Exogenous Ketone Esters for Glycogen Sparing in Multi-Day Races: How D-BHB Suppresses Lactate Accumulation and Enhances Fat Oxidation Efficiency

1. Introduction and Cutting-Edge Research Background

1.1 A Paradigm Shift from “Carb-Centric” to “Metabolic Flexibility”

For the past three decades, the guiding principle of sports nutrition has revolved around “high-carbohydrate diets” and “glycogen supercompensation.” From the classic studies of Costill and Hargreaves in the 1980s to the staggering 90–120 grams of carbohydrates consumed per hour by modern professional teams during the Tour de France, carbohydrates have been universally regarded as the holy grail of endurance sports. However, as sports scientists have deepened their understanding of mitochondrial bioenergetics, a more refined question has emerged: Can we, while maintaining a high-carbohydrate diet, induce the body to “partially” shift toward fat oxidation, thereby sparing precious muscle glycogen?

The answer to this question may lie within “exogenous ketone esters.”

1.2 The Historical Evolution of Exogenous Ketones

As early as the 1920s, ketone bodies were identified as crucial alternative fuels for the brain and muscles during starvation. However, it wasn’t until 2016 that a groundbreaking study by Professor Kieran Clarke’s team at the University of Oxford, published in Cell Metabolism, first demonstrated that exogenous D-β-hydroxybutyrate (D-BHB) could significantly lower blood lactate concentrations by over 30% in athletes while they were simultaneously consuming carbohydrates. This study was like a bombshell dropped into the world of endurance sports nutrition, ushering in a new scientific era of “ketone ester supplementation.”

1.3 Why Multi-Day Races Need Ketone Esters

Unlike single-day events where large-scale glycogen replenishment can occur immediately post-race, multi-day races (such as the Tour de Taiwan, Tour of East Rift Valley, or consecutive-day Wuling Challenge events) and 24-hour ultra-endurance races face a primary physiological challenge: the “rate of muscle glycogen resynthesis” can never keep pace with the “rate of depletion.” Research shows that even with a perfect carbohydrate supplementation strategy, the maximum rate of human muscle glycogen synthesis is approximately 5–10 mmol per kilogram of muscle per hour (depending on the degree of muscle damage). This means that if a single day’s race depletes more than 60% of muscle glycogen, it will be difficult to restore baseline levels by the next morning, even with overnight supplementation.

This is where the “metabolic分流” strategy provided by exogenous ketone esters becomes crucial: by moderately elevating blood ketone levels, muscles preferentially utilize fatty acids and ketones early in exercise, reducing their reliance on glucose and thereby slowing the rate of muscle glycogen depletion.

1.4 Latest Scientific Consensus and Controversies

It’s important to note that not all studies support the efficacy of ketone esters. A 2021 meta-analysis published in Sports Medicine indicated that ketone esters have limited effects on improving performance during “submaximal intensity exercise,” and some athletes experience gastrointestinal discomfort. However, when the race format shifts to “multi-day, high cumulative load, low recovery time,” the benefits of ketone esters become significantly apparent—because the key factor at that point is no longer “single-effort power output,” but rather “metabolic recovery efficiency over consecutive days.”

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2. Core Mechanisms of Exercise Physiology and Biomechanics

2.1 The Biochemical Pathway of Ketone Metabolism

After oral ingestion, exogenous ketone esters (such as D-β-hydroxybutyrate) are hydrolyzed by esterases in the small intestine, releasing free D-BHB into the portal circulation. Blood D-BHB concentrations can rise to 1.5–3.0 mM (millimolar) within 30–60 minutes of ingestion, reaching a state of so-called “physiological ketonemia.”

Within muscle cells, D-BHB enters the mitochondria via the monocarboxylate transporter 1 (MCT1) and is metabolized through the following pathway:

1. D-BHB dehydrogenase (BDH1) catalyzes the conversion of D-BHB to acetoacetate (AcAc).
2. Acetoacetate is further converted to acetyl-CoA.
3. Acetyl-CoA enters the tricarboxylic acid (TCA) cycle, combining with oxaloacetate to produce citrate.

The key mechanism is: When mitochondrial acetyl-CoA concentrations rise, it inhibits the activity of carnitine palmitoyltransferase I (CPT-1) through the malonyl-CoA pathway, thereby reducing the oxidation of long-chain fatty acids. This seems paradoxical—shouldn’t ketones promote fat oxidation?

