It’s long been known that living at higher altitudes can affect physiology, including reducing the incidence of diabetes. The reason why has evaded scientists for decades. That has changed with a new discovery that was hiding in plain sight.
From 1927-1947, the Harvard Fatigue Laboratory in Cambridge, Massachusetts tested the effects of various stresses on the human body. Credited with inventing modern exercise physiology, one of the areas the lab focused on, primarily in order to help pilots and soldiers in World War II, was how high altitudes impacted the body.
In the International High Altitude Expedition to Chile in 1935, researchers discovered that as people experience hypoxia, or low oxygen, there is an increase in red blood cell production as well as increased glucose tolerance. They also found in simulated high-altitude studies that hemoglobin in red blood cells decreased their affinity for oxygen.
Subsequent studies revisited and expanded on these findings through the years, but it was never clear why the hypoxia experienced at high altitudes improved blood glucose tolerance.
That has now changed thanks to a new study out of the Gladstone Institutes that has recently been published in the journal, Cell Metabolism.
It turns out the red blood cells found proliferating in subjects on that mountain in Chile all those years ago were the key.
Vanishing glucose
In a previous study, the Gladstone researchers had shown that mice put into low oxygen environments had lower blood glucose levels than normal. Again though, they didn’t know why. The most logical reason would be that the glucose was being shuttled to muscle and fat cells by insulin signaling. But when they put the mice through PET/CT scans, 70% of the glucose that vanished from the blood stream was still unaccounted for.
“When we gave sugar to the mice in hypoxia, it disappeared from their bloodstream almost instantly,” says Yolanda Martí-Mateos, first author of the new study. “We looked at muscle, brain, liver – all the usual suspects – but nothing in these organs could explain what was happening.”
Michael Short / Gladstone Institutes
In the current study, the researchers got to the “why” of the issue. It turns out that in hypoxic conditions, red blood cells soak up glucose like sponges. In fact, glucose is the only energy source red blood cells can use, as they lack mitochondria, which can convert oxygen to energy.
When oxygen is low red blood cells switch up their metabolism to consume more glucose. This leads to the production of a molecule called 2,3-DPG, which in turn loosens the grip the hemoglobin inside red blood cells has on oxygen so that it can be released and used by tissues.
High altitude in a pill
In short, red blood cells do their best to get more oxygen into the body in hypoxic conditions and the fuel they need to do that is glucose. So when they boost oxygen, the side effect is that they eliminate glucose from the blood. And this finding could have benefits for conditions like diabetes.
In fact, in another phase of the research, the team exposed diabetic mice to hypoxia. They also used a drug developed at Gladstone called HypoxyStat to induce a hypoxic state in the rodents. In both cases, high blood sugar levels were brought into the normal range. While HypoxyStat was initially developed to combat mitochondrial diseases like Leigh Syndrome, the researchers now feel it could have a role in fighting diabetes.
“This is one of the first uses of HypoxyStat beyond mitochondrial disease,” says senior study author Isha Jain. “It opens the door to thinking about diabetes treatment in a fundamentally different way – by recruiting red blood cells as glucose sinks.”
