetes is associated with changes
in contractile function there was no evidence of impaired endothelial-dependent
relaxation. The changes seen in vessels from diabetic patients did not mimic those
produced by acute exposure to elevated concentrations of glucose. This suggests that
if the vascular alterations observed in diabetes are due to exposure to high glucose
concentrations in vivo, prolonged exposure (or factors not present in vitro) are
required for abnormalities to develop.