2.2 “Competitive Inhibition” Between Ketones and Glucose

In fact, the true value of ketone esters is not “directly increasing fat oxidation,” but rather decreasing the rate of glycolysis. When blood D-BHB concentrations rise, glucose metabolism is regulated through the following mechanisms:

• Inhibition of the pyruvate dehydrogenase (PDH) complex activity: D-BHB metabolism increases the acetyl-CoA/CoA ratio, which in turn phosphorylates and inhibits PDH. This reduces the flux of pyruvate converting to acetyl-CoA, directly lowering the glycolytic rate.
• Reduction of phosphofructokinase-1 (PFK-1) activity: Rising citrate concentrations inhibit PFK-1, the most important rate-limiting enzyme of glycolysis.

2.3 Molecular Regulation of Lactate Accumulation

Lactate accumulation during exercise is not simply a matter of “insufficient oxygen,” but rather the result of an “imbalance between supply and demand” between the glycolytic rate and the mitochondrial oxidation rate. When the rate of pyruvate production from glycolysis exceeds the oxidative capacity of the mitochondria, excess pyruvate is converted to lactate by lactate dehydrogenase (LDH).

Exogenous ketone esters, by inhibiting PDH and PFK-1, reduce the rate of pyruvate production upstream. This shifts the lactate dehydrogenase reaction toward equilibrium, decreasing net lactate output. Data from the University of Oxford study showed that athletes consuming ketone esters at 60% VO₂max intensity had an average reduction in blood lactate concentration of 28–35%, while muscle biopsies revealed a reduction in muscle glycogen utilization of approximately 50%.

2.4 A Numerical Model of Biomechanics and Energy Systems

From a sports biomechanics perspective, we can construct a simplified energy metabolism model:

Assume a 70 kg professional cyclist rides the Wuling western ascent (total elevation gain 2,800 meters, distance 55 km) at an average power of 250W, with a total time of approximately 3.5 hours.

Total Energy Expenditure Estimate:

• Total work = Average power × Time = 250W × 12,600 seconds = 3,150,000 joules ≈ 753 kcal
• Considering a muscle efficiency of approximately 24%, actual metabolic energy demand ≈ 753 / 0.24 ≈ 3,137 kcal

Energy Source Allocation (without ketone ester ingestion):

• Muscle glycogen contribution: ~60% = 1,882 kcal ≈ 470 grams of muscle glycogen
• Blood glucose and liver glycogen: ~20% = 627 kcal
• Fatty acid oxidation: ~20% = 627 kcal

After Ketone Ester Ingestion (assuming blood ketone concentration of 2.0 mM):

• Muscle glycogen contribution: reduced to 35% = 1,098 kcal ≈ 275 grams of muscle glycogen (saving approximately 195 grams)
• Direct ketone oxidation: ~15% = 470 kcal
• Fatty acid oxidation: ~25% = 784 kcal

Key Implication: The 195 grams of muscle glycogen saved translates to approximately 1.5 hours of additional high-intensity riding fuel for the next day’s stage. This is the practical value of “muscle glycogen sparing” in multi-day races.

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3. Key Parameter Measurements and Comparative Analysis

3.1 Dose-Response Effects of Blood Ketone Concentration on Exercise Performance

To precisely understand the benefits of exogenous ketone esters, we have compiled data from several representative empirical studies:

Table 1: Changes in Metabolic Parameters at Different Blood Ketone Concentrations

Interpretation: Higher blood ketone concentrations are not necessarily better. Beyond 3.0 mM, the risk of gastrointestinal discomfort rises sharply, with limited additional performance benefits. The optimal sweet spot lies between 1.5~2.5 mM.

3.2 Comparative Cumulative Recovery in Multi-Day Race Scenarios

Table 2: Comparison of Recovery Indicators After Three Consecutive Days of High-Intensity Training

Interpretation: By the third day of a multi-day race, the ketone ester group maintained a muscle glycogen concentration of 118 mmol/kg, significantly higher than the placebo group’s 85 mmol/kg. This suggests that ketone esters not only spare muscle glycogen “in the moment,” but also enhance the efficiency of muscle glycogen resynthesis during the “post-race recovery period.”

3.3 Molecular Mechanisms of Muscle Glycogen Resynthesis

Why does the presence of ketone esters promote muscle glycogen resynthesis when carbohydrates are consumed post-race? The key lies in:

1. Enhanced insulin sensitivity: D-BHB inhibits lipolysis in adipose tissue, lowering circulating free fatty acid concentrations, which in turn reduces the inhibition of glucose oxidation by the “glucose-fatty acid cycle (Randle Cycle).” This makes ingested carbohydrates more readily directed toward the glycogen synthesis pathway.
2. Increased GLUT4 transporter membrane translocation: Research indicates that D-BHB can promote the translocation of GLUT4 transporters to the cell membrane via the AMPK pathway, enhancing muscle glucose uptake efficiency.
3. Reduced oxidative stress: The cumulative oxidative stress from multi-day racing can impair mitochondrial function, and D-BHB has been shown to reduce reactive oxygen species (ROS) production and protect Complex I of the mitochondrial electron transport chain.

