Red Blood Cells Serve as a Primary Glucose Sink to Improve Glucose Tolerance at Altitude

High altitude conditions result in improved glucose tolerance and lower diabetes risk across species, yet the underlying physiological mechanism remains unclear. Using mouse models, we found that hypoxia alone robustly improved glucose tolerance, independent of insulin sensitivity. This effect persisted for weeks after mice returned to normoxia. PET-CT imaging revealed that internal organs explained only a small fraction of increased glucose uptake in hypoxia, suggesting the presence of an unknown glucose sink. We hypothesized that increased glucose tolerance might be linked to the hypoxia-induced increase in red blood cells (RBCs), whose metabolism relies entirely on glucose. Experimental manipulation of RBC numbers through phlebotomy or transfusion directly altered blood glucose levels, demonstrating the necessity and sufficiency of RBCs as primary glucose sinks in hypoxia. Moreover, RBCs produced during systemic hypoxia exhibited a sustained [~]3-fold increase in glucose uptake, rapidly synthesizing the hemoglobin allosteric regulator 2,3-DPG that allows for increased oxygen release in hypoxia. Therapeutically, we demonstrated that both chronic hypoxia and our recently developed pharmacological hypoxia mimetic, HypoxyStat, effectively rescued hyperglycemia in mouse models of type 1 and type 2 diabetes. Our findings identify RBCs as critical regulators of systemic glucose metabolism under hypoxic conditions, illuminating a conserved physiological adaptation and suggesting novel therapeutic avenues for hyperglycemic disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/650365v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@b6e505org.highwire.dtl.DTLVardef@175e720org.highwire.dtl.DTLVardef@198efdborg.highwire.dtl.DTLVardef@1ab2418_HPS_FORMAT_FIGEXP M_FIG C_FIG