For decades scientists noticed that people who live up in the mountains develop type 2 diabetes less often than those at sea level. The pattern was clear, but the underlying biology remained a mystery—until now.
Researchers at the Gladstone Institutes have uncovered a surprising mechanism: when oxygen is thin, red blood cells start soaking up massive amounts of glucose from the bloodstream. In effect, the cells act like tiny sugar sponges, pulling sugar out of circulation and helping the body stay lean on glucose.
The study, published in Cell Metabolism, demonstrates that red blood cells can re‑wire their metabolism under hypoxic (low‑oxygen) conditions. This shift not only improves oxygen delivery to tissues at altitude but also drops blood‑sugar levels, offering a plausible explanation for the reduced diabetes risk observed in high‑altitude populations.
Red Blood Cells as a Hidden Glucose Sink
Dr. Jain’s laboratory has spent years exploring hypoxia and its metabolic consequences. In mouse experiments, animals breathing low‑oxygen air showed a dramatic plunge in blood glucose after a meal, a hallmark of lower diabetes susceptibility. Yet, the organs examined showed no obvious glucose‑burning activity.
Using a novel imaging technique, the team discovered that the missing glucose was being captured by the red blood cells themselves. Traditionally viewed as passive oxygen carriers, these cells turned out to be active participants in glucose disposal.
Further tests confirmed that hypoxic mice produced more red blood cells, and each cell took up more glucose than its normoxic counterpart. Collaborators from the University of Colorado and the University of Maryland helped pinpoint the molecular pathway: under oxygen scarcity, red cells convert glucose into a compound that releases oxygen more readily to tissues.
"We were astonished by how much glucose the red blood cells could consume," says Dr. D’Alessandro. "It reshapes our understanding of whole‑body glucose balance, especially during hypoxia."
New Angles for Diabetes Therapy
The researchers also noted that the glucose‑lowering effect persisted for weeks after the mice returned to normal oxygen levels. Building on this insight, they tested a drug called HypoxyStat—a pill that mimics low‑oxygen conditions by tightening hemoglobin’s grip on oxygen. In diabetic mouse models, HypoxyStat erased high blood sugar and outperformed several standard treatments.
Dr. Jain highlights the broader potential: "By recruiting red blood cells as glucose sinks, we may be able to tackle diabetes from a completely new angle."
Beyond diabetes, the findings could impact exercise physiology and the response to traumatic injury, where oxygen deprivation and rapid glucose demand often coexist.
Study Funding
This work was supported by multiple National Institutes of Health grants, the California Institute for Regenerative Medicine, the Hillblom Foundation, the W.M. Keck Foundation, and private donor Dave Wentz.