Ketogenic diets and exogenous ketone supplements have gained popularity as strategies to elevate serum ketone bodies, serving as an alternative energy source for tissues with high energy demands, including the brain, muscles, and heart. The ketogenic diet is characterized by low carbohydrate and high-fat intake, while ketone supplements are typically available as esters or salts. Achieving nutritional ketosis, defined by serum ketone concentrations of ≥ 0.5 mmol/L, mimics the metabolic effects of fasting, leading to various metabolic shifts and potential health benefits.
Understanding Ketosis and Ketogenic Diets
The human body is adapted to survive periods of limited food availability by shifting its substrate preference to sustain bodily functions. During fasting, starvation, carbohydrate restriction, or prolonged intense exercise, the body stimulates lipid utilization from lipid reserves through mitochondrial beta-oxidation. This process increases whole-body fat oxidation rates twofold to threefold. The liver's mitochondria then produce ketone bodies as an alternative fuel source to replace glucose. These ketone bodies (KB), including acetoacetic acid (acetoacetate), acetone, and beta-hydroxybutyric acid (βHB), can be utilized by the brain, heart, and skeletal muscle through the citric acid cycle (Krebs cycle), acting as an energy source when glucose is scarce. β-hydroxybutyrate provides more adenosine triphosphate (ATP) per mole of substrate than pyruvate for brain and muscle tissue.
Ketosis, referred to by Hans Krebs as "physiological ketosis," is defined as blood βHB concentrations of ≥ 0.5 mmol/L. The maximum concentration of KB is around 8 mmol/L in undisturbed glucose metabolism, while blood pH remains unchanged. Upon refeeding, the presence of insulin and reduction of glucagon will reduce lipolysis and diminish the ketogenetic flux in the liver. Besides starvation, also diets low in carbohydrate content can be used to reach a state of ketosis. The latter carbohydrate restricted diets vary in their proportion of carbohydrates. The challenge, however, has been to raise circulating KB levels by using a palatable diet without significant elevated concentrations of plasma cholesterol and