New research reveals how hypoxia-induced red blood cell adaptation reshapes glycemic control, providing new insights into diabetes biology and potential treatment strategies.

study: Red blood cells serve as the primary glucose sink to improve glucose tolerance at high altitudes. Image credit: nobeastsofierce / Shutterstock

In a recent study published in the journal cell metabolismresearchers found that red blood cells (red blood cells) functions as a major glucose sink under hypoxic conditions, thereby improving systemic glucose tolerance.

Improved hypoxia and glycemic control at high altitudes

Epidemiological observations show that populations living above 3,500 meters above sea level have lower rates of diabetes than those at sea level. High-altitude regions of Tibet, Peru, the United States, and Nepal have consistently shown lower fasting blood glucose levels and improved glucose tolerance. Animals adapted to high altitudes exhibit similar metabolic patterns. At high altitude, glycemic regulation appears to be enhanced despite reduced oxygen availability, creating a physiological paradox.

Short-term hypoxia is known to stimulate glucose uptake in peripheral tissues. However, these effects are temporary. The persistence of improved glycemic control during chronic hypoxia suggests deeper systemic adaptations. The biological mechanisms underlying this sustained effect remain unclear, calling for investigation into whether red blood cells directly contribute to systemic glucose disposal.

Design of a normobaric hypoxic mouse model

To isolate the effects of oxygen deprivation, the researchers used a normobaric hypoxia model in 8-week-old male mice. Animals were maintained for up to 3 weeks in either normoxic (21% oxygen) or hypoxic (8% oxygen, equivalent to altitudes above 5,000 meters). Blood sugar, body weight, glucose tolerance test, and insulin tolerance test were monitored longitudinally.

To determine whether increased red blood cell mass affected blood sugar, the researchers used two complementary strategies. Serial phlebotomy removed 15% of the total blood volume every 3 days to reverse hypoxia-induced polycythemia. In parallel experiments, we transfused packed red blood cells from hypoxic or normoxic donor mice into normoxic recipients.

Glucose uptake was assessed using 2-deoxy-2-.[18F] Fluoro-D-glucose positron emission tomography/computed tomography imaging and stable isotope tracking with uniformly labeled carbon-13 glucose and carbon-13 2-deoxy-D-glucose. Plasma glucose and intracellular metabolites were quantified by liquid chromatography-mass spectrometry. Assessing glucose transporter 1 by flow cytometry (GLUT1) and glucose transporter 4 (GLUT4) Rich in red blood cells. Proteomics and imaging techniques investigated the localization of glycolytic enzymes and their interaction with band 3 proteins under different oxygen conditions.

Hypoxia rapidly lowers blood sugar independent of insulin

Chronic hypoxia resulted in a significant decrease in basal blood glucose levels within 2 days after exposure. Glucose tolerance improved over 1, 2, and 3 weeks and persisted for more than 1 month after the mice returned to normoxic conditions. In contrast, insulin sensitivity was not improved and was transiently reduced under hypoxia. The authors interpreted this decrease as a compensatory response to persistent hypoglycemia rather than enhanced insulin action.

Moderate hypoxia (11% oxygen) and intermittent hypoxia similarly improved fasting blood glucose levels and glucose tolerance, suggesting potential translational relevance. Hepatic gluconeogenesis does not account for the decrease in blood glucose levels, indicating that increased glucose disposal rather than decreased production is responsible for the observed hypoglycemia.

Red blood cells are identified as the major glucose sink

Whole-body imaging revealed that classical glucose-consuming organs such as muscle, liver, heart, and brain account for only a small portion of the increased glucose uptake under hypoxia. This finding suggested the existence of another major glucose consuming compartment.

Under chronic hypoxia, RBC numbers increased nearly two-fold. When serial phlebotomy reversed the erythrocytosis, blood glucose levels normalized, but the improvement in glucose tolerance disappeared. Conversely, transfusion of red blood cells from hypoxic donors into normoxic mice induced hypoglycemia without exposure to hypoxia. These experiments demonstrated that increased RBC abundance is necessary and sufficient to cause hypoxia-associated hypoglycemia in this model.

Enhanced glucose uptake and transporter expression per cell

In addition to increased cell number, individual RBCs under hypoxia showed enhanced glucose uptake capacity. Stable isotope tracing showed faster intracellular accumulation of phosphorylated 2-deoxy-D-glucose. Ex vivo experiments confirmed an approximately 2.5-fold increase in glucose uptake per cell.

Flow cytometry revealed that GLUT1 and GLUT4 expression was upregulated in hypoxic erythrocytes. Biotin labeling experiments showed that newly synthesized RBCs contributed substantially to the increase in GLUT1 abundance, suggesting that erythropoiesis under hypoxia generates a metabolically adapted RBC population.

Metabolic rewiring via the Lübeling-Lapopol shunt

Metabolomic tracking demonstrated that glucose flux in hypoxic erythrocytes is directed to 2,3-diphosphoglycerate production via the Lübeling-Rapoport shunt. Both the level of 2,3-diphosphoglycerate and the isotope labeling rate were increased. This adaptation enhances the release of oxygen from hemoglobin to tissues while increasing glucose consumption. The authors noted that accurate quantitative flux measurements require additional targeted analysis.

Under hypoxic conditions, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Band 3 Inhibitory binding to membrane proteins increases glycolytic flux. This molecular mechanism provided a structural explanation for the promotion of glucose metabolism in red blood cells under hypoxia.

Therapeutic implications in diabetes models

Hypoxia exposure and hypoxic red blood cell transfusion ameliorated hyperglycemia and increased glucose tolerance despite insulin deficiency in a mouse model of type 1 diabetes. In a high-fat diet model of type 2 diabetes, treatment with a drug (HypoxyStat) that increases the oxygen affinity of hemoglobin and induces tissue hypoxia improved blood glucose and glucose tolerance without direct transfusion of red blood cells.

These findings suggest that targeting RBC metabolism or safely mimicking hypoxia-induced red blood cell adaptations may provide a therapeutic approach to hyperglycemic conditions.

Red blood cells as regulators of whole-body glucose metabolism

This study identified RBCs as a previously unrecognized regulator of systemic glucose metabolism. Hypoxia increases RBC production and increases per-cell glucose utilization, allowing RBCs to function as an important glucose sink independent of insulin signaling. Red blood cells improve oxygen supply and reduce circulating glucose levels by metabolizing glucose via glycolysis and the Leubering-Rappoport shunt.

This finding expands our understanding of systemic glucose homeostasis and suggests potential treatment strategies for type 1 and type 2 diabetes. Modulating red blood cell metabolism and exploiting hypoxic adaptation may represent innovative tools in metabolic disease management.