Platelet Metabolism in Diabetes Mellitus

Grants and Contracts Details

Description

Abstract Heart disease and stroke are the No. 1 and 5 causes of deaths in the US. Both Type 1 and Type 2 diabetes mellitus (T1DM and T2DM) significantly increases the risk for heart attacks and strokes. Intense glycemic control has been reported to reduce major cardiovascular events by >30% in T1DM, suggesting that hyperglycemia is one of the major contributors to DM-associated heart attack and stroke risk escalation. However, how hyperglycemia exacerbate such risk is unclear. Platelets are vascular first-responders that activate for hemostasis upon blood vessel damage; whereas pathogenic platelet activation leads to spurious thrombosis and acute vascular obstruction. This proposals aims to understand how hyperglycemia leads to platelet hyperactivity and their increased propensity to form thrombi in DM, and to develop new therapeutic strategies to mitigate DM- associated heart attacks and strokes. Utilizing an integrated metabolism toolkit including state-of-the- art Stable Isotope Resolved Metabolomics (SIRM), we demonstrated critical role of altered platelet metabolism in thrombin-induced platelet activation. Specifically, thrombin stimulation alters platelet metabolism that is centered on glycogen metabolism, pentose phosphate pathway (PPP), and fructose 1,6-bisphosphate (F1,6BP), namely, “the glycogen-PPP-F1,6BP axis”, modulating energy, redox and calcium homeostasis in platelets and leading to their activation. Literature and our compelling preliminary data further reveal that hyperglycemia increases glycogen storage and its mobilization that generates ATP, PPP inhibition, reactive oxygen species (ROS), and intracellular calcium [Ca2+]i, all of which are in line with increased propensity for platelets to activate. Therefore, our overarching hypothesis is that hyperglycemia changes the glycogen-PPP-F1,6BP axis in platelets to drive platelet hyperactivity and thus thrombotic risk in DM. This CCTS UK-WU DRC project will focus on pilot studies addressing two key questions raised by the reviewers of our recent R01 application which scored 29 percentile. In Aim 1, we will determine how F1,6BP regulates [Ca2+]i under normoglycemic and hyperglycemic conditions. In Aim 2, we will determine how hyperglycemia alters glucose uptake, intraplatelet glucose levels, and PPP-mediated ROS regulation. Our team is in a unique position to address our hypothesis, as we possess recognized expertise in metabolism and metabolomics (Qingjun Wang PhD and Matthew Gentry PhD), platelet biology (Sidney Whiteheart PhD), and T1DM (Lisa Tannock MD), and we have strong partnership with the University of Kentucky Metabolomics and Redox Metabolism Cores. Upon completion of the proposed project, we will have acquired additional crucial preliminary data delineating hyperglycemia-induced changes in the glycogen-PPP-F1,6BP axis and supporting a novel mechanism for metabolic dysregulation in platelets to mediate hyperglycemia-induced platelet hyperactivity and thrombosis in DM. Our work will also identify new therapeutic targets for mitigating DM-associated heart attacks and strokes.
StatusFinished
Effective start/end date2/23/1311/30/22

Funding

  • Washington University in St. Louis

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