Red Blood Cells Act as Glucose Sponges at High Altitude, Lowering Diabetes Risk

Scientists have explained why people living at high altitudes have lower rates of diabetes than those at sea level, discovering that red blood cells act as glucose sponges in low-oxygen conditions. The findings, published in the journal Cell Metabolism in 2026, reveal a previously unappreciated mechanism of glucose metabolism.

Researchers at Gladstone Institutes in San Francisco showed how red blood cells can shift their metabolism to soak up sugar from the bloodstream. At high altitude, this adaptation fuels the cells' ability to more efficiently deliver oxygen to tissues throughout the body, but it also has the beneficial side effect of lowering blood sugar levels.

"Red blood cells represent a hidden compartment of glucose metabolism that has not been appreciated until now," said senior author Isha Jain, a Gladstone investigator and professor of biochemistry at UC San Francisco. "This discovery could open up entirely new ways to think about controlling blood sugar."

The research builds on established observations of decreased diabetes incidence at high altitude. A previous study of over 285,000 adults in the United States found that people living at high altitudes (1,500-3,500 meters) were significantly less likely to have diabetes than those living at sea level, even after adjusting for factors like diet, age and ethnicity. Between the 1920s and 1940s, the Harvard Fatigue Laboratory observed improved glucose tolerance in healthy volunteers who were transported to the Chilean Andes at altitudes of up to 6,000 metres.

During previous experiments, researchers noticed that mice breathing low-oxygen air had dramatically lower blood glucose levels than normal. When they gave sugar to the mice in hypoxia, it disappeared from their bloodstream almost instantly. "We looked at muscle, brain, liver—all the usual suspects—but nothing in these organs could explain what was happening," said Yolanda Martí-Mateos, a postdoctoral scholar in Jain's lab and first author of the study.

Using PET/CT imaging, the team revealed that red blood cells were the missing "glucose sink." In low-oxygen conditions, mice not only produced significantly more red blood cells, but each cell took up more glucose than red blood cells produced under normal oxygen. Manipulation of RBC numbers directly altered blood glucose, leading researchers to identify hypoxia-induced RBCs as the primary glucose sink.

The researchers showed how, in low-oxygen conditions, glucose is used by red blood cells to produce a molecule that helps cells release oxygen to tissues—something that's needed in excess when oxygen is scarce. "What surprised me most was the magnitude of the effect," said Angelo D'Alessandro of the University of Colorado Anschutz Medical Campus. "Red blood cells are usually thought of as passive oxygen carriers. Yet, we found that they can account for a substantial fraction of whole-body glucose consumption, especially under hypoxia."

The scientists demonstrated that the benefits of chronic hypoxia persisted for weeks to months after mice returned to normal oxygen levels. Hypoxia alone was found to robustly improve glucose tolerance and the effect persisted for weeks after return to normal oxygen levels.

Researchers tested HypoxyStat, a drug recently developed to mimic the effects of low-oxygen air. HypoxyStat is a pill that works by making hemoglobin in red blood cells grab onto oxygen more tightly, keeping it from reaching tissues. The drug completely reversed high blood sugar in mouse models of diabetes, working even better than existing medications. The therapy completely abolished high-fat diet induced hyperglycaemia in diabetic mice.

"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."

The researchers acknowledged some limitations with the study. Only young male mice were studied, limiting generalisability. Because age and sex significantly impact how red blood cells are produced, more research is needed to determine whether these findings hold true for females and older populations. The research focused on one specific mouse strain known for its sensitivity to blood sugar.

Whilst researchers evidenced that upregulation of glucose transporters is specific to hypoxia-induced RBCs, the molecular mechanism by which this occurs was not found.

The findings could extend beyond diabetes to exercise physiology or pathological hypoxia after traumatic injury, where trauma remains a leading cause of mortality in younger populations and shifts in red blood cell levels and metabolism may influence glucose availability and muscle performance.

"This is just the beginning," Jain said. "There's still so much to learn about how the whole body adapts to changes in oxygen, and how we could leverage these mechanisms to treat a range of conditions."