Researchers have identified why living at high altitudes reduces diabetes risk: red blood cells absorb excess glucose in low-oxygen conditions. This metabolic shift lowers blood sugar levels, as shown in mouse experiments. A new drug mimicking this effect reversed diabetes in mice, suggesting potential treatments.
For years, studies have noted lower diabetes rates among people at high elevations, where oxygen is scarce. Scientists at Gladstone Institutes have now pinpointed the mechanism behind this observation.
In low-oxygen environments, known as hypoxia, red blood cells alter their metabolism to absorb large amounts of glucose from the bloodstream. This process turns the cells into efficient "glucose sinks," reducing circulating blood sugar and aiding oxygen delivery to tissues. The findings, published in Cell Metabolism on February 19, 2026, resolve a key question in physiology.
"Red blood cells represent a hidden compartment of glucose metabolism that has not been appreciated until now," said senior author Isha Jain, PhD, 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."
Experiments on mice exposed to low-oxygen air revealed rapid glucose clearance after feeding, with no uptake explained by major organs like muscle, brain, or liver. Instead, imaging showed red blood cells handling the glucose. Under hypoxia, mice produced more red blood cells, each absorbing greater amounts of sugar.
"When we gave sugar to the mice in hypoxia, it disappeared from their bloodstream almost instantly," noted first author Yolanda Martí-Mateos, PhD, a postdoctoral scholar in Jain's lab. "We looked at muscle, brain, liver -- all the usual suspects -- but nothing in these organs could explain what was happening."
Collaborators Angelo D'Alessandro, PhD, from the University of Colorado Anschutz Medical Campus, and Allan Doctor, MD, from the University of Maryland, helped uncover the molecular details. Red blood cells use glucose to produce a molecule that facilitates oxygen release in oxygen-poor conditions.
"What surprised me most was the magnitude of the effect," D'Alessandro said. "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 metabolic benefits persisted for weeks after returning mice to normal oxygen levels. Researchers tested HypoxyStat, a pill developed in Jain's lab that mimics hypoxia by tightening hemoglobin's oxygen binding. In diabetic mouse models, it fully reversed high blood sugar, surpassing standard treatments.
"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 study, titled "Red Blood Cells Serve as a Primary Glucose Sink to Improve Glucose Tolerance at Altitude," was funded by the National Institutes of Health and other organizations.
