People who live at high altitude have long been known to have lower diabetes rates. A new study explains why, pointing to red blood cells as powerful sugar sponges and hinting at a new class of diabetes drugs.
People who live in thin mountain air have a surprising health advantage: they are less likely to develop diabetes than people at sea level. A new study from Gladstone Institutes in San Francisco may finally explain why — and it points to an unexpected player in blood sugar control.
Researchers report that in low-oxygen conditions, like those found at high altitude, red blood cells shift gears and start soaking up glucose from the bloodstream. That not only helps them deliver oxygen more efficiently throughout the body, but also lowers blood sugar in the process.
The work, published in the journal Cell Metabolism, suggests that red blood cells act as a kind of hidden sugar sponge when oxygen is scarce. Over time, that effect could help protect against diabetes, a chronic disease that affects hundreds of millions of people worldwide.
Senior author Isha Jain, a Gladstone investigator, a core investigator at Arc Institute and a professor of biochemistry at UC San Francisco, has spent years studying how low oxygen — a state known as hypoxia — changes the body’s metabolism. Earlier experiments in mice hinted that something unusual was happening.
When mice were kept in low-oxygen air, their blood sugar levels dropped sharply. After a meal, they cleared glucose from their blood much faster than normal, a pattern associated with lower diabetes risk. But when Jain’s team used imaging tools to track where the sugar was going, the usual organs did not add up.
First author Yolanda Martí-Mateos, a postdoctoral scholar in Jain’s lab, recalls how puzzling the early data were.
“When we gave sugar to the mice in hypoxia, it disappeared from their bloodstream almost instantly,” she said in a news release. “We looked at muscle, brain, liver—all the usual suspects—but nothing in these organs could explain what was happening.”
Using a different imaging approach, the researchers finally spotted the missing destination: red blood cells. These cells, best known for carrying oxygen, had long been considered metabolically simple. They were not expected to be major players in how the body uses sugar.
The new experiments told a different story. In low-oxygen conditions, mice produced more red blood cells, and each of those cells took up more glucose than red blood cells made under normal oxygen levels. In other words, the cells themselves became a powerful “glucose sink,” a term scientists use for tissues that pull large amounts of sugar out of circulation.
Jain and her colleagues then teamed up with red blood cell experts Angelo D’Alessandro at the University of Colorado Anschutz Medical Campus and Allan Doctor at the University of Maryland, to dig into the molecular details.
They showed that under hypoxia, red blood cells use the extra glucose to make a molecule that helps them release oxygen more easily to tissues. That adaptation is crucial when oxygen is scarce, such as at high altitude or in certain diseases. The bonus is that, as they do this, the cells also lower blood sugar.
The scale of the effect was unexpected.
“What surprised me most was the magnitude of the effect,” D’Alessandro said in the news release. “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 findings overturn a long-standing assumption about how the body manages glucose.
“Red blood cells represent a hidden compartment of glucose metabolism that has not been appreciated until now,” added Jain. “This discovery could open up entirely new ways to think about controlling blood sugar.”
To see how durable the effect might be, the scientists followed mice after they were returned from low-oxygen conditions to normal air. The benefits of chronic hypoxia — better blood sugar control and enhanced glucose uptake — persisted for weeks to months, suggesting that the body’s adaptations are not fleeting.
The team then tested whether they could mimic high-altitude biology with a pill instead of a mountain. They turned to HypoxyStat, a drug recently developed in Jain’s lab to recreate some of the effects of low-oxygen air.
HypoxyStat works by making hemoglobin, the oxygen-carrying protein in red blood cells, hold onto oxygen more tightly. That means less oxygen reaches tissues, tricking the body into behaving as if it were at altitude.
In mouse models of diabetes, HypoxyStat did more than just nudge blood sugar in the right direction. According to the study, the drug completely reversed high blood sugar and performed even better than existing diabetes medications in those animals.
Jain notes that this is an early but important test of the drug outside its original purpose.
“This is one of the first use of HypoxyStat beyond mitochondrial disease,” she said. “It opens the door to thinking about diabetes treatment in a fundamentally different way—by recruiting red blood cells as glucose sinks.”
If the approach holds up in further studies and eventually in humans, it could represent a new class of diabetes therapies that tap into the body’s own oxygen-sensing and red blood cell systems, rather than targeting the pancreas or liver alone.
Beyond diabetes, the researchers say the discovery could have implications for exercise science and trauma care. In intense exercise or after serious injury, oxygen levels in tissues can drop, and red blood cell numbers and metabolism can change. Understanding how those shifts affect glucose availability and muscle performance could help doctors better manage recovery and athletes optimize training.
For now, the work adds a new chapter to the story of how the body adapts to life with less oxygen — and how those adaptations might be harnessed to fight disease.
Jain emphasizes that many questions remain.
“This is just the beginning,” she 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.”
Source: Gladstone Institutes