Bold claim: living high up may lower your risk of diabetes and other metabolic diseases. But the full story is more nuanced and surprisingly intricate.
In recent years, researchers have been intrigued by people living at tall elevations around the world. Surveys consistently show that high-altitude populations—from the Andes to certain regions in the United States—tend to have lower blood sugar levels and lower diabetes rates. There’s also some evidence that glucose control works more effectively for these groups compared with communities at sea level. This pattern isn’t limited to humans; animals adapted to thin air also appear to share it. Yet, the reason behind this trend has remained elusive—until now.
A new study published in Cell Metabolism brings us closer to an explanation, though the answer might not be what readers expect. The researchers suggest a key role for red blood cells (RBCs) in how the body handles glucose under low-oxygen (hypoxic) conditions. Led by Isha Jain, PhD, the team includes scientists from the Gladstone Institutes, the Arc Institute, and UCSF. Their findings indicate that when oxygen is scarce, red blood cells start pulling more glucose from the bloodstream. This glucose uptake helps tissues cope with hypoxia and may also lower blood glucose overall, potentially shedding light on the reduced diabetes risk seen in high-altitude residents.
To many, red blood cells are simply oxygen carriers without nuclei or mitochondria. But this study reveals they may be active players in glucose metabolism, especially under stress from low oxygen. Jain notes that red blood cells represent an underexplored area of glucose regulation and could open up entirely new approaches to managing glucose in the blood.
How the mystery unfolded
The project began when scientists observed that hypoxic exposure in mice led to markedly lower blood glucose, and meals shortly after hypoxia led to rapid blood glucose suppression. They initially expected the missing glucose to be sequestered in organs like muscle or liver. Yet imaging showed those organs didn’t account for the drop.
Dr. Yolanda Martí-Mateos, a postdoc in Jain’s lab, described the puzzling finding: mice under hypoxia who were given sugar exhibited a quick removal of that sugar from the bloodstream. Despite checking tissues such as muscle, brain, and liver, the team couldn’t pinpoint the usual suspects responsible for clearing the excess glucose. They discovered that roughly 70 percent of the additional glucose clearance remained unexplained by traditional pathways.
This led them to consider circulating cells—the red blood cells themselves—as potential glucose sinks. RBCs are plentiful and increase in number during hypoxic stress, making them plausible contributors. Experiments showed that preventing the rise in RBCs during hypoxia kept blood glucose at normal levels, while adding RBCs to subjects breathing normal air lowered glucose levels.
RBCs as a glucose sink
The researchers thus identified a previously hidden mechanism: during hypoxia, there’s not only more RBCs, but the new RBCs produced in low-oxygen conditions carry more glucose transporter proteins—particularly GLUT1—than those formed under normal conditions. Mature RBCs can’t rapidly adjust transporter levels, but newly formed RBCs entering circulation are already primed to take up more glucose.
Further, glucose uptake from hypoxia-produced RBCs occurred about 2.5 times faster than from RBCs formed under normal oxygen levels. When you combine more RBCs with a higher glucose-uptake capacity, the overall effect on blood glucose becomes substantial.
A rapid metabolic adaptation under low oxygen
A key part of the story involves 2,3-DPG, a molecule that forms quickly inside RBCs and helps release oxygen from hemoglobin to tissues when oxygen is scarce. The study found that under hypoxia, enzymes that drive glucose metabolism detach from RBC membranes and accelerate glucose processing in a matter of minutes to hours, a response observed in both mouse and human cells. This suggests the mechanism could be conserved across many organisms.
These insights open doors to potential therapies. In mouse models of both type 1 and type 2 diabetes, the team tested three strategies to lower blood glucose: exposing animals to low-oxygen environments, transfusing more RBCs, or using a drug called HypoxyStat. HypoxyStat increases hemoglobin’s affinity for oxygen, creating a tissue-hypoxia state even when air is normal. With HypoxyStat, high-fat-diet mice showed normalized blood glucose and improved glucose tolerance.
In Jain’s view, this research points to a novel way to treat diabetes by turning the person’s own red blood cells into glucose sinks, rather than relying solely on insulin pathways. The team notes that some effects persisted beyond the hypoxia period, with improved glucose tolerance lasting longer than two weeks after normal oxygen levels resumed.
Limitations and questions
Despite its promise, the study has notable limitations: it used young male mice of a single strain, which may not fully reflect broader biology. Sex, age, and genetic differences could alter how red blood cells regulate glucose. The team also hasn’t fully clarified how glucose is processed after conversion to 2,3-DPG. Other metabolic pathways—like glycogen breakdown or intestinal glucose absorption—might also contribute to the observed changes.
Nevertheless, the findings help explain some long-standing observations. For instance, high-altitude residents often show better glucose control, while populations with genetic adaptations that limit RBC production (like certain Sherpa groups) may exhibit poorer control. Hormonal treatments that raise RBC numbers have been linked to improved glucose metabolism as well.
What this could mean for the future
The study challenges the notion that red blood cells are mere oxygen carriers and suggests the blood itself has metabolic capabilities worth leveraging for disease treatment. If safety and efficacy are established, strategies that increase the number of younger RBCs or enhance their glucose uptake without raising blood viscosity could become new avenues for metabolic therapies, including diabetes. Hypoxia-mimicking drugs like HypoxyStat may be among potential candidates if proven safe.
Beyond diabetes, these insights could inform approaches to improve athletic performance, speed up recovery from injury, and support anyone who relies on oxygen to fuel bodily energy.
For those curious to read the full details, the study is available in Cell Metabolism.
Would you find it surprising if your blood cells themselves could directly regulate your blood sugar? Do you think this red-blood-cell-centric view could change how we approach diabetes treatment, or do you worry about unintended consequences of manipulating blood oxygen signals? Share your thoughts in the comment section.
