Ketones in Cellular Physiology: Metabolic, Signaling, and Therapeutic Advances

Medicine Sports Medicine Biochemistry Life Sciences
ketones metabolism signaling therapeutics low-carbohydrate diet endurance exercise hypoglycemia prevention

Research Report: The Role of Ketones in Cellular Physiology: Metabolic, Signaling, and Therapeutic Advances

Academic Background

For a long time, carbohydrate (CHO) intake has been considered a key factor in enhancing athletic performance during endurance exercise. The traditional view holds that a high-carbohydrate low-fat diet (HCLF) can increase glycogen stores in muscles and the liver, thereby delaying the onset of fatigue. However, in recent years, very-low-carbohydrate high-fat diets (LCHF) have gradually gained attention, especially among endurance athletes. LCHF is believed to provide energy by increasing fat oxidation, thus reducing reliance on carbohydrates. Nevertheless, whether LCHF affects athletic performance, particularly during prolonged high-intensity exercise, remains controversial.

Additionally, exercise-induced hypoglycemia (EIH) has been identified as one of the critical factors leading to fatigue. Early studies indicated that carbohydrate intake could prolong exercise duration by preventing EIH. However, with the increasing focus on glycogen reserves, research on EIH gradually faded into the background. In recent years, EIH has regained attention, especially within the context of LCHF diets.

Paper Source

This paper was co-authored by Philip J. Prins, Timothy D. Noakes, Alex Buga, and other scholars from multiple universities and research institutions, including Grove City College, Cape Peninsula University of Technology, and The Ohio State University. The paper was published in the journal American Journal of Physiology-Cell Physiology on January 9, 2025.

Study Design

The study adopted a randomized crossover design aimed at evaluating the time-to-exhaustion (TTE) performance of well-trained triathletes at 70% of their maximum oxygen uptake (VO2max) after a six-week adaptation period to either an HCLF (380 g/day) or LCHF (40 g/day) diet. The primary objectives of the study included: 1. Assessing whether the LCHF diet impairs TTE performance; 2. Exploring whether the intake of a small amount of carbohydrates (10 g/hour) can extend TTE by preventing EIH under conditions of low glycogen availability; 3. Investigating changes in metabolic homeostasis during the adaptation process to the LCHF diet.

Research Methods

The study recruited ten male triathletes who underwent six weeks of HCLF and LCHF dietary adaptation periods while maintaining constant caloric intake and training load. After the dietary adaptation period, the athletes performed TTE tests in a fasting state, during which they consumed either carbohydrates or a placebo. Throughout the testing process, researchers monitored the athletes’ metabolic, physiological, and perceptual indicators, including gas exchange, heart rate, subjective exercise intensity, and concentrations of glucose, ketones, and lactate in blood samples.

Key Results

  1. Impact of Dietary Adaptation on Athletic Performance: After six weeks of HCLF and LCHF dietary adaptation, there was no significant difference in the TTE performance of the athletes. This indicates that even under conditions of lower glycogen reserves, the LCHF diet can sustain prolonged high-intensity exercise performance.
  2. Effect of Carbohydrate Intake on Athletic Performance: The intake of a small amount of carbohydrates (10 g/hour) significantly extended TTE performance across all dietary conditions, with an average increase of 22%. This effect was primarily achieved by preventing EIH rather than by increasing the rate of carbohydrate oxidation.
  3. Metabolic Adaptation Process: The LCHF diet significantly reduced 24-hour glucose concentrations, but these normalized after four weeks, while blood ketone levels also stabilized. This suggests that the LCHF diet requires at least a four-week adaptation period to achieve metabolic homeostasis.

Discussion and Implications

The results of this study challenge the traditional view that high carbohydrate intake is crucial for sustaining prolonged endurance exercise performance. The findings indicate that the LCHF diet does not impair athletic performance, and the intake of a small amount of carbohydrates can significantly enhance performance by preventing EIH. Additionally, the study revealed changes in metabolic homeostasis during the LCHF dietary adaptation process, emphasizing the importance of a four-week adaptation period.

These findings have important implications for athletes’ nutritional strategies. Firstly, the LCHF diet can serve as an alternative dietary option for endurance athletes, especially when there is a need to reduce carbohydrate intake. Secondly, the effectiveness of a small amount of carbohydrate intake during prolonged exercise suggests that athletes do not need to consume large amounts of carbohydrates to maintain performance, providing new insights for optimizing sports nutrition strategies.

Research Highlights

  1. Feasibility of the LCHF Diet: The study is the first to demonstrate that the LCHF diet can sustain prolonged high-intensity exercise performance, challenging the conventional high-carbohydrate diet concept.
  2. Effectiveness of Small Amounts of Carbohydrate Intake: The study found that consuming only a small amount of carbohydrates can significantly improve athletic performance by preventing EIH, offering a new direction for optimizing sports nutrition strategies.
  3. Metabolic Adaptation Time: The study revealed changes in metabolic homeostasis during the LCHF dietary adaptation process, emphasizing the importance of a four-week adaptation period.

Conclusion

Through a randomized crossover design, this study systematically evaluated the impact of LCHF and HCLF diets on endurance exercise performance. The results show that the LCHF diet does not impair athletic performance, and the intake of a small amount of carbohydrates can significantly enhance performance by preventing EIH. These findings provide new scientific evidence for athletes’ nutritional strategies and lay the groundwork for further research on the application of the LCHF diet in sports.