Platelet Dysfunction in Type 1 Diabetes: Stressing the Thromboxanes

Overall death from cardiovascular disease (CVD) has declined over the past 20 years; yet, the population with diabetes has seen minimal benefit (1,2). When broken out by diabetes type, individuals with type 1 diabetes mellitus (T1DM) have approximately a 10-fold age-adjusted increased risk of CVD, even higher than that observed in those with type 2 diabetes mellitus (T2DM), with women being more affected then men (3,4). This is in the face of drastically improved insulin therapy regimens over the past decades, suggesting that hyperglycemia itself may not explain this increased CVD. Paradoxically, though, high-quality clinical studies regarding the risks of CVD in T1DM and the potential mechanisms underlying this pathophysiology remain woefully underrepresented as compared with similar studies related to individuals with T2DM, who are known to have persistently elevated platelet reactivity and a depressed inhibitory response to aspirin (5,6). Furthermore, the published studies that do exist are performed variably on pediatric and adult T1DM patients and show highly conflicting results (7–14). Taken together, the current state of the field is a hindrance to the proper care and treatment of individuals with T1DM. A number of risk factors have been proposed to elevate CVD risk in T1DM patients, including hyperglycemia, dyslipidemia, inflammation, oxidative stress, and genetics, among others (3). A significant contributing factor to the diabetic prothrombotic state is the aberrant regulation of antiplatelet-activating mechanisms that normally maintain high levels of inhibitory cAMP to prevent aggregation (1). Molecules directly affecting platelet cAMP production are the arachidonic acid metabolites thromboxane A2 (TXA2) and prostacyclin (PGI2). TXA2 is produced in the platelets themselves and is a positive-feedback mediator of platelet activation, while PGI2 is produced in endothelial cells and is an inhibitor of platelet aggregation (see Fig. 1 for a summary of TXA2 and PGI2 synthetic and signaling pathways in the platelet). In this issue of Diabetes, Zaccardi et al. (15) aim to definitively determine the state of platelet reactivity in adult T1DM patients, the responsiveness of their platelets to aspirin prophylaxis, and the potential mechanisms mediating any platelet dysfunction in T1DM. Study subjects were adult T1DM patients with well-controlled diabetes (mean age 37 years) without any poorly controlled comorbid conditions or pharmaceuticals that could confound interpretation of the results. Baseline characteristics were essentially identical among all of the groups, except for reticulated (immature) platelets, which were slightly lower in the T1DM subjects as compared with the healthy control subjects. The authors found that T1DM subjects, particularly females, had significantly higher thromboxane metabolite (TXM) excretion, a by-product of TXA2 released from activated platelets. The oxidative stress urinary marker, 8-iso-PGF2a, and the vascular endothelial cell dysfunction urinary marker, proteinuria, were also elevated in T1DM patients as compared with healthy individuals. Both of these markers correlated strongly and directly with TXM excretion. The metabolite of endothelial cell–derived antiplatelet PGI2, 2,3-dinor-6-keto-PGF1a, was comparable between T1DM and healthy subjects. Taken together, T1DM subjects show indications of excess TXA2 production, oxidative stress, and endothelial cell dysfunction, potentially setting up an environment that promotes platelet activation. As the platelet activator TXA2 is synthesized by cyclooxygenase 1 (COX-1) in the platelets, the authors wanted to determine if inhibition of COX-1 with aspirin, which is irreversible and semi-selective, could improve T1DM subjects’ platelet reactivity. Following once-daily 100 mg aspirin consumption for 21 days, sera from healthy and T1DM subjects were analyzed for TXB2, a readout of maximal biosynthetic capacity of platelet COX-1, which showed a comparable reduction at 12 and 24 h after treatment in both T1DM and healthy control subjects. Although the 7day recovery kinetics of serum TXB2 and the baselineadjusted urinary TXM from T1DM and healthy subjects were comparable, the amount of TXM in the urine of T1DM patients remained elevated compared with healthy control