Living at altitude and less diabetes: red blood cells as a 'glucose sink'

Why this news matters

For years, something curious has been known: people who live at high altitude — in Tibet, the Andes, or elevated areas of the United States — tend to have lower blood glucose (blood sugar levels) and less diabetes than those who live at sea level. The observation was there, but a clear explanation was missing. A new study now offers an unexpected answer, and the protagonist is a cell to which we almost never pay attention in sugar metabolism: the red blood cell.

A long-standing observation without a clear explanation

When we spend several days at high altitude, the number of red blood cells increases significantly; under intense hypoxia (reduced oxygen availability) it can even double. This is the body's way of compensating for the lack of oxygen: more red blood cells carry more oxygen to the tissues. This adaptive phenomenon is well known. What was not understood was why, in addition, these individuals consistently showed lower blood glucose — something also observed transiently in those who spend several weeks above 2,500 metres.

The key experiment: the sugar disappeared 'almost instantly'

"When we administered sugar to mice in hypoxia, it disappeared from their bloodstream almost instantly," explains Yolanda Martí-Mateos, first author of the study published in the journal Cell Metabolism. "We examined the muscles and various organs, but nothing explained what was happening. And, moreover, that sudden disappearance was independent of insulin, which is the hormone that traditionally regulates blood glucose." That detail matters: insulin is the classic pathway for lowering blood sugar, so a mechanism that acts without it is particularly striking.

Red blood cells: unsuspected regulators

The researchers at the Gladstone Institutes and the Arc Institute (United States) then suspected the red blood cells themselves. "They had never been considered regulators of glucose homeostasis. They are composed mainly of haemoglobin and lack a nucleus and mitochondria, so they have relatively few known mechanisms for regulating their metabolism," notes Martí-Mateos.

To test this bold hypothesis they carried out two complementary experiments. On one hand, they prevented the increase in red blood cells during hypoxia by means of blood draws: blood glucose normalised. On the other, they transfused 'extra' red blood cells into mice with normal oxygenation: this alone was sufficient to cause blood glucose to fall. These results demonstrated that red blood cells are necessary and sufficient to explain the sudden drop in blood sugar.

'Glucose sink': more GLUT-1 transporters

To reconstruct the path of sugar inside the red blood cell, the researchers injected 'labelled' glucose molecules and tracked them in real time using mass spectrometry. They discovered that red blood cells function as a genuine 'glucose sink', absorbing sugar from the blood.

However, for sugar to enter the cell it needs a gateway: a glucose transporter called GLUT-1. And here came another surprise: in hypoxia, not only are there more red blood cells, but the newly produced ones also carry more GLUT-1 transporters. Once inside, glucose is converted much more rapidly into 2,3-DPG (2,3-diphosphoglycerate), a molecule that binds to haemoglobin and helps it release oxygen to the tissues. In other words: exactly what the body needs at altitude. A single mechanism achieves two things at once: improving oxygen transport and lowering blood glucose.

A mechanism conserved in humans as well

"This regulatory mechanism was observed in mice, but also in human red blood cells, suggesting that it has been conserved across different species throughout evolution," analyses Martí-Mateos. That point is relevant: it increases the plausibility that what was seen in the laboratory holds meaning for our own physiology.

New avenues for treating diabetes?

"This discovery opens the door to a radically different approach to treating diabetes, by mobilising red blood cells," highlights Isha Jain, co-author of the work. In mice used as models of type 1 and type 2 diabetes, exposure to low oxygen concentrations reversed their hyperglycaemia, and red blood cell transfusions alone were also sufficient to lower their blood sugar levels. The main challenge, the authors acknowledge, is finding a way to enhance the capacity of red blood cells to remove sugar from the blood without increasing their number excessively.

Why caution is essential

It is important to be very clear: this is not a treatment, and it should not be interpreted as an invitation to 'seek out altitude' or to expose oneself to low oxygen in order to lower blood sugar. Increasing the number of red blood cells is not without risk: it can thicken the blood and raise the risk of thrombosis, among other problems. Ascending to high altitude also carries its own risks (altitude sickness). The value of this study is in opening a research avenue, not in providing a prescription.

Clínica Valorian's analysis

We find this an elegant piece of work because it shifts the focus: for decades, the entire narrative around blood sugar centred on the pancreas and insulin. Here an unexpected actor appears — the red blood cell — capable of regulating blood glucose via a completely different pathway. It is a good reminder that physiology still holds surprises, and that the human body's adaptation to extreme environments (such as high altitude) can teach us a great deal about disease.

That said, we keep our feet on the ground: a brilliant mechanism in mice does not equate to a therapy in humans, and the road to the clinic is usually long. In the meantime, what genuinely protects against type 2 diabetes remains well known and within our reach: a balanced diet, regular physical activity, good rest, and medical monitoring when risk factors are present. Science advances; the fundamentals do not change.