A ketogenic diet restores aerobic training benefits in hyperglycemic male mice by normalizing blood sugar and improving muscle remodeling, according to a new study that identifies the diet as a potential therapy for impaired exercise adaptation.
Researchers report that hyperglycemic mice fed a high-fat, very low-carbohydrate ketogenic diet regained improvements in peak oxygen consumption, or VO2peak, after aerobic training. Mice fed a standard high-carbohydrate diet did not.
The findings address a long-standing problem in diabetes research: chronic high blood sugar blunts the body’s ability to adapt to aerobic exercise, limiting gains in cardiovascular fitness.
Low-Carb Diet Normalizes Blood Sugar and Boosts VO2peak With Training
The study examined male mice with moderate hyperglycemia induced by low-dose streptozotocin. After two weeks, mice were assigned either standard chow or a ketogenic diet composed of 90% fat and 10% protein, with no carbohydrates.
Within one week, blood glucose levels in ketogenic-fed mice returned to normal ranges and remained stable throughout the study. Mice on standard chow remained hyperglycemic.
After eight weeks of voluntary wheel training, mice on the Ketogenic Diet Restores showed restored improvements in VO2peak, a key measure of aerobic capacity. Hyperglycemic mice on standard chow had blunted VO2peak gains despite completing similar running distances.
“Lowering glucose appears essential to restoring the adaptive response to exercise,” the researchers wrote, noting that running activity was equal across groups.
Sedentary mice did not show differences in VO2peak, indicating the diet’s benefit emerged only when combined with training.
Muscle Remodeling and Capillary Growth Drive Aerobic Improvements
Investigators linked improved aerobic capacity to structural changes in skeletal muscle. Ketogenic-fed mice demonstrated a higher proportion of oxidative muscle fibers and increased capillary density after training.
Hyperglycemic mice on standard chow failed to show those training-induced adaptations.
Capillary density and oxidative fiber type both correlated with VO2peak, suggesting improved oxygen delivery to muscle tissue drives the enhanced aerobic capacity.
TheKetogenic Diet Restores also increased mitochondrial size and density in muscle, even without exercise. Protein markers associated with mitochondrial remodeling, including those involved in fusion and mitophagy, were elevated.
At rest and during exercise, ketogenic-fed mice relied more heavily on fatty acid oxidation and showed reduced markers of glucose metabolism. Muscle glycogen stores were significantly lower compared with chow-fed mice.
“These data indicate a shift away from carbohydrate metabolism toward fat utilization,” the authors reported.
Carbohydrate Reintroduction Improves Performance Despite Lower Glycogen
Although VO2peak improved with training in ketogenic-fed hyperglycemic mice, time to exhaustion did not significantly exceed that of chow-fed mice.
Researchers attributed the disconnect to reduced glycogen stores, which are critical for sustained high-intensity performance.
To test the hypothesis, investigators reintroduced carbohydrates for one week in mice previously maintained on the Ketogenic Diet for 16 weeks. Exercise performance improved significantly after short-term carbohydrate restoration.
The findings suggest that while carbohydrate restriction may enhance aerobic adaptation under hyperglycemic conditions, strategic carbohydrate intake could be necessary to optimize performance.
In contrast, euglycemic control mice did not experience enhanced training adaptations on the ketogenic diet, underscoring the role of glucose normalization in the observed benefits.
The authors caution that the study was conducted in male mice and used a strict ketogenic formulation that may not directly translate to humans. Still, they conclude that carbohydrate restriction may offer therapeutic potential for individuals with hyperglycemia who experience impaired aerobic training response.
The study adds to growing evidence that metabolic context influences dietary effects on exercise adaptation.
