The Role of Red Blood Cell in Stroke-Related Hyperglycemia

Project Summary/Abstract Acute hyperglycemia following an ischemic stroke is a significant contributor to poor clinical outcome, even though it is temporary. While intensive insulin treatment can correct hyperglycemia, it does not necessarily improve patient outcome, suggesting the presence of early hyperglycemic injuries that are resistant to glucose

control. Red blood cells (RBCs), often overlooked in stroke research, are particularly vulnerable to hyperglycemia due to their exclusive reliance on glucose for energy and limited adaptability to metabolic disturbances in high glucose condition. Our pilot study has identified abnormal RBC indices in stroke patients

experiencing acute hyperglycemia, which, in turn, were predictive of poor stroke outcome. Further analyses revealed that acute hyperglycemia may initiate a shift in RBC glucose metabolism from the pentose phosphate pathway (PPP) towards the hexosamine pathway, potentially resulting in increased oxidative stress within

RBCs. Notably, these RBC changes were unresponsive to glucose normalization, but were able to impair the function of brain endothelial cells, indicating their novel role in acute hyperglycemic injury in ischemic stroke. In this multiple PI project, we aim to investigate the role of RBCs in stroke-related hyperglycemia through

translational research and mechanistic studies. We will characterize acute hyperglycemia-related RBC alterations in clinical stroke patients, with specific focus on RBC glucose metabolism and the consequent oxidative stress (Aim 1). We will then delve deeper into the mechanisms of RBC alterations in in vitro

hyperglycemic models and assess their impact on brain endothelial functions (Aim 2). Finally, we will validate our findings in a well-established acute hyperglycemic stroke mouse model and explore the potential of modifying RBCs to mitigate brain injury and improve stroke outcome in the context of acute hyperglycemia

(Aim 3). Successful completion of this project will yield a comprehensive understanding of the effects of acute hyperglycemia on RBCs and their consequences on vascular function, ultimately translating into enhanced clinical care and patient will-being.