Red Blood Cells as ‘Glucose Sinks’: New Insights into Diabetes & Altitude Research

For years, researchers have observed a curious trend: people living at higher elevations tend to develop type 2 diabetes less frequently than those at sea level. While the correlation was well-established, the underlying biological mechanisms remained a mystery. Now, a team at the Gladstone Institutes has identified a surprising reason – red blood cells appear to act as “glucose sponges” in low-oxygen environments, effectively soaking up excess sugar from the bloodstream. This discovery, published in Cell Metabolism on February 19, 2026, not only explains a longstanding physiological puzzle but also points toward potential new avenues for diabetes treatment.

Red Blood Cells: An Unexpected Role in Glucose Control

The research centers on the body’s response to hypoxia, a state of reduced oxygen levels. As explained by senior author Isha Jain, PhD, a Gladstone Investigator, core investigator at Arc Institute, and professor of biochemistry at UC San Francisco, “Red blood cells represent a hidden compartment of glucose metabolism that has not been appreciated until now.” The team’s work demonstrates that when oxygen levels drop, red blood cells shift their metabolism to actively absorb glucose. This process isn’t simply a byproduct of adapting to low oxygen; it appears to be a deliberate metabolic change.

Initial clues came from experiments with mice. Researchers found that when exposed to low oxygen, mice cleared glucose from their bloodstream much more rapidly than expected. However, examining the usual suspects – muscle, brain, and liver – failed to account for the dramatic drop in blood sugar. “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.”

The breakthrough came with the realization that red blood cells themselves were the missing “glucose sink.” This was unexpected, as red blood cells are traditionally viewed primarily as oxygen carriers, lacking the complex metabolic machinery of other cells. Further experiments confirmed that under low oxygen conditions, animals produced more red blood cells, and each cell absorbed more glucose compared to those formed under normal oxygen levels. You can find more details about the research team and their work at the Gladstone Institutes news page.

How Does It Work? The Molecular Details

To understand the mechanism behind this metabolic shift, Jain’s team collaborated with researchers at the University of Colorado Anschutz Medical Campus and the University of Maryland. Their investigation revealed that in low oxygen conditions, red blood cells utilize glucose to generate a molecule that facilitates oxygen release to tissues. This process becomes particularly crucial when oxygen is scarce, ensuring that vital organs receive adequate oxygen supply. Angelo D’Alessandro, PhD, of the University of Colorado Anschutz Medical Campus, noted the surprising magnitude of the effect: “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.”

This finding builds on previous research into how organisms adapt to low oxygen levels. A 2023 study from Jain’s lab, highlighted by the Arc Institute, demonstrated how metabolism is rewired in response to hypoxia. That earlier work also observed a significant drop in blood glucose, prompting the investigation into the role of red blood cells.

Implications for Diabetes Treatment and Beyond

The researchers also observed that the beneficial effects of prolonged hypoxia persisted for weeks to months after mice were returned to normal oxygen levels. This suggests that the metabolic reprogramming of red blood cells can have lasting effects on glucose control.

Building on this discovery, the team evaluated HypoxyStat, a drug developed in Jain’s lab that mimics the effects of low oxygen exposure. HypoxyStat works by enhancing hemoglobin’s ability to bind oxygen, effectively reducing oxygen delivery to tissues. In mouse models of diabetes, HypoxyStat not only reversed high blood sugar but also outperformed existing treatments. Jain explains, “This is one of the first use of HypoxyStat beyond mitochondrial disease. It opens the door to thinking about diabetes treatment in a fundamentally different way — by recruiting red blood cells as glucose sinks.”

The potential applications extend beyond diabetes. D’Alessandro suggests relevance for exercise physiology, as muscle cells also benefit from increased oxygen delivery, and for managing pathological hypoxia following traumatic injuries. Trauma remains a significant cause of death, particularly among younger individuals, and understanding how red blood cell metabolism impacts glucose availability and muscle performance could be crucial for improving outcomes. You can read more about the initial discovery in a ScienceDaily report.

Understanding Hypoxia and Glucose Metabolism

Hypoxia, or low oxygen levels, triggers a cascade of physiological responses aimed at maintaining oxygen delivery to tissues. While the body’s response to hypoxia is complex, this research highlights a previously underappreciated role for red blood cells. Glucose, a simple sugar, is the primary fuel source for cells. In individuals with diabetes, the body either doesn’t produce enough insulin (a hormone that helps glucose enter cells) or cells become resistant to insulin, leading to high blood sugar levels. The Gladstone Institutes’ research suggests that activating the “glucose sponge” effect in red blood cells could offer a novel approach to lowering blood sugar and improving glucose control.

What Comes Next: From Mouse Models to Human Trials

The findings from this study are promising, but further research is needed to determine whether the same mechanisms operate in humans and whether HypoxyStat or similar drugs can be safely and effectively used to treat diabetes in people. The next steps will likely involve larger animal studies to refine the dosage and delivery of HypoxyStat, followed by clinical trials in humans. Researchers will also need to investigate potential side effects and identify individuals who might benefit most from this type of treatment. The team is also exploring the long-term effects of red blood cell metabolic reprogramming and its potential impact on other health conditions. Ongoing research will also focus on identifying other factors that influence the glucose-absorbing capacity of red blood cells, potentially leading to new strategies for preventing and treating metabolic disorders.