Red Blood Cells Are Pulling Sugar from Your Blood - and Nobody Noticed Until Now

The epidemiology has been clear for years. People living at high altitudes - where the thinner air means lower oxygen levels - have substantially lower rates of type 2 diabetes than people at sea level. Even modest elevations show the pattern in population data across the United States. Researchers assumed that exercise, diet, or some other lifestyle factor explained the difference. But a Gladstone Institutes team decided to look more carefully at the physiology, and they found something no one was expecting: the answer was in the blood itself.

Red blood cells - the workhorse cells that carry oxygen around the body, cells considered metabolically simple and largely passive - turn out to be a major glucose sink in low-oxygen conditions. They pull sugar from the bloodstream at a rate that accounts for a substantial fraction of the improved glucose tolerance seen in hypoxia. The finding, published in Cell Metabolism, resolves a longstanding puzzle in physiology and opens a different way to think about treating diabetes.

Seventy percent of the glucose was unaccounted for

The investigation began with a numerical problem. Gladstone Investigator Isha Jain, PhD, had shown in a 2023 study that mice breathing low-oxygen air had dramatically lower blood glucose levels. When her team used PET/CT imaging to track where the glucose was going, they could not account for 70% of the increased clearance after analyzing all major organs - muscle, liver, brain. Something else was consuming enormous amounts of glucose, and it was invisible to standard imaging techniques.

"When we gave sugar to the mice in hypoxia, it disappeared from their bloodstream almost instantly," said Yolanda Marti-Mateos, PhD, a postdoctoral scholar in Jain's lab and first author of the paper. "We looked at muscle, brain, liver - all the usual suspects - but nothing in these organs could explain what was happening."

Red blood cells are constantly in motion through the bloodstream, which is exactly why PET scanning cannot track them. The team began to suspect the RBCs themselves were the missing sink.

Confirming the mechanism with old-school experiments

To test the idea, Jain's team used a deliberately simple approach: phlebotomy and transfusion. First, they repeatedly drew blood from hypoxic mice to keep their red blood cell counts at normal levels. That intervention alone was sufficient to normalize blood glucose and eliminate the hypoxic glucose drop - demonstrating that the extra RBCs were responsible for the effect.

Then they did the opposite: transfusing red blood cells into normal mice breathing regular air. Adding more red blood cells was enough to lower blood sugar. The cells themselves, in greater numbers, were pulling glucose out of circulation.

Flow cytometry revealed the molecular mechanism. Red blood cells from hypoxic mice had significantly higher levels of GLUT1, a glucose transporter protein, at the cell surface. But mature red blood cells cannot make new proteins - they have no nucleus. The team discovered that the upregulation of GLUT1 was happening during the cells' development in the bone marrow. Hypoxia programs developing red blood cells to carry more glucose transporters. Once those cells enter circulation, they retain that enhanced glucose uptake capacity for their entire lifespan of several months.

What red blood cells do with the glucose

The glucose absorbed by red blood cells in hypoxia is rapidly converted to a molecule called 2,3-diphosphoglycerate, or 2,3-DPG. This molecule binds to hemoglobin and causes it to release oxygen more readily to tissues - exactly what the body needs when oxygen availability is reduced at altitude.

The switch is governed by a competition at the cell membrane. Under normal oxygen conditions, key glycolytic enzymes - the proteins that run glucose metabolism - are sequestered at the membrane by binding to a protein called Band 3, putting a brake on glucose consumption. When oxygen levels fall, hemoglobin releases its oxygen and changes shape, and deoxygenated hemoglobin outcompetes the glycolytic enzymes for Band 3 binding sites, freeing those enzymes to accelerate glucose metabolism and produce more 2,3-DPG.

"Red blood cells are usually thought of as passive oxygen carriers," said Angelo D'Alessandro of the University of Colorado Anschutz Medical Campus, who collaborated on the study. "Yet, we found that they can account for a substantial fraction of whole-body glucose consumption, especially under hypoxia."

A drug that replicates the effect

Jain's lab had previously developed a molecule called HypoxyStat, designed to make hemoglobin hold onto oxygen more tightly, reducing the oxygen delivered to tissues and inducing a state of local tissue hypoxia without the person having to breathe thin air. When the team tested HypoxyStat in mouse models of diabetes, it completely reversed elevated blood sugar - an effect the researchers describe as working even better than existing diabetes medications in those models.

"This is one of the first uses of HypoxyStat beyond mitochondrial disease," Jain said. "It opens the door to thinking about diabetes treatment in a fundamentally different way - by recruiting red blood cells as glucose sinks."

Important caveats before thinking about human applications

This research was conducted in mice. The mechanism - Band 3 competition, GLUT1 upregulation in hypoxic bone marrow, 2,3-DPG production as a glucose sink - was confirmed in both mouse and human red blood cells in vitro, which suggests conservation across species. But whether HypoxyStat or related strategies would safely and effectively lower blood glucose in people with diabetes requires clinical trials that have not yet been conducted. Tissue hypoxia induced pharmacologically carries potential risks, particularly for organs like the heart and brain that are sensitive to oxygen deprivation, and those risks must be carefully evaluated in humans before therapeutic applications can be considered.

The benefits of chronic hypoxia also persisted for weeks to months after mice returned to normal oxygen in this study - an observation that raises intriguing questions about long-term metabolic programming, but also one that is far from translated to a therapeutic context.