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Does High Blood Sugar Blunt the Benefits of Exercise?
Why do some people benefit more from exercise than others? The scientific literature on the subject points to people who seem to naturally exhibit what researchers call a “low response to training,” which means that these individuals can’t reap the full health benefits of aerobic exercise. The mystery of what causes that low response is more than a mere point of biological intrigue. Finding an answer has serious individual and public-health ramifications because low responders are more likely to become obese and develop metabolic diseases such as diabetes.
In 2020, a team of researchers led by assistant professor of medicine Sarah Lessard at the Joslin Diabetes Center discovered that high blood sugar—a condition known as hyperglycemia—was sufficient to induce a low response to training in both mice and humans. In a follow-up paper published earlier this year, Lessard and her colleagues reported that they were able to prevent a low response to training in hyperglycemic mice by administering a drug that is designed to lower blood sugar levels. Their results point to a resolution of this health mystery and lay the foundation for a treatment that could help millions of patients improve their health with exercise.
In the 1990s, researchers showed that “some people respond to exercise better than others even though they’re doing the same exercise program,” said Lessard, “and we’ve always been interested in what caused this. If blood sugar is really the problem and we prevent the increase in blood sugar, then we should restore the ability to improve the exercise capacity with training—and that’s what this study did.”
Lessard’s research has particularly important implications for the swelling numbers of diabetic patients in the United States. This year, more than one million Americans will be diagnosed with diabetes, joining 37 million others already diagnosed. Diabetes is an increasingly common chronic disease that results from an interplay of environmental and genetic factors, and is characterized by the body’s inability to process blood sugar. That leads to an increased risk of stroke, heart failure, loss of limbs, and premature death. Given its complex causes, diabetes is treated with a mix of interventions that include glucose-lowering drugs, insulin therapy, dietary changes, and exercise. But for patients who exhibit a low response to training, one of the most effective and accessible methods for managing their health—aerobic exercise—has limited effects.
The researchers used oxygen consumption to measure how individuals respond to training. When people perform repeated aerobic exercise such as going for a run or a bike ride, this causes structural changes in muscle tissue, stimulating the formation of new blood vessels and prompting other adaptations that enable the muscles to utilize more oxygen. Regular exercisers experience this as an improvement in athletic performance as it becomes easier to run or bike the same distance.
Lessard and her colleagues monitored an oxygen-use metric known as VO2 max, which quantifies how efficiently an individual converts it into work, to understand how changes in blood sugar levels affect aerobic fitness. VO2 max is particularly useful for studying low responders because they don’t show improvements in maximum oxygen uptake with exercise. Diabetics have been shown to have lower peak oxygen intake levels compared to people without metabolic disease, but this is also true of many non-diabetics. In 2020, Lessard and her colleagues identified chronic high blood sugar as a common denominator in people with and without diabetes who exhibited a low response to training; that finding suggested that steps taken to lower their blood sugar might improve their response to exercise.
“If the muscle is exposed to high blood sugar levels for a long period of time, it accumulates structural proteins that surround the muscle fiber,” Lessard said. “We think the sugar itself is causing this barrier around the muscle preventing it from forming new blood vessels and getting more oxygenated.”
In her latest study, Lessard tested this hypothesis with Canagliflozin, a relatively new drug that is already widely prescribed among diabetics, which lowers blood-sugar levels by causing the body to secrete glucose in urine. The drug was administered to hyperglycemic mice that had access to a running wheel and their VO2 max levels were measured over the course of several weeks. The results seemed to confirm the researchers’ hypothesis: the mice that received the Canagliflozin treatment responded to exercise much like normal mice. In other words, Canagliflozin appears to prevent a low response to training from developing in mouse models of diabetes.
Now Lessard hopes to determine whether the drug—or other techniques for lowering blood sugar, such as dietary changes—can reverse a low response to training in hyperglycemic populations, rather than simply preventing it from occurring in the first place. “Clinically, that’s a really important thing because we know that a lot of people already have this low response to exercise,” she said. “The proportion of the population with high blood sugar is increasing so it really could impact a lot of people with pre-diabetes, type I diabetes, and type 2 diabetes. This gives us the thought that maybe we should think about how we control blood sugar if we want to get the most out of exercise in all these different populations.”