High blood sugar levels can decrease the benefits of aerobic exercise.

All doctors recommend regular aerobic exercise, since increased aerobic fitness is important for better overall health. But scientists at the Joslin Diabetes Center have now discovered that some benefits of aerobic exercise can be affected by higher-than-normal blood sugar levels, a condition known as hyperglycemia.

These diminished gains are seen in mouse and human models with chronic hyperglycemia that is in the “prediabetes” range, says Sarah Lessard, Ph.D., Joslin’s assistant researcher in the Clinical, Behavioral and Outcomes Research section and lead author of a role in Metabolism of nature that presents the work. The study also showed that this maladaptive trait is independent of obesity and blood insulin levels.

Clinical studies have shown that people with diabetes or chronically high blood sugar levels strive to improve their aerobic exercise ability compared to people with normal blood sugar levels. “The idea behind this study was to see if we induce a high blood sugar level in mice, will it impair their ability to improve their aerobic condition?” says Lessard, who is an assistant professor of medicine at Harvard Medical School. The study also aimed to uncover the mechanisms that can lead to low levels of fitness in people with hyperglycemia.

His team used two mouse models that reflect the two main causes of hyperglycemia in humans. A group of mice ate a western diet, high in sugar and saturated fat, causing weight gain in addition to hyperglycemia. The other group was modified to produce less insulin, causing similar increases in blood sugar as the western diet, despite the mice eating a low-sugar, low-fat diet and maintaining a normal body weight. Both groups underwent a training protocol in which they ran with wheels in their cages to improve their aerobic condition.

In both hyperglycemic groups, the animals ran about 500 kilometers over the course of the study but, on average, did not improve their aerobic exercise ability compared to mice with lower blood sugar levels, Lessard says.

Looking in more detail at the skeletal muscle in these mice, she and her colleagues saw that the muscle was not adapting to aerobic challenge as the muscle would normally.

Muscle tissue can reshape itself, which is one reason why exercise is made easier when we do it regularly, Lessard says. Over time, aerobic exercise like running or swimming can alter muscle fibers to be more efficient in using oxygen during exercise. “We also cultivate new blood vessels to allow more oxygen to be delivered to the muscle, which helps increase our levels of aerobic fitness,” she says.

Scientists propose that high blood sugar levels can prevent muscle remodeling in part by modifying “extracellular matrix” proteins in the space between muscle cells, where blood vessels form.

Previous work by Lessard’s laboratory had shown that a biological pathway known as the “JNK” signaling pathway can act as a kind of molecular switch to signal muscle cells to adapt to aerobic or strength training. The scientists found that these JNK pathway signals crossed in hyperglycemic mice, activating the pathways associated with strength training, even though the mice were doing aerobic exercise. “As a result, the muscles of hyperglycemic animals have larger fibers and fewer blood vessels, which is more typical of strength training, rather than aerobic training,” says Lessard.

After these findings in animals in clinical trials with young adult volunteers, Joslin scientists found that those who had higher blood sugar levels in response to glucose intake, a condition known as glucose intolerance, showed the lowest aerobic exercise capacity. “By looking at how their muscles responded to a single episode of typical aerobic exercise, we also saw that those with the lowest glucose tolerance had the highest activation of the JNK signaling pathway, which blocks aerobic adaptations,” she says.

“The good news is that, although our mouse hyperglycemic models failed to improve aerobic fitness with training, they still achieved other important health benefits of exercise, including decreased fat mass and glucose metabolism.” Lessard says. “Therefore, regular aerobic exercise remains a key recommendation for maintaining health in people with or without hyperglycemia.” It’s important to note that people with hyperglycemia can also benefit from other forms of exercise, such as strength training, which is recommended to maintain health, he says.

Overall, the study suggests several approaches that could help people with chronic hyperglycemia overcome obstacles to developing aerobic capacity. One is to adopt a diet designed to keep blood sugar levels low. Another is to take existing diabetes medications designed to keep blood sugar levels in normal ranges.

“We often think of diet and exercise as separate ways to improve our health,” says Lessard. “But our work shows that there is more interaction between these two lifestyle factors than previously known, and suggests that we may want to consider them together to maximize the health benefits of aerobic exercise.”