High-fat ketogenic diet may help muscles respond to exercise in high blood sugar

A study has reported that a high-fat, ketogenic diet normalised blood glucose and enhanced aerobic capacity in mice with hyperglycaemia, which suggests that dietary composition may determine how effectively muscle responds to exercise

To maintain good health, conventional advice has long emphasised regular exercise and restriction of dietary fat. Exercise supports weight control and muscle development, strengthens the heart and improves the body’s capacity to absorb and use oxygen for energy production. Maximal oxygen uptake – or aerobic capacity – remains one of the most robust predictors of cardiovascular health and longevity. Yet for individuals with chronically elevated blood glucose, these expected physiological gains frequently fail to materialise.

Persistently high blood sugar, or hyperglycaemia, increases the risk of cardiovascular and renal disease. It also appears to blunt the normal adaptive response of skeletal muscle to exercise. In such individuals, muscle tissue does not increase oxygen uptake efficiently after training, which limits improvements in aerobic fitness. A recent study has now indicated that dietary fat intake, rather than restriction alone, may influence this impaired response.

The research, led by Dr. Sarah Lessard, an exercise medicine scientist and associate professor at the Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, Virginia, USA, examined the effects of a high-fat, low-carbohydrate ketogenic diet in a mouse model of hyperglycaemia. After one week on the ketogenic diet, blood glucose concentrations in the animals returned to normal ranges.

“After one week on the ketogenic diet, their blood sugar was completely normal, as though they did not have diabetes at all,” said Lessard. She added that prolonged adherence to the diet led to substantial changes in skeletal muscle structure and metabolism.

“Over time, the diet caused remodelling of the mice’s muscles, which made them more oxidative and improved their response to aerobic exercise,” she added.

The ketogenic diet derives its name from ketosis, a metabolic state in which the body shifts from glucose to fat as its principal fuel source. This transition leads to the production of ketone bodies which serve as alternative energy substrates. The approach remains controversial because it promotes high intake of dietary fat and marked restriction of carbohydrates, in contrast to the low-fat dietary guidance historically endorsed by many public health authorities.

Despite this controversy, ketogenic regimens have been associated with clinical benefit in specific contexts, including epilepsy and Parkinson’s disease. In the early twentieth century, prior to the discovery of insulin, physicians also used carbohydrate restriction to manage diabetes because of its capacity to reduce blood glucose concentrations.

In the present study, mice consumed a high-fat, low-carbohydrate diet and had access to running wheels to permit voluntary aerobic exercise. Analysis of skeletal muscle revealed an increase in slow-twitch fibres. These fibres, also termed type I fibres, contain higher mitochondrial density and rely predominantly on oxidative metabolism. Their presence supports sustained, endurance-type activity and correlates with greater aerobic capacity.

“Their bodies were more efficiently using oxygen, which is a sign of higher aerobic capacity,” said Lessard. Enhanced oxygen utilisation reflects improved mitochondrial function and greater capacity to oxidise fatty acids, processes that underpin endurance performance and metabolic health.

Lessard has previously reported that individuals with high blood sugar display lower exercise capacity. She had sought to determine whether dietary intervention might restore the physiological response to training. The current findings suggest that hyperglycaemia does not merely coexist with reduced fitness but may interfere directly with the molecular pathways that enable muscle to adapt.

Exercise exerts beneficial effects across multiple organ systems, including adipose tissue, liver and cardiovascular structures. However, the study has reinforced the view that diet and physical activity do not operate independently.

“What we are really finding from this study and from our other studies is that diet and exercise are not simply working in isolation,” said Lessard, who also holds an appointment in the Department of Human Nutrition, Foods, and Exercise at Virginia Tech’s College of Agriculture and Life Sciences.

“There are a lot of combined effects, and we can obtain the greatest benefit from exercise if we consume a healthy diet at the same time,” she said.

The investigators have emphasised that translation to human populations remains essential. The next phase of research will seek to determine whether individuals with hyperglycaemia or type 2 diabetes derive comparable improvements in aerobic capacity and metabolic flexibility when they adopt a ketogenic dietary pattern.

Lessard has acknowledged that strict carbohydrate restriction presents practical challenges for long-term adherence. She suggested that less restrictive approaches, such as the Mediterranean diet, may prove more feasible for many individuals. This dietary pattern includes carbohydrates from minimally processed fruits, vegetables and whole grains, while it limits refined sugars and saturated fats. Importantly, it has also been associated with improved glycaemic control.

The findings add nuance to the longstanding debate on dietary fat and metabolic health. Rather than focus solely on fat restriction, the research has underscored the importance of metabolic context. For individuals with hyperglycaemia, targeted dietary composition may determine whether exercise delivers its full physiological benefit.

For further reading please visit: 10.1038/s41467-026-69349-5