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

Authors: Trevor P. Fidler, Alex Marti, Katelyn Gerth, Elizabeth A. Middleton, Robert A. Campbell, Matthew T. Rondina, Andrew S. Weyrich and E. Dale Abel

Journal: Diabetes. 2019 Feb 14. pii: db180981. doi: 10.2337/db18-0981. [Epub ahead of print]

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, dyslipidemia, and increased inflammation, in addition to an altered hormonal milieu. In vitro analysis of platelets revealed that normal glucose reduces platelet activation while hyperglycemic conditions increase platelet activation. We therefore hypothesized that hyperglycemia increases platelet glucose utilization, which increases platelet activation to promote thrombosis. Glucose uptake and glycolysis were increased in platelets isolated from mice treated with streptozotocin (STZ), to induce T1DM in concert with induction of glucose transporter 3 (GLUT3). Platelets from STZ-treated mice exhibited increased activation following administration of PAR4 peptide and convulxin. In contrast, platelets isolated from (glucose transporter 1 (GLUT1 and GLUT3) double knockout (DKO) mice, which lack the ability to utilize glucose, failed to increase activation in hyperglycemic mice. Diabetic mice displayed decreased survival in a collagen/epinephrine induced pulmonary embolism model of in vivo platelet activation, relative to non-diabetic controls. Survival following pulmonary embolism was increased in diabetic DKO mice, relative to non-diabetic controls. These data reveal that increased platelet glucose metabolism in vivo, contributes to increased platelet activation and thrombosis in a model of T1DM.

Link to journal online: http://diabetes.diabetesjournals.org/content/early/2019/02/08/db18-0981.long