Microangiopathy is a major cause of morbidity and mortality in diabetes mellitus,
and its pathogenesis remains poorly understood. Abnormalities of both in vivo and
in vitro haemostasis have been extensively reported, particularly changes in
platelet function have been described in cross-sectional studies, and cause-endeffect relationships have been postulated. It is also suggested that neutrophil
accumulation at sites of inflammation, including vascular endothelium, can induce
tissue damage. Three classes of mediators are particularly likely to participate in
the pathogenesis of neutrophil-mediated vascular injury : granule enzymes,
reactive oxygen metabolites, and products of membrane phospholipids.
The aims of this thesis were to investigate changes in platelet function in insulindependent diabetic patients in relation to glycaemic control, and microvascular
disease in the form of retinopathy. In addition, the changes in platelet function in
non-insulin-dependent diabetic patients at diagnosis, and the effect of glycaemic
control and oral hypoglycaemic therapy were assessed. As a measure of neutrophil
activity, neutrophil elastase was measured in insulin-dependent diabetic patients
with retinopathy. The changes in elastase levels in response to acute insulin-
induced hypoglycaemia in non-diabetic subjects were also evaluated. A further aim
was to measure a marker for free radical activity in insulin-dependent diabetes.
The changes in platelet density, thromboxane production and receptor sensitivity
demonstrated are consistent with platelets from diabetic patients being
hyperaggregable and contributing towards microvascular disease. The increase in
neutrophil elastase levels in insulin-dependent diabetic patients, and the rise in
normals in response to hypoglycaemia are consistent with leucocyte-endothelial
interaction contributing towards diabetic vascular disease. Although, the marker
for free radical activity was not increased in the retinopathic insulin-dependent
diabetic patients studied, it is probable that abnormalities of lipid metabolism
related to free radical activity may still contribute to diabetic vascular disease.
Although good glycaemic control can delay the onset and slow the progress of diabetic
complications, specific therapeutic agents that interfere with haemostasis,
leucocyte function and free radical activity may also have a protective role in the
development of diabetic complications. In addition, use of these agents may also give
greater understanding of the aetiopathogenesis of diabetic microangiopathy.