PXD071719-1

PXD071719 is an original dataset announced via ProteomeXchange.

Title	Red Blood Cells Serve as a Primary Glucose Sink to Improve Glucose Tolerance at Altitude
Description	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 towards 2,3-DPG. Mechanistically, acute hypoxia promotes displacement of 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.
HostingRepository	PRIDE
AnnounceDate	2026-02-23
AnnouncementXML	Submission_2026-02-22_16:12:10.050.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD071719
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Shaun Bevers
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-08 06:46:22	ID requested
⏵ 1	2026-02-22 16:12:11	announced

10.1016/j.cmet.2026.01.019;

Mart, í, -Mateos Y, Safari Z, Bevers S, Midha AD, Flanigan WR, Joshi T, Huynh H, Desousa BR, Blume SY, Baik AH, Rogers S, Issaian AV, Doctor A, D'Alessandro A, Jain IH, Red blood cells serve as a primary glucose sink to improve glucose tolerance at altitude. Cell Metab, 38(3):529-545.e8(2026) [pubmed]

10.6019/PXD071719;

ProteomeXchange project tag: Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project, Extreme Conditions (B/D-HPP)

submitter keyword: Red Blood Cells, Cross-Linking, Hypoxia

Angelo D'Alessandro
contact affiliation	University of Colorado - Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics, Aurora, CO USA
contact email	ANGELO.DALESSANDRO@CUANSCHUTZ.EDU
lab head
Shaun Bevers
contact affiliation	University of Colorado - Anschutz Medical Campus
contact email	shaun.bevers@cuanschutz.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/02/PXD071719

PRIDE project URI

• PRIDE
  1. PXD071719
     1. Label: PRIDE project
     2. Name: Red Blood Cells Serve as a Primary Glucose Sink to Improve Glucose Tolerance at Altitude