Fig. 2.

Platelets and purinergic signaling in diabetes. Platelets release ATP upon stimulation by hyperglycemia or oxidative stress via pannexin 1, which is subsequently degraded to ADP and adenosine (Ado). ATP and ADP activate P2X₁ and P2Y₁ receptors leading to increase in calcium concentration and platelet aggregation. ADP activates P2Y₁₂ receptors resulting in platelet activation and stabilization of platelet aggregation. Activation of P2Y₁₂ receptors positively regulates P2Y₁ receptor-mediated action, while activation of P2Y₁ receptors negatively regulates the effect of P2Y₁₂ receptors. In contrast, Ado exerts inhibitory effects on platelet activation via A_2A and A_2B receptors. Activity of nucleotidase such as nucleoside triphosphate diphosphohydrolase (NTPase), an enzyme that hydrolyzes ATP and ADP, is elevated. Decreased productions of nitric oxide (NO) and prostacyclin (PGI₂) in diabetes stimulate platelet activation. On the other hand, activated platelets further promote vascular injury by increasing oxidative stress and thromboxane A2 (TxA2) production and decreasing NO bioavailability. Black arrows toward up indicate increasing effects, while black arrows toward down indicate decreasing effects