Platelet function in diabetes mellitus : relationships to hyperglycaemia, antidiabetic treatment and microangiopathy

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.

List of scientific papers

I. Yngen M, Ostenson CG, Li N, Hjemdahl P, Wallen NH (2001). Acute hyperglycemia increases soluble P-selectin in male patients with mild diabetes mellitus. Blood Coagul Fibrinolysis. 12(2): 109-16.
https://pubmed.ncbi.nlm.nih.gov/11302472

II. Yngen M, Ostenson CG, Hjemdahl P, Wallen NH (2005). Meal-induced platelet activation in type 2 diabetes mellitus: affects treatment with repaglinide and glibenclamide. [Manuscript]

III. Yngen M, Ostenson CG, Hu H, Li N, Hjemdahl P, Wallen NH (2004). Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation. Diabetologia. 47(3): 537-40. Epub 2004 Feb 13
https://pubmed.ncbi.nlm.nih.gov/14963650

IV. Hu H, Li N, Yngen M, Ostenson CG, Wallen NH, Hjemdahl P (2004). Enhanced leukocyte-platelet cross-talk in Type 1 diabetes mellitus: relationship to microangiopathy. J Thromb Haemost. 2(1): 58-64.
https://pubmed.ncbi.nlm.nih.gov/14717967

V. Yngen M, Norhammar A, Hjemdahl P, Wallen NH (2005). Effects of improved metabolic control on platelet reactivity in patients with type 2 diabetes mellitus following coronary angioplasty. [Manuscript]