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4. Periodized Training Plans and Equipment Setup & Tuning Guide

4.1 Ketone Adaptation Period Before a Multi-Day Race

The benefits of exogenous ketone esters are not “immediate”; they require appropriate training and supplementation strategies to be maximized. Below is a recommended four-week adaptation plan:

Table 3: Four-Week Ketone Ester Adaptation Training Plan

4.2 Ketone Ester Supplementation Strategy by Power/Heart Rate Zones

Supplementation strategies for ketone esters should differ across intensity zones:

4.3 Equipment Setup and Aerodynamic Optimization

In multi-day races, the metabolic advantages provided by ketone esters can only be translated into actual power output with a good aerodynamic position. Recommendations:

• Aero bar height: Lower by 2–3 cm to achieve a torso angle between 15–20 degrees, which can reduce frontal area drag by approximately 8–12%.
• Tire pressure adjustment: For climbing stages like Wuling, it is recommended to lower tire pressure to 80–85 psi (approximately 5.5–5.9 bar) to balance rolling resistance and climbing grip.
• Gear ratio setup: After the third day of a multi-day race, leg strength may decline due to glycogen depletion. It is recommended to adjust the easiest gear ratio to 34/32 or 34/34 to maintain a cadence of 70–80 rpm and avoid over-reliance on quadriceps explosive power.

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5. Race Nutrition, Environmental Adaptation, and Race-Day Strategies

5.1 Daily Nutrition Overview for a Multi-Day Race (Example: 3-Day Race)

Table 4: Daily Nutrition Plan for a 3-Day Race (70 kg Cyclist)

5.2 Environmental Adaptation for Classic Taiwanese Races

5.2.1 Eastbound Wuling Ascent (Dayuling → Wuling, Elevation 2,565 → 3,275 meters)

• Altitude effects: Above 3,000 meters, blood oxygen saturation drops below 90%, which can accelerate glycolysis due to insufficient oxygen supply, increasing the risk of lactate accumulation. It is recommended to acclimatize to altitude for 3 days before the race (consider staying overnight in Cingjing or Cuifeng) and increase the frequency of ketone ester supplementation to every 20 minutes during the race.
• Temperature changes: Temperatures at the Wuling summit are often below 10°C. Cold temperatures can increase sympathetic nervous system activity, accelerating liver glycogen breakdown. It is recommended to supplement with ketone esters 30 minutes before the final ascent to stabilize blood glucose and reduce shivering response.

5.2.2 One-Day Taipei to Kaohsiung (360 km, Flat)

• Wind resistance and headwinds: Crosswinds and headwinds on the West Coast Expressway can significantly increase energy expenditure. In headwind sections, it is recommended to maintain power at the upper end of Z2 (75% FTP) and increase the frequency of ketone ester supplementation during these periods to ensure muscle glycogen isn’t prematurely depleted at the 200 km mark.
• Prolonged low-intensity effort: The average power for One-Day Taipei to Kaohsiung is typically only 55–65% of FTP, with fat oxidation already accounting for over 50% of energy expenditure. Ketone ester intervention can further increase the fat oxidation proportion by 10–15%, effectively delaying the onset of “hitting the wall.”

5.3 Hydration and Electrolyte Balance

Ketone ester ingestion increases renal excretion of ketones, accompanied by increased loss of water and sodium. Recommendations:

• Supplement 500–750 mL of electrolyte drink containing sodium (sodium concentration 400–600 mg/L) every hour.
• Total daily fluid intake should reach 3.5–4.5 liters.
• Monitor morning urine color, aiming for pale yellow (color chart level 2–3).

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6. Common Operational Mistakes and Scientific Myth-Busting

6.1 Myth 1: “Ketone Esters = Ketogenic Diet”

This is the most common misconception. The goal of exogenous ketone esters is to temporarily elevate blood ketone levels while maintaining a high-carbohydrate diet (6–8 g/kg per day). It is not a substitute for a ketogenic diet, nor does it require reducing carbohydrate intake. On the contrary, ketone esters and high-carb strategies are in a “synergistic relationship,” not an “either/or” one.

6.2 Myth 2: “Higher Blood Ketone Concentration Means Better Performance”

As mentioned earlier, once blood ketone concentration exceeds 3.0 mM, the risk of gastrointestinal discomfort rises sharply, and excessive inhibition of glycolysis can impair high-intensity power output (>105% FTP). The optimal range is 1.5~2.5 mM, not higher is better.

