High Altitude Protects Against Diabetes by Turning Red Blood Cells Into Glucose Sponges

Living at high altitude appears to protect against diabetes, and scientists have finally discovered the reason. When oxygen levels drop, red blood cells switch into a new metabolic mode and absorb large amounts of glucose from the blood. This helps the body cope with thin air while also reducing blood sugar levels.

For years, researchers have observed that people who live at high elevations, where oxygen is scarce, tend to develop diabetes less often than those at sea level. In the US, people living 1,500m (4,920ft) above sea level are 12 per cent less likely to have diabetes than those living at altitudes below 500m (1,640ft). Although the trend was well documented, the biological explanation behind it was unclear.

Scientists at Gladstone Institutes now say they have identified the reason. Their research shows that in low oxygen environments, red blood cells begin absorbing large amounts of glucose from the bloodstream. In effect, the cells act like sugar sponges under conditions similar to those found on the world's tallest mountains.

In findings published in Cell Metabolism, the team demonstrated that red blood cells can alter their metabolism when oxygen levels drop. This shift allows the cells to deliver oxygen to tissues more efficiently at high altitude. At the same time, it lowers circulating blood sugar, offering a potential explanation for reduced diabetes risk.

According to senior author Isha Jain, PhD, a Gladstone Investigator, core investigator at Arc Institute, and professor of biochemistry at UC San Francisco, the study resolves a longstanding question in physiology. "Red blood cells represent a hidden compartment of glucose metabolism that has not been appreciated until now. This discovery could open up entirely new ways to think about controlling blood sugar."

Jain's lab has spent years studying hypoxia, the term for reduced oxygen levels in the blood, and its effects on metabolism. In earlier experiments, her team noticed that mice exposed to low oxygen air had dramatically lower blood glucose levels. The animals rapidly cleared sugar from their bloodstream after eating, which is typically linked to lower diabetes risk. However, when researchers examined major organs to determine where the glucose was being used, they found no clear answer.

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

Using a different imaging method, the researchers discovered that red blood cells were serving as the missing "glucose sink," meaning they were taking in and using significant amounts of glucose from circulation. This was unexpected because red blood cells have traditionally been viewed as simple oxygen carriers.

Follow up experiments in mice confirmed the finding. Under low oxygen conditions, the animals produced more red blood cells overall, and each individual cell absorbed more glucose compared with cells formed under normal oxygen levels.

To uncover the molecular details behind this shift, Jain's group partnered with Angelo D'Alessandro, PhD, of the University of Colorado Anschutz Medical Campus, and Allan Doctor, MD, from University of Maryland, who has long studied red blood cell biology.

Their work showed that when oxygen is limited, red blood cells use glucose to generate a molecule that helps release oxygen to tissues. This process becomes especially important when oxygen is in short supply. The red blood cells convert the glucose into a molecule that causes them to give up their oxygen more easily. "This ensures that red blood cells can efficiently release what little oxygen they carry into our tissues, helping us survive hypoxia," Martí-Mateos said.

According to Martí-Mateos, "red blood cells born in hypoxia are special, as they possess more glucose transporters than regular blood cells."

"What surprised me most was the magnitude of the effect," D'Alessandro says. "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 researchers also found that the metabolic benefits of prolonged hypoxia lasted for weeks to months after mice were returned to normal oxygen levels.

They then evaluated HypoxyStat, a drug recently developed in Jain's lab that mimics low oxygen exposure. HypoxyStat is taken as a pill and works by causing hemoglobin in red blood cells to bind oxygen more tightly, limiting the amount delivered to tissues. In mouse models of diabetes, the medication completely reversed high blood sugar and outperformed existing treatments.

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

"There's a lot of work to do before any of this reaches patients, but the biology is genuinely encouraging," said Jain.