Institutionen för medicin / Department of Medicine
Abstract
Diabetes mellitus is associated with accelerated atherosclerosis and
increased morbidity and mortality in micro-and macrovascular
complications. The metabolic derangements that accompany diabetes can
adversely influence platelets and vascular endothelial function, which
may contribute to the pathogenesis of diabetic angiopathy. This thesis
aimed to examine the effect of acute and postprandial hyperglycaemia, as
well as the impact of treatment with insulinotropic drugs and improved
metabolic control on platelet function in patients with diabetes
mellitus. The relationship between platelet function and microvascular
complications was also investigated. In addition, platelet function was
related to endothelial and inflammatory markers.
Acute hyperglycaemia, elicited by an oral glucose tolerance test, induced
platelet activation as indicated by elevated plasma levels of soluble
P-selectin in patients with diettreated type 2 diabetes. In a cross-over
study, evaluating the effects of two oral antidiabetic treatments,
platelet hyperreactivity (increased ADP-induced P-selectin expression)
was observed after a carbohydrate-rich meal in type 2 diabetes patients.
Premeal treatment with repaglinide or glibenclamide reduced postmeal
hyperglycaemia, but not the meal-induced platelet activation. Repaglinide
treatment was associated with attenuated platelet and endothelial
activity in the fasting state, but this effect was not related to
glycaemic control or reduced postmeal hyperglycaemia. Platelet function
in the fasting state was similar in wellcontrolled patients with type 2
diabetes, without macrovascular complications and healthy controls, but
the plasma levels of inflammatory markers (e.g. ICAM-1, TNF-alpha) were
significantly elevated in the patients.
Type 1 diabetes was associated with platelet and leukocyte
hyperreactivity to in vitro stimulation, and this was more marked in
patients with microangiopathy. Agonist-induced leukocyte-platelet
cross-talk was enhanced in type 1 diabetes and was correlated to platelet
hyperreactivity in patients with microangiopathy. Furthermore, patients
with type 1 diabetes and microangiopathy had elevations of sCD40L,
Creactive protein and soluble E-selectin in serum, compared to healthy
controls, indicating lowgrade inflammation and vascular endothelial
perturbation.
In well-controlled patients with type 2 diabetes undergoing coronary
angioplasty, platelet reactivity (ADP-induced P-selectin expression) was
reduced in patients with tight glycaemic control compared to patients
with deteriorated glycaemic control at 3 months after coronary
angioplasty.
In conclusion, acute and postprandial hyperglycaemia in type 2 diabetes
as well as microangiopathy in type 1 diabetes are associated with certain
aspects of platelet activation. The insulinotropic drug repaglinide, but
not glibenclamide, attenuates fasting, but not postmeal platelet
reactivity. Improved glycaemic control reduces platelet reactivity in
type 2 diabetes patients undergoing coronary angioplasty. This thesis
also supports the existence of an inflammatory component early on in type
2 diabetic disease, and in type 1 diabetic microangiopathy