Abstract 016: Glucose Metabolism is Required for Platelet Hyperactivation in a Murine Model of Type 1 Diabetes Mellitus

Abstract

Patients with type 1 diabetes mellitus (T1DM) have increased thrombosis and platelet activation. The mechanisms for platelet hyperactivation in diabetes are incompletely understood. T1DM is accompanied by hyperglycemia, hyperlipidemia, increased inflammation, and an alternated hormonal milieu. In vitro analysis of platelets demonstrates that low glucose reduces platelet activation while hyperglycemic conditions increase platelet activation. We therefore hypothesized that hyperglycemia increases platelet glucose utilization, which directly increases platelet activation to promote thrombosis. To test this hypothesis platelets were isolated from mice treated with streptozotocin (STZ), to induce T1DM and revealed increased glucose uptake and glycolysis along with induction of glucose transporter 3 (GLUT3). Functionally, platelets from STZ-treated mice exhibited increased activation following administration of PAR4 peptide and convulxin. In contrast, platelets isolated from platelet specific (glucose transporter 1 (GLUT1 and GLUT3) double knockout (DKO) mice, which lack the ability to utilize glucose, failed to increase activation in hyperglycemic mice. In addition, diabetic mice displayed decreased survival in a collagen/epinephrine induced pulmonary embolism model relative to non-diabetic controls. In contrast, survival following pulmonary embolism was increased in diabetic DKO mice, relative to non-diabetic controls. Together these data reveal that in a model of T1DM hyperglycemia increases platelet GLUT3 protein expression, glucose metabolism, platelet activation and thrombosis.