Hypoxia Remedy Might Assist Management Diabetes, Preclinical Examine Suggests

Low oxygen reduces blood sugar by promoting glucose uptake in red blood cells in mice, offering potential therapeutic approaches for diabetes.

Around the world, more than two million people live at elevations of 4,500 meters or higher—over half the height of Mount Everest.¹ While the crisp mountain air may be pollution-free, it also carries significantly lower oxygen levels compared to that at sea level.

To investigate how such hypoxic conditions affect mammals, Isha Jain, a biochemist at the Gladstone Institutes, utilizes mouse models. In 2023, Jain and her team found that mice rewire their metabolism resulting in reduced blood sugar when exposed to hypoxia.² Epidemiological data revealed a similar pattern: People living at even modest elevations had lower blood glucose, better glucose tolerance, and reduced diabetes risk.³

Now, Jain and her team discovered that red blood cells (RBCs) in animals exposed to hypoxia absorb and use glucose from the blood, reducing levels of the circulating molecule.⁴ Their findings, published in Cell Metabolism, highlight RBCs as glucose metabolism regulators, offering potential therapeutic approaches for hyperglycemic disorders such as diabetes.

Jain and her team started off by testing glucose levels in mice housed at various oxygen concentrations. Compared to mice exposed to normal oxygen (normoxic) levels, those under hypoxic conditions showed reduced blood glucose and improved glucose tolerance. PET scans to track labeled glucose revealed that internal organs did not absorb more glucose in hypoxic animals, indicating that something else was taking up glucose during hypoxia.

The researchers hypothesized that RBCs played a role since hypoxia increases the abundance of these cells, which also show increased breakdown of glucose through the glycolytic pathway under these conditions. Jain and her team transfused RBCs from mice housed under different oxygen levels into recipient mice maintained in normal oxygen levels. Mice that received hypoxic RBCs showed reduced blood glucose, indicating that RBCs regulate hypoxia-induced glucose levels.

To test whether RBCs from hypoxic mice absorb more glucose, Jain and her team injected labeled glucose into mice. Tracking the label revealed that glucose accumulated within the RBCs more rapidly in hypoxic mice compared to those housed under normal oxygen concentrations.

The researchers then sought to understand how oxygen stress rewired glucose metabolism. Other scientists had previously hypothesized that during normoxia glycolytic enzymes get sequestered at RBC membranes, reducing glycolysis. A drop in oxygen levels triggers deoxyhemoglobin to come to the RBC membrane and displace the glycolytic enzymes there, releasing the enzymes into the cytosol to promote glycolysis.

Consistent with this, Jain and her team observed that glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key glycolytic enzyme, localized to the cell membrane in cultured normoxic RBCs while hypoxia redistributed it to the cytosol.

Finally, the researchers explored the therapeutic potential of their findings. Exposing diabetic mice to hypoxic conditions reduced their hyperglycemia and rescued the impaired glucose tolerance. They also treated animals with HypoxyStat, a small-molecule compound they developed to pharmacologically induce hypoxia.⁵ Control-treated animals on a high-fat diet developed hyperglycemia, while those treated with HypoxyStat did not develop high blood glucose despite consuming a high-fat diet, suggesting that hypoxia therapy could help combat diet-induced obesity and hyperglycemia.