High Altitude & Diabetes: How Red Blood Cells Lower Blood Sugar – New Treatment Hope
- Washington DC: For years, researchers have observed a curious trend: individuals living at high altitudes appear to be less prone to developing type 2 diabetes.
- The research centers around how red blood cells respond to hypoxia – a state of low oxygen levels common at high altitudes.
- “Red blood cells represent a hidden compartment of glucose metabolism that has not been appreciated until now,” explains Isha Jain, PhD, a Gladstone Investigator, core investigator at Arc...
Washington DC: For years, researchers have observed a curious trend: individuals living at high altitudes appear to be less prone to developing type 2 diabetes. Now, scientists at the Gladstone Institutes have pinpointed a key reason why, revealing a surprising role for red blood cells in regulating blood sugar. The findings, published in , in the journal Cell Metabolism, suggest a potential new avenue for diabetes treatment.
The research centers around how red blood cells respond to hypoxia – a state of low oxygen levels common at high altitudes. Traditionally viewed primarily as oxygen carriers, these cells appear to take on a second, crucial function when oxygen is scarce: they begin to absorb glucose directly from the bloodstream, effectively acting as “sugar sponges.”
“Red blood cells represent a hidden compartment of glucose metabolism that has not been appreciated until now,” explains Isha Jain, PhD, a Gladstone Investigator, core investigator at Arc Institute, and professor of biochemistry at UC San Francisco, and senior author of the study. “This discovery could open up entirely new ways to think about controlling blood sugar.”
The Mystery of the Missing Glucose
The team’s investigation began with observations of mice exposed to low oxygen environments. They noticed a dramatic reduction in blood glucose levels in these animals, with sugar disappearing rapidly from the bloodstream after feeding. However, when researchers examined the usual suspects – muscle, brain, and liver – they couldn’t identify where the glucose was being utilized.
“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 study. “We looked at muscle, brain, liver — all the usual suspects — but nothing in these organs could explain what was happening.”
Using advanced imaging techniques, the researchers finally discovered the answer: red blood cells were the missing “glucose sink,” actively taking up and metabolizing significant amounts of glucose.
How Red Blood Cells Become Sugar Sponges
Further investigation revealed the molecular mechanism behind this phenomenon. Under low oxygen conditions, red blood cells alter their metabolism to generate a molecule that aids in oxygen delivery to tissues. This process, however, requires glucose as fuel. Essentially, the cells prioritize oxygen delivery in hypoxic environments, and glucose consumption becomes a necessary byproduct.
Angelo D’Alessandro, PhD, of the University of Colorado Anschutz Medical Campus, who collaborated on the study, was struck by the magnitude of the effect. “What surprised me most was the magnitude of the effect,” he 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.”
Experiments confirmed that animals at higher altitudes produced more red blood cells, and each cell absorbed more glucose compared to those in normal oxygen levels. This suggests a direct link between altitude, red blood cell function, and glucose regulation.
A Potential New Diabetes Treatment
The benefits of this metabolic shift appear to be long-lasting. The researchers found that the positive effects of prolonged hypoxia persisted for weeks to months after mice were returned to normal oxygen levels.
Building on these findings, the team tested HypoxyStat, a drug developed in Jain’s lab that mimics the effects of low oxygen exposure. HypoxyStat works by increasing the affinity of hemoglobin in red blood cells for oxygen, effectively limiting oxygen delivery to tissues. In mouse models of diabetes, the medication not only reversed high blood sugar but also outperformed existing treatments.
“This is one of the first use of HypoxyStat beyond mitochondrial disease,” Jain notes. “It opens the door to thinking about diabetes treatment in a fundamentally different way — by recruiting red blood cells as glucose sinks.”
Beyond Diabetes: Implications for Other Conditions
The potential implications of this research extend beyond diabetes. Researchers suggest that understanding how red blood cells adapt to hypoxia could also be relevant to exercise physiology and the management of traumatic injuries.
D’Alessandro points out that trauma remains a leading cause of death, particularly among younger individuals, and changes in red blood cell production and metabolism could significantly impact glucose availability and muscle performance in these situations. “This is just the beginning. 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,” Jain concludes.