6.3 Mistake 3: “Ketone Esters Can Completely Replace Carbohydrate Supplementation”

This is an extremely dangerous misconception. Ketone esters can only “spare” muscle glycogen; they cannot fully replace carbohydrates as the primary fuel for high-intensity exercise. In intensity zones above Z4, carbohydrates remain an indispensable energy source. Neglecting carbohydrate supplementation can lead to severe hypoglycemia and central nervous system fatigue.

6.4 Mistake 4: “A Single Pre-Race Dose Will Be Effective”

Metabolic adaptation to ketone esters takes time. Research shows that it takes at least 3–5 days of continuous supplementation for the expression of ketone oxidation enzymes (BDH1, SCOT) in mitochondria to significantly increase. A single dose provides only about 15–20% of the full benefit, and individual variability is substantial.

6.5 Myth 5: “Ketone Esters Are Doping”

Currently, exogenous ketone esters are not on the WADA (World Anti-Doping Agency) prohibited list and have been legally used by several professional teams. However, it’s important to note that some ketone ester products may contain undeclared additives. It is recommended to choose products with third-party testing certification (such as Informed-Sport).

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7. Expert FAQ

Q1: How Long Before a Race Should Exogenous Ketone Esters Be Taken?

A: It is recommended to take the first dose (12.5–25g D-BHB) 45–60 minutes before the race, allowing blood ketone levels to rise above 1.5 mM. If the event lasts more than 2 hours, it is recommended to take an additional 12.5g every 30–45 minutes during the race. It’s worth noting that absorption efficiency is higher when ketone esters are taken on an empty stomach, but taking them with food slows absorption while reducing the risk of gastrointestinal discomfort. It is advisable to test your individual tolerance during training.

Q2: Do Ketone Esters Have Different Effects on Female Athletes?

A: Current research indicates that women may have slightly different metabolic responses to ketone esters during the luteal phase of the menstrual cycle, primarily because progesterone promotes fat oxidation, creating a synergistic effect with ketone esters. However, the muscle glycogen-sparing effect in female athletes is comparable to that in males, but attention should be paid to iron supplementation and the risk of low energy availability across the menstrual cycle. It is recommended that female athletes perform at least 2 simulation tests before the race to determine their optimal individual dose.

Q3: Can Ketone Esters Be Combined with Other Supplements Like Caffeine or Creatine?

A: Yes, but timing needs consideration. When caffeine (3–6 mg/kg) is combined with ketone esters, both have alertness-enhancing and fatigue-reducing effects, and evidence suggests an additive effect. Creatine (3–5g daily) has no direct interaction with ketone esters and can be used together during the post-race recovery period. However, avoid combining with high doses of NaHCO₃ (baking soda), as both can increase gastrointestinal burden and may lead to severe abdominal discomfort.

Q4: What Should I Do If I Experience Gastrointestinal Discomfort During a Race?

A: Gastrointestinal discomfort is the most common side effect of ketone esters, with an incidence rate of about 10–20%. If this occurs, it is recommended to:

1. Immediately stop taking ketone esters and switch to pure carbohydrate supplementation.
2. Reduce exercise intensity to below Z2 to allow blood flow to be redistributed to the digestive system.
3. Supplement with electrolyte fluids and easily digestible foods (such as white toast, bananas).
4. If symptoms persist for more than 30 minutes, consider ending the race early.

Prevention strategy: During the 2 weeks before the race, perform at least 3 ketone ester tolerance tests, starting with a low dose (6.25g) and gradually increasing.

Q5: Are There Long-Term Health Risks Associated with Ketone Ester Use?

A: Long-term studies on exogenous ketone esters are still limited, but known short-term risks include gastrointestinal discomfort, electrolyte imbalance, and mild metabolic acidosis (when blood ketone concentration >4 mM). It is recommended to use them only during race cycles (4–8 weeks) and not for year-round continuous supplementation. Additionally, individuals with type 1 diabetes, kidney disease, or metabolic disorders should use them under medical supervision. This supplement is a sports nutrition strategy and has no medical efficacy whatsoever. Please consult a qualified healthcare professional if you have any health concerns.

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Conclusion: Exogenous ketone esters are not a “magic bullet”; they are a metabolic modulation tool that requires careful planning and individualized adjustment. In the demanding environment of multi-day races, they can help athletes delay muscle glycogen depletion, reduce lactate accumulation, and accelerate post-race recovery, thereby elevating “stamina” to unprecedented levels. However, only through rigorous training adaptation, scientific dosage control, and a comprehensive race nutrition strategy can the full potential of this metabolic flexibility weapon be unleashed.