TOPLINE:

A ketogenic diet normalized blood glucose and restored improvements in peak oxygen consumption (VO₂peak) with aerobic training in hyperglycemic male mice. The diet enhanced muscle remodeling, including increases in oxidative fiber type and capillary density, while promoting mitochondrial changes and fatty acid oxidation independent of exercise.

METHODOLOGY:

• Chronic hyperglycemia is associated with a blunted adaptive response to aerobic exercise training in both humans and animal models, with VO₂peak being consistently lower in individuals with hyperglycemia even when exercise training levels are matched.
• Researchers induced hyperglycemia (random blood glucose levels > 200 mg/dL) in 8-week-old male mice with intraperitoneal injections of low‑dose streptozotocin (40 mg/kg on two consecutive days) to test whether a carbohydrate‑restricted, high‑fat ketogenic diet could lower blood glucose and restore aerobic training adaptations.
• They stratified hyperglycemic mice to receive either standard high-carbohydrate chow (80% kcal carbohydrate, 10% kcal fat, and 10% kcal protein) or a ketogenic diet (90% kcal fat, 0% kcal carbohydrate, and 10% kcal protein) for 16 weeks; vehicle-injected normoglycemic mice fed standard chow served as controls.
• After 8 weeks of dietary treatment, mice were randomly allocated to undergo exercise training by voluntary wheel running or to remain sedentary in static cages for an additional 8 weeks while continuing their assigned diets.
• Outcomes included VO₂peak measured by graded maximal exercise testing to exhaustion, skeletal muscle fiber-type composition and capillary density assessed by immunofluorescence, and mitochondrial morphology evaluated by transmission electron microscopy.

TAKEAWAY:

• In hyperglycemic mice, the ketogenic diet normalized blood glucose levels within 1 week and maintained normoglycemia throughout the 8-week dietary treatment period without inducing hypoglycemia, while mice on standard chow continued to exhibit blood glucose levels > 200 mg/dL.
• Exercise-trained hyperglycemic mice on the ketogenic diet demonstrated restored improvements in VO₂peak, whereas exercise-trained hyperglycemic mice on standard chow showed blunted improvements in VO₂peak.
• The ketogenic diet restored exercise‑induced skeletal muscle remodeling, increasing oxidative fiber proportion and capillary density, both of which correlated with improved VO₂peak.
• In addition, the keto diet increased the oxidation of fatty acids and lowered the levels of glucose‑regulatory proteins and glycogen in muscle and liver. It was also linked to higher muscle mitochondrial density and larger mitochondrial size.

IN PRACTICE:

“It is also possible that nonketogenic diets that help to lower glucose levels by inclusion of low glycemic index carbohydrates (eg, Mediterranean diet) or employing more moderate carbohydrate restriction may also be beneficial in enhancing aerobic adaptation in those with hyperglycemia,” the authors wrote.

SOURCE:

The study was led by Pattarawan Pattamaprapanont, Fralin Biomedical Research Institute at Virginia Tech Carilion in Roanoke, Virginia. It was published online on in Nature Communications.

LIMITATIONS:

The study was conducted exclusively in male mice. The ketogenic diet used contained 90% fat and 0% carbohydrate, which is more restrictive than typical human ketogenic diets. Fasting ketone levels and postglucose load insulin levels were not measured.

DISCLOSURES:

This study received support from the Diabetes Research Center core facilities funded by the National Institutes of Health. A few authors were supported by Mary K. Iacocca Senior Visiting Fellowships, Joslin Diabetes Center, the Sao Paulo Research Foundation, and the American Diabetes Association. No relevant conflicts of interest were disclosed by the authors.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.