Researchers have uncovered a biological quirk that helps explain why people who live at high altitude tend to have lower rates of diabetes: red blood cells act like a sponge for glucose when oxygen is scarce, pulling sugar out of circulation and shifting metabolism to deliver oxygen more efficiently. Lab work in mice, imaging advances, and an experimental drug that mimics the effect back up the idea that oxygen availability changes how blood sugar is handled. The findings point to new directions for treatments, though more research is needed across ages, sexes, and genetic backgrounds.
Scientists at Gladstone Institutes in San Francisco studied how red blood cells behave when oxygen levels fall, and the results flipped a common assumption on its head. Instead of being passive oxygen carriers only, red blood cells in low-oxygen settings take up a lot more glucose, lowering the sugar that floats through the bloodstream. That simple shift offers a plausible explanation for the lower diabetes risk observed in mountain-dwelling populations.
A large epidemiological study of more than 285,000 U.S. adults previously found that people living between 1,500 and 3,500 meters were significantly less likely to have diabetes than sea-level residents, even after accounting for diet, age and ethnicity. Those population patterns set the stage for lab investigators to dig into mechanisms and see what tissues were actually clearing glucose. Skeptics expected liver, muscle, or brain to explain the change, but the trail led elsewhere.
“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, in the press release. That quote captures the core surprise: an overlooked cell type doing metabolic heavy lifting when oxygen is limited. By treating red blood cells as active participants, the team opened up a new angle on how the body manages fuel under stress.
Earlier mouse experiments looking at hypoxia provided the first clues: animals breathing thinner air cleared sugar from their blood almost immediately after a meal, a pattern usually linked to lower diabetes risk. “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 the study’s first author. That forced the researchers to try a different imaging approach and eventually pointed them to the red blood cells themselves.
Under reduced oxygen, the mice not only made more red blood cells but each cell also absorbed far more glucose than it did at normal oxygen levels. The team used alternative imaging to show glucose literally inside circulating red blood cells, removing it from the pool available to other tissues. That mechanism explains both the rapid drop in blood sugar after eating and the link between altitude and lower diabetes prevalence.
To test whether this pathway could be harnessed therapeutically, the researchers developed an experimental compound called HypoxyStat that mimics the high-altitude effect. In lab studies, the drug normalized blood sugar in diabetic mice, offering a proof of concept that targeting red blood cell metabolism could be a route to treatment. The results are promising, but mouse models are only a first step toward human therapies.
The team acknowledged limitations: the experiments used one mouse strain known for sensitivity to blood sugar, and the animal work focused on young male mice to reduce variability. Because age and sex influence red blood cell production and glucose handling, follow-up studies will need to include female and older animals and multiple genetic backgrounds. “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.” The path from unexpected lab finding to safe human treatment is long, but the discovery reframes red blood cells as a dynamic metabolic compartment. For now, the work gives a clear biological explanation for why thin air might protect against high blood sugar, and it points to fresh directions for diabetes research and drug development.
