Prostacyclin (PGI2) and NO attenuate platelet adhesion to the endothelium as well as platelet aggregation. Upon binding of PGI2 to its G-protein-coupled cell surface receptor, an increment in the intraplatelet concentration of cyclic adenosine monophosphate (cAMP) is seen. Contemporaneously, as NO diffuses across the platelet membrane it activates guanylate cyclase and increases cyclic guanosine monophosphate (cGMP) concentrations. These inhibitory pathways culminate in the phosphorylation of cAMP and cGMP-dependent protein kinases and inactivation of myosin light chain kinase involved in platelet aggregation (25, 27). In patients with diabetes, platelets have been shown to have a decreased response to NO and PGI2 inhibitory signals (29).
Increased Advance Glycation End Products and Metabolic Alterations
Advance glycation end products (AGE) are the terminal products of nonenzymatic reaction between glucose and the amino group of proteins. They accumulate at an accelerated rate in the tissues of diabetic patients. Proteins of the platelet membrane are also subject to glycation, which reduces membrane fluidity and alters the lipid membrane dynamics contributing to enhanced platelet hyperfunction (30, 31).
Similarly, hyperglycemia causes an increase in glycated LDL (GlycLDL), which makes this lipoprotein more susceptible to oxidative stress. GlycLDL modifies platelet biology by decreasing NO production and increasing intracellular calcium concentrations as well as inhibiting membrane Na+/K+-adenosine triphosphatase (Na+/K+-ATPase) and Ca2+-ATPase activities (32). Other lipid abnormalities seen in hyperglycemia include glycation of HDL, which enhances HDL clearance, and glycation of Apolipo-protein B that results in impaired recognition of LDL by hepatocyte receptors and prolonged LDL half-life. The resulting lipoprotein profile is that of elevated plasma VLDL, LDL, and lipoprotein(a) and low HDL (33). This metabolic dyslipidemia may, in turn, enhance the sensitivity of platelets to aggregating agents, thereby contributing to the hypercoagulable state in diabetic patients (Fig. 1).
Platelets have been shown to be a target of insulin action as they have functional receptors capable of triggering a phosphorylation cascade in response to insulin. Stimulation through insulin receptors increases intracellular NO, reduces Ca2+, and thus decreases platelet aggregation responses to ADP,
Fig. 1. Oxidative stress in diabetes and mechanisms of platelet activation. AGE advanced glycated end products, ROS reactive oxygen species, LDL low density lipoprotein, PGF2a prostaglandin F 2a [Source: (36)].
thrombin, and collagen (34). In this context, there is a diminished insulin platelet insulin receptor number and binding affinity, which might contribute to platelet hyperreactivity in DM2 (35).
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