Exercise can improve blood sugar and insulin sensitivity—or how effectively the body’s cells respond to insulin to absorb sugar. However, some people don’t respond to it. New research now shows that gut microbes and the amino acid leucine can determine whether exercise improves blood sugar and insulin control.

The findings, published in Cell Metabolism, may explain why some people respond better to exercise than others.

Previous studies suggested that gut microbes and certain amino acids might interfere with the benefits of exercise, but the exact mechanisms aren’t clear. So, researchers led by Yao Wang analyzed how overweight and obese men with prediabetes responded to a 12-week high-intensity exercise program in terms of insulin sensitivity and blood sugar control. 

The team also looked at obese mice to understand how gut microbes, the amino acid leucine, and fat cells influence exercise benefits.

Immune molecules

After 12 weeks of exercise, many circulating immune molecules changed similarly in all participants, but one molecule called sIL-6R decreased in people who responded well to exercise and increased in non-responders. Higher sIL-6R levels were linked to insulin resistance and inflammation. 

Further analyses showed that white fat tissue is the main source of sIL-6R, especially in obese men. This means that fat tissue not only stores energy but also influences how the body responds to exercise, the authors say.

In obese mice, exercise lowered the levels of sIL-6R, and artificially increasing sIL-6R blocked the benefits of exercise on insulin and blood sugar. The amino acid leucine also triggered fat cells to release sIL-6R, but blocking its production in fat cells could reverse this effect. 

Diabetes prevention

Mice receiving microbes from people who respond poorly to exercise showed higher blood levels of leucine and sIL-6R as well as worse insulin sensitivity, reduced blood sugar control, and more inflammation in fat tissue. Instead, mice receiving microbes from responders had lower levels of sIL-6R and improved metabolism. 

Further experiments showed that blocking sIL-6R or its production in fat cells reversed the negative effects observed in mice receiving microbes from people who respond poorly to exercise. Reducing sIL-6R also restored insulin sensitivity and lowered inflammation. 

Although factors such as sex and variability in gut microbiota colonization may affect the generalizability of the findings, the authors say, “therapeutic interventions targeting adipocyte-derived sIL-6R represent a promising strategy for maximizing exercise efficacy in personalized diabetes prevention.”