Red blood cells serve as a primary glucose sink to improve glucose tolerance at altitude.

High-altitude conditions improve glucose tolerance and reduce diabetes risk, but the physiological mechanism is not well understood. Using mouse models, we found that hypoxia alone robustly improved glucose tolerance and that the effect persisted for weeks after returning to normal oxygen levels. PET/CT imaging suggested a significant, unknown glucose sink beyond major internal organs. We hypothesized that hypoxia-induced red blood cells (RBCs) serve as this sink. Manipulating RBC numbers through phlebotomy or transfusion directly altered blood glucose, establishing RBCs as necessary and sufficient for this effect. In chronic hypoxia, RBCs showed a sustained ∼3-fold increase in glucose uptake and ∼2-fold increase in GLUT1 protein abundance, specifically in newly synthesized RBCs, which ultimately contributes to increased glycolytic flux toward 2,3-diphosphoglycerate (2,3-DPG). Mechanistically, acute hypoxia displaces GAPDH from inhibitory band 3 binding through competitive interactions with deoxyhemoglobin, thereby boosting glycolytic flux and driving 2,3-DPG production. We also found that hypoxia or our small-molecule hypoxia mimetic, HypoxyStat, rescued hyperglycemia in mouse models of type 1 and type 2 diabetes. Our findings identify RBCs as key regulators of systemic glucose metabolism, highlighting a novel therapeutic approach for hyperglycemic disorders.