diabetes

For decades, scientists have observed a curious phenomenon: people living at high altitudes exhibit lower rates of type 2 diabetes. Now, researchers at the Gladstone Institutes have uncovered a key mechanism behind this protective effect, revealing that red blood cells dramatically alter their function in low-oxygen environments, effectively acting as “glucose sinks” and absorbing excess sugar from the bloodstream. This discovery, published in the journal Cell Metabolism, could pave the way for novel diabetes treatments that harness the untapped metabolic potential of these vital cells.

The research challenges long-held assumptions about red blood cells, traditionally viewed primarily as oxygen transporters. The team’s findings demonstrate that under hypoxic conditions – those with reduced oxygen levels – red blood cells shift their metabolism to actively consume glucose, not just to fuel their oxygen-carrying capacity, but too to lower overall blood sugar levels. This adaptation appears to be a crucial component of the body’s response to altitude, offering a potential explanation for the observed lower diabetes incidence in high-altitude populations.

“Red blood cells represent a hidden compartment of glucose metabolism that has not been appreciated until now,” explained Isha Jain, PhD, Gladstone Investigator and senior author of the study. “This discovery could open up entirely recent ways to suppose about controlling blood sugar.”

Uncovering the ‘Hidden Glucose Sink’

Jain’s team initially observed the phenomenon while studying the effects of hypoxia on metabolism. Previous research had shown that mice exposed to low-oxygen air exhibited significantly lower blood glucose levels. However, tracking the glucose revealed a surprising result: major organs like the muscles, brain, and liver couldn’t account for the rapid disappearance of glucose from the bloodstream. “When we gave sugar to the mice in hypoxia, it disappeared from their bloodstream almost instantly,” said 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.”

Further investigation using advanced imaging techniques pinpointed red blood cells as the primary consumers of glucose. These cells, previously considered metabolically inert, were revealed to be actively absorbing glucose at a substantial rate in low-oxygen conditions. Experiments confirmed that not only did mice produce more red blood cells in hypoxia, but each individual cell also took up more glucose than under normal oxygen levels.

To understand the underlying mechanisms, Jain collaborated with Angelo D’Alessandro, PhD, of the University of Colorado Anschutz Medical Campus, and Allan Doctor, MD, from University of Maryland. Their research showed that in low-oxygen conditions, glucose is utilized by red blood cells to produce a molecule that enhances their ability to release oxygen to tissues – a critical function when oxygen is scarce. D’Alessandro noted the magnitude of the effect, stating, “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.”

A New Avenue for Diabetes Treatment

The benefits of this metabolic shift appeared to be long-lasting. The researchers found that the positive effects of chronic hypoxia persisted for weeks to months even after mice were returned to normal oxygen levels. Building on these findings, the team tested HypoxyStat, a drug developed in Jain’s lab designed to mimic the effects of low-oxygen air. According to Gladstone Institutes, HypoxyStat works by increasing the affinity of hemoglobin in red blood cells for oxygen, effectively reducing oxygen delivery to tissues. In mouse models of diabetes, HypoxyStat completely reversed high blood sugar, demonstrating even greater efficacy than existing medications.

“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 potential implications extend beyond diabetes. D’Alessandro suggests that these findings could also be relevant to understanding exercise physiology and the metabolic responses to traumatic injury, where shifts in red blood cell levels and metabolism may influence glucose availability and muscle performance. Trauma remains a leading cause of mortality, particularly in younger populations.

“This is just the beginning,” Jain concluded. “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.”

Further research will be crucial to determine the feasibility of translating these findings into effective therapies for humans. The team plans to investigate the long-term effects of manipulating red blood cell metabolism and explore potential strategies for safely and effectively harnessing their glucose-absorbing capacity.

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Disclaimer: The information provided in this article is for general knowledge and informational purposes only, and does not constitute medical advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.