Effects of high glucose on platelet activation

Diabetes mellitus (DM) is associated with increased cardiovascular mortality and morbidity, due to diabetic angiopathy. Hyperglycaemia is one of the factors that may cause platelet dysfunction in diabetic patients. This work investigated the mechanisms underlying hyperglycaemia-induced platelet hyperreactivity and its impact in diabetic patients.

The studies involved healthy subjects and type 2 DM patients. Platelet and leukocyte activation and platelet- leukocyte aggregate formation were measured by whole blood flow cytometry. High glucose dose-dependently enhanced Agonist-induced platelet activation in vitro. The enhancement was agonist-specific. High glucose elevated platelet P-selectin expression (reflecting platelet secretion) but not fibrinogen binding (platelet aggregability) in adenosine diphosphate (ADP)stimulated samples, whilst it enhanced both platelet P-selectin expression and fibrinogen binding in thrombin receptor activating peptide (TRAP)-stimulated blood. High glucose also elevated TRAP-, but not ADP-induced platelet-leukocyte aggregate formation. Similar effects were seen with 30 mM L-glucose, sucrose, and galactose. Protein kinase C (PKC) blockade by bisindolylinaleimide I (BIM-I) did not counteract the enhancement of platelet P-selectin expression by high glucose, but abolished the enhancement by high glucose of TRAP-induced platelet fibrinogen binding. Superoxide anion scavenging by superoxide dismutase (SOD) attenuated the enhancement by high glucose of ADP- and TRAP-induced platelet P-selectin expression, but did not influence platelet fibrinogen binding.

The influence of a carbohydrate-rich meal on platelet reactivity was investigated in type 2 DM patients and matched healthy subjects. Platelet activation was measured before and after a standardized meal in an open, randomized, cross-over study of oral antidiabetic treatment with repaglinide and glibenclamide. ADP and the thromboxane A2 (TxA2) analogue U46619 were used as platelet agonists. Measurements were performed on three occasions: at baseline (on diet only), and after six weeks of treatment with either drug. The results revealed that food intake markedly augmented platelet P-selectin expression and platelet-leukocyte aggregation induced by U46619. The meal also slightly enhanced ADP-induced platelet P-selectin expression, but did not influenced platelet activation in unstimulated samples. Similar enhancements of platelet reactivity were, however, not seen in healthy subjects who did not have postprandial hyperglycemia. Both repaglinide and glibenclamide treatment mildly reduced the postprandial hyperglycemia in the patients, but did not attenuate the meal-induced enhancement of platelet reactivity.

In conclusion, high glucose levels enhance platelet reactivity to agonist stimulation through elevated osmolality. This occurs via superoxide anion production that enhances platelet P-selectin expression (secretion), and PKC signalling that enhances TRAP-induced fibrinogen binding (aggregablity). Food intake enhances TxA2- and ADP-induced platelet activation in type 2 diabetic patients but not in healthy subjects, presumably due to postprandial hyperglycemia.

List of scientific papers

I. Sudic D, Razmara M, Forslund M, Ji Q, Hjemdahl P, Li N. (2006). High glucose levels enhance platelet activation: involvement of multiple mechanisms. Br J Haematol. 133(3): 315-22.
https://doi.org/10.1111/j.1365-2141.2006.06012.x

II. Razmara M, Hjemdahl P, Yngen M, Östenson CG, Wallén NH, Li N (2006). Food intake enhances thromboxane receptor mediated platelet reactivity in type 2 diabetic patients but not healthy subjects. [Submitted]