Glucose metabolism is essential for platelet function

Patients with diabetes display increased thrombosis and platelet activation. Preliminary metabolomics analysis of platelets from patients with T2DM revealed an accumulation of glycolytic and TCA intermediates relative to healthy controls. In vitrostudies of platelets under hyperglycemic conditions suggest that glucose metabolism may lead to increased platelet activation. Platelets import glucose via two glucose transporters:GLUT1, which is expressed on the plasma membrane, and GLUT3, of which 15% resides on the plasma membrane and the remaining 85% resides on α-granule membranes. Following stimulation, platelet α-granules translocate to the plasma membrane and release their cargo. To better understand the role of glucose metabolism on plateletfunction we generated platelet-specific knockouts of GLUT1 (GLUT1 KO), GLUT3 (GLUT3 KO) and GLUT1+GLUT3 (DKO) using a Pf4 Cre recombinase transgenic mouse crossed to mice that harbor floxed GLUT3 or GLUT1 alleles. Generation of these mouse models allowed us to test the hypothesis that glucose metabolism is essential for platelet function. We found that GLUT3 not only facilitates platelet activation-mediated glucose uptake, but it also facilitates glucose uptake into α-granules under basal conditions. These data indicate that GLUT3-mediated α-granule glucose uptake is essential for platelet activation, degranulation,and deletion of GLUT3 in platelets leads to increased survival in a collagen/epinephrine-induced pulmonary embolism model.Deletion of both GLUT1 and GLUT3 (DKO) in platelets results in the complete inhibition of glucose uptake and glycolysis. DKO mice displayed thrombocytopenia (~33% reduction), decreased circulating platelet t1/2and had an impaired abilityto increase platelet production following treatment with antiserum. Additionally, DKO platelets had a significantly reduced ability to activate and mobilize calcium in response to multiple agonists, release α-granules, and demonstrated impaired activation of thrombosis in vivo. Together these data indicate that glucose metabolism is essential for platelet production, maintenance, activation, and in vivo thrombosis.