Diabetes rates are lower in high-altitude environments – scientists may have discovered the reason

Diabetes rates are lower at high altitudes, but researchers aren’t sure why. Now, a new study in mice has revealed a possible explanation. Red blood cells, which play a central role in transporting oxygen throughout the body, may lower blood sugar levels by converting glucose into compounds that help release oxygen to tissues.

If the results can be replicated in humans, it would also suggest that drugs in early stages of development could mimic this pathway.

“This study highlights the important role that red blood cells can play in controlling diabetes,” study lead author Isha Jain, a biochemist at the Gladstone Institute and the University of California, San Francisco, told Live Science. That is the concept we should aim for in the future.

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The higher the altitude, the lower the blood sugar level

It is well known that people living at high altitudes with low oxygen levels, such as the Andes and Himalayas, tend to have lower rates of diabetes, but the reason for this association is not clear. In a 2023 study, scientists observed a similar phenomenon in mice. When the mice were exposed to low oxygen conditions, they developed a condition called “hypoxia,” which occurs when there is insufficient oxygen supply to tissues, and their blood sugar levels also decreased.

However, the loss of glucose could not be explained by the amount of glucose absorbed into muscles and other organs in the scan, and it was not clear where the glucose was going.

From the highlands to the laboratory

To test whether red blood cells were involved in lowering blood sugar levels, the study authors exposed mice to a hypoxic chamber containing 8% oxygen. This mimicked high-altitude air, and another group of mice were kept in air containing 21% oxygen, which mimicked normal atmospheric conditions, Jain said.

After several weeks, both groups of mice were injected with glucose and their blood sugar levels were measured over time. Compared to mice in a normal oxygen environment, mice in hypoxic conditions had a much smaller increase in blood sugar levels, suggesting they were able to remove glucose from the blood more quickly. This effect persisted for several weeks after the animals were returned to normal oxygen levels, suggesting that the hypoxic environment was having a lasting effect on metabolism, the experts said.

The researchers also performed image scans to track how much glucose was being absorbed by major organs and tissues, such as the liver and muscles. However, most of the glucose lost could not be explained. This led us to investigate whether cells in the circulating blood might themselves be consuming glucose.

To further test this idea, they directly manipulated the number of red blood cells. The researchers periodically removed blood from oxygen-deprived mice to keep red blood cell levels near normal, and found that doing so eliminated the hypoglycemic effects of hypoxia. In contrast, transfusion of red blood cells into mice breathing normal air lowered blood sugar levels, suggesting that the number of red blood cells alone was responsible for lowering blood sugar levels.

The researchers then injected the mice with labeled glucose and tracked the glucose in their bodies. They found that red blood cells from anoxic mice absorbed substantially more glucose than red blood cells from comparison mice. Mice under hypoxic conditions rapidly converted glucose into molecules that bind to hemoglobin, the protein in red blood cells that carries oxygen. This bond makes it easier for hemoglobin to release oxygen into tissues when oxygen levels are low.

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Further analysis revealed that red blood cells produced in oxygen-deprived mice also contained high levels of a protein called GLUT1, which sits on cell membranes and helps glucose enter cells. These red blood cells have about twice as much GLUT1 and absorb about three times as much glucose as normal red blood cells. By labeling existing red blood cells before exposing the mice to hypoxic conditions, the researchers confirmed that only new cells generated under hypoxic conditions exhibited these adaptations.

Daniel Tennant, a hypoxia and metabolism researcher at the University of Birmingham who was not involved in the study, said the study shows that in addition to causing an increase in red blood cells, low oxygen environments change the structure of red blood cells so that they consume more sugar.

Lars Kästner, a red blood cell biologist at Germany’s Saarland University who was not involved in the study, noted that thin air is known to increase the number of red blood cells, which facilitates oxygen transport throughout the body. Red blood cells use glucose as fuel. So it’s not surprising that hypoxia leads to lower blood sugar levels, because there are more red blood cells to remove it, he told Live Science.

“From a systemic perspective, this makes a lot of sense,” he said.

This is essentially an “evolutionarily conserved corrective mechanism” to better supply oxygen to the body at high altitudes, Tennant told Live Science.

Sonia Rocha, a biochemist at the University of Liverpool who was not involved in the study, said that at high altitudes, the body increases the number of red blood cells by changing the expression of genes that control metabolism and increasing production of a hormone called erythropoietin, which prompts the bone marrow to produce more red blood cells.

This is why elite athletes train at high altitude for competitions. Their bodies produce more red blood cells, which allows for “more efficient circulation to distribute oxygen to tissues,” she told Live Science.

Diabetic drugs that mimic oxygen deprivation?

In another experiment, the researchers treated mice with HypoxyStat, an experimental compound developed in Jain’s lab that increases the strength with which hemoglobin binds oxygen, preventing its release and mimicking hypoxia. The idea is that mimicking oxygen deprivation with drugs could increase red blood cell counts and help regulate blood sugar levels.

However, Rocha noted that more trials are needed before drugs like HypoxyStat can be tested in humans.

Although red blood cell transfusions are not a practical treatment for diabetes, the authors suggest that the findings suggest potential directions, such as engineering red blood cells to act as better glucose sinks. “This opens the door to thinking about diabetes treatment in a fundamentally different way,” Jain said in a statement.