Living at high altitudes may reduce risk of diabetes and other metabolic diseases

For many years, scientists have been puzzled by individuals who live in high-elevation areas throughout the world. Surveys of high-altitude populations, from areas of the Andes to regions of the United States, report lower glucose and diabetes rates.

In addition, there seem to be greater rates of glucose control among these populations compared to those living at sea level. This phenomenon exists not only among humans living in high-altitude environments, but it is also seen among animals that have adapted to high-altitude living conditions.

However, the reason for this phenomenon has remained unknown.

Now, a new study published in Cell Metabolism provides an answer for scientists, but it is not perhaps what one would have expected. The answer appears to be related to a new understanding of red blood cells.

The research team, led by Isha Jain, PhD, includes scientists from the Gladstone Institutes, the Arc Institute, and the University of California, San Francisco (UCSF). The researchers found that when oxygen becomes limited, red blood cells begin to extract excessive amounts of glucose from the blood. This extraction of glucose helps the human body cope with low levels of oxygen, and it can also reduce glucose levels in the blood, possibly explaining the well-documented reduction in diabetes risk among people living at high altitudes.

"Red blood cells represent an unexplored area of glucose metabolism," commented Jain in a news release. "This could provide entirely new ways of approaching the regulation of glucose in the blood."

The findings from the current research add a piece to a long-standing puzzle.

The initial hypothesis for the study was established when the research team observed that when mice were exposed to a hypoxic environment, they exhibited significantly decreased glucose levels in the blood. Additionally, following a meal, the blood glucose levels were rapidly reduced in the animals. This decrease was shown to be correlated with a low risk of developing diabetes.

The researchers had anticipated that the missing glucose would be found in various parts of the body, such as muscle or the liver. However, upon performing imaging scans, the researchers discovered that glucose was not missing from these areas.

According to Dr. Yolanda Martí-Mateos, who was a postdoctoral researcher in Jain’s lab, mice with hypoxia that received sugar had their sugar disappear from the circulation soon after they received it. The team then examined the muscle, brain, and liver, for example, but none of those organs provided an adequate explanation for what they observed.

It was also determined that approximately 70 percent of the additional glucose clearance could not be accounted for.

This led the researchers to look for an explanation outside of traditional sources of metabolic regulation and instead examine cells circulating in the bloodstream itself. While red blood cells, which lack nuclei and mitochondria and have historically been considered to be nothing more than oxygen carriers, may seem like unlikely suspects, they are in fact one of the most abundant types of cells in the body. Their numbers also increase markedly during hypoxic stress.

Experiments demonstrated that preventing the increase of red blood cells during hypoxic stress led to blood glucose levels returning to normal levels. Conversely, when red blood cells were added to subjects breathing normal air, their blood glucose levels decreased.

Thus, the researchers identified their missing "glucose sink."

More than just an increase in the number of red blood cells, the research team found that hypoxia also modifies the way newly formed red blood cells manage glucose.

Specifically, new red blood cells produced in low-oxygen conditions have a greater quantity of glucose transporter proteins, particularly those associated with GLUT1, than those produced in normal conditions. Importantly, while mature red blood cells cannot adjust their glucose transporter protein levels, newly produced red blood cells enter the circulation already primed to take up larger quantities of glucose.

Moreover, when the researchers tracked glucose uptake from red blood cells produced in hypoxic conditions, they found that glucose was taken up approximately 2.5 times more quickly compared to red blood cells produced under normal conditions. Combining the higher number of cells with the findings regarding the amount of glucose removed from the body, the overall effect on blood glucose levels was significant.

The process of converting sugar rapidly to a molecule called 2,3-DPG occurs inside the cells, and this compound facilitates the release of oxygen from hemoglobin to the tissues. This is a major adaptation when the supply of oxygen is low.

According to collaborator Angelo D’Alessandro, PhD, of the University of Colorado Anschutz Medical Campus, “I was really shocked by the magnitude of the effect.” He continued, “Traditionally, red blood cells were thought to be passive carriers of oxygen. Our finding shows they can contribute a significant amount of glucose consumption across the body, especially under hypoxic conditions.”

The researchers also found a rapid change in metabolism. In the presence of adequate oxygen, the enzymes that drive the metabolic processes were attached to the cell membranes and therefore inactive. When oxygen levels dropped, hemoglobin changed molecular structure and caused the release of those enzymes, which allowed glucose metabolism to accelerate over a short time frame. This mechanism was identified in mouse and human cells; therefore, it is likely to be conserved among many different types of organisms.

Now that the mechanism has been established, the research team is working to see whether they can leverage it to develop applications for the treatment of diseases using the enzyme-based mechanisms found in red blood cells.

Three distinct approaches were utilized to reduce blood glucose in mouse models of both type 1 and type 2 diabetes: a low-oxygen environment, a transfusion of additional red blood cells, or administration of the drug HypoxyStat.

HypoxyStat increases hemoglobin's affinity for oxygen, thereby inducing an environment of tissue hypoxia even while breathing ambient air. Using the drug HypoxyStat, researchers were able to return blood glucose levels in mice on a high-fat diet to a normal range and restore glucose tolerance to normal levels.

"The findings from this research open up possibilities for treating diabetes using a completely new approach by using the red blood cells of a person as glucose sinks," Jain stated.

The effects of prolonged hypoxia on glucose levels in the bloodstream lasted more than two weeks after the mice were allowed to return to normal oxygen levels. While blood glucose returned to normal in about two weeks, improved glucose tolerance lasted for more than a month, indicating a long-term impact on the red blood cell population.

The current study has many limitations. The experiments were all performed on young male mice that were of only one strain, and that strain has been shown to have a much higher rate of glucose intolerance than most other strains. Biological differences in the composition of red blood cells between males and females, as well as the age of the mice, will likely have an impact on the study. The research team was unable to determine how glucose would be processed by the mice after it was converted to the 2,3-DPG form.

In addition, other metabolic pathways may play a role in causing blood sugar levels to change in response to chronic hypoxia, such as glycogen breakdown and the absorption of glucose through the intestines.

Nevertheless, the findings from this research explain some previous observations that have been difficult to interpret. For example, people who live at high altitudes tend to have better control over their glucose levels. In contrast, people from the Sherpa community, who have genetic adaptations that limit the number of red blood cells they can produce, have poorer glucose control. Hormonal treatments that increase the number of red blood cells in an individual have also been found to result in improved glucose metabolism.

It is possible that scientists have underestimated the metabolic function of blood itself.

The data indicate that researchers should explore new treatment options for diabetes that do not depend on insulin action. The future of diabetes treatment may lie in methods that increase the number of younger red blood cells in an individual's body or enable their increased sugar uptake without increasing blood viscosity. If ongoing research demonstrates safety, hypoxia-mimicking drugs such as HypoxyStat may be potential candidates for metabolic disease treatment.

Beyond diabetes, the information from this study could be used to inform further investigation into how researchers might improve athletic performance, aid recovery from injury, and help anyone else who relies on oxygen to fuel the body's energy.

Research findings are available online in the journal Cell Metabolism.

The original story "Living at high altitudes may reduce risk of diabetes and other metabolic diseases" is published in The Brighter Side of News.

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