Mechanisms responsible for hyperreactivity of platelets in people with diabetes

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Increased expression of the surface GPs Ib and IIb/IIIa has been observed in platelets from subjects with both type 1 and type 2 diabetes (43). GP Ib-IX binds to von Willebrand factor in the subendothelium and is responsible for adherence of platelets at sites of vascular injury. Interaction between GP Ib-IX and von Willebrand factor leads to activation of platelets. Activation of GP IIb/IIIa leads to the binding of fibrinogen and aggregation of platelets. Thus, increased expression of either or both of these two surface glycoproteins is likely to contribute to the increased reactivity that has been observed platelets from people with diabetes.

Winocour and his colleagues have shown an association between decreased membrane fluidity and hypersensitivity of platelets to thrombin (34). Reduced membrane fluidity may be a reflection of increased glycation of membrane proteins. A reduction in membrane fluidity occurs following incubation of platelets in media containing concentrations of glucose similar to those seen in blood from subjects with poorly controlled diabetes. Because membrane fluidity is likely to alter membrane receptor accessibility by ligands, reduced membrane fluidity may contribute to hypersensitivity of platelets. Accordingly, improved glycemic control would be expected to decrease glycation of membrane proteins, increase membrane fluidity, and decrease hypersensitivity.

Intracellular mobilization of calcium is critical in several steps involved in the activation of platelets. Platelets from subjects with type 2 diabetes exhibit increased basal concentrations of calcium (57). Increased phosphoinositide turnover, increased inositide triphosphate production, and increased intracellular mobilization of calcium are evident in response to exposure to thrombin of platelets from subjects with type 2 diabetes (58). The increased concentrations of several second messengers may contribute to the hypersensitivity seen in platelets from diabetic compared with nondiabetic subjects. Additionally, increased production of thromboxane A2 may contribute to the increased platelet reactivity (31,34).

We have found that the osmotic effect of increased concentrations of glucose increase directly platelet reactivity (59). Exposure of platelets in vitro to increased concentrations of glucose is associated with increased activation of platelets in the absence and presence of added agonist. Exposure of platelets to isotonic concentrations of glucose or mannitol increases platelet reactivity to a similar extent (59). Thus, the osmotic effect of hyperglycemia on platelet reactivity may contribute to the greater risk of death and reinfarction that has been associated with hyperglycemia in patients with diabetes and MI (60-62).

Insulin alters reactivity of platelets (63). Exposure of platelets to insulin decreases platelet aggregation in part by increasing synthesis of nitric oxide (NO) that, in turn, increases intraplatelet concentrations of the cyclic nucleotides, cyclic guanosine monophosphate (cGMP), and cyclic adenosine monophosphate (cAMP). Both of these cyclic nucleotides are known to inhibit activation of platelets. Thus, it is not surprising that an insulin concentration-dependent increase in NO production exerts anti-aggregatory effects. Insulin deficiency typical of type 1 diabetes and seen in advanced stages of type 2 diabetes may contribute to increased platelet reactivity by decreasing the tonic inhibition of platelet reactivity otherwise induced by insulin. Furthermore, abnormal insulin signaling may contribute in subjects with type 2 diabetes. Accordingly, the increased resistance to insulin typical of type 2 diabetes may contribute to increased platelet reactivity by decreasing tonic inhibition of platelets that would have been induced otherwise by the high prevailing concentration of insulin.

Constitutive synthesis of NO is reduced in platelets from subjects with both type 1 and type 2 diabetes (64). Thus, tonic inhibition of platelets and insulin-dependent suppression of reactivity may be reduced in subjects with diabetes.

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