New research from the University of Michigan and the University of Sydney has revealed surprising insights into how calorie restriction impacts muscle protein changes and insulin sensitivity.
The study, which focused on rats, showed that limiting calories not only improves insulin sensitivity—a key factor in blood sugar control—but also causes molecular changes that are sex-dependent.
This discovery may have important implications for the treatment of age-related diabetes and type 2 diabetes.
The study, published in the Journal of Gerontology, Series A: Biological Sciences and Medical Sciences, found that calorie restriction triggered different molecular responses in male and female rats.
Interestingly, around 70% of the molecular changes in the rats’ muscles were sex-dependent, meaning that the two sexes responded differently at the cellular level, even though the outcome—improved glucose uptake—was similar.
This suggests that different pathways might lead to the same beneficial result in both males and females.
Professor Greg Cartee, the principal investigator of the study and a professor at the University of Michigan’s School of Kinesiology, explained the importance of studying both men and women separately, rather than assuming that findings from one sex apply to both.
“You can’t study one sex and assume it means the truth for the other,” Cartee said. “Even when the outcome is quite similar, the pathways to getting to that outcome can be different.”
The research team used a technique called protein phosphorylation, which involves adding phosphate groups to proteins to change their activity.
Phosphorylation acts as a chemical switch, turning proteins on or off, and is crucial in many cellular processes. The team studied the changes in protein phosphorylation in the skeletal muscles of rats that had been subjected to a calorie-restricted diet.
For eight weeks, the 24-month-old rats were fed 35% less food, and the researchers measured insulin-stimulated glucose uptake in their muscles. Both male and female rats showed increased glucose uptake, but females had a greater response, regardless of diet.
The researchers found that insulin caused changes in protein phosphorylation at more than twice as many sites in female rats compared to males, although calorie restriction led to more changes in protein phosphorylation in males compared to females.
Cartee likened the difference to using Google Maps, where there are multiple routes to the same destination. “Males and females don’t use completely separate ‘roads’ to achieve increased glucose uptake; they may travel the same roads but use different lanes or drive at different speeds along the way,” he explained.
The study also identified two key proteins—Lmod1 and Ehbp1l1—that were found to be critical in insulin-responsive phosphorylation. These proteins are known to be associated with regulating blood sugar levels in humans, suggesting they could be important targets for future therapies aimed at improving glucose metabolism, especially in individuals with diabetes.
Additionally, the research team measured a wide range of metabolites in the rats’ bodies, which are chemicals produced from the diet or metabolism.
About 40% of the metabolites were altered by calorie restriction in both male and female rats, with some metabolites changing in only one sex. This further reinforces the idea that male and female rats respond differently at the molecular level to calorie restriction.
This research opens up new avenues for developing sex-specific treatments for conditions like type 2 diabetes. Cartee emphasized that understanding the molecular pathways that lead to improved glucose uptake in both sexes could help create more effective treatments.
“By identifying these key proteins and metabolic changes, we can target the underlying mechanisms of insulin resistance and glucose metabolism more precisely,” he said.
Overall, the findings suggest that tailored strategies based on sex differences could lead to better interventions for managing age-related diabetes and other metabolic disorders.
As research in this area continues, the hope is that these insights will lead to more personalized treatments that can help improve the health of both men and women, particularly in controlling blood sugar and preventing diabetes-related complications.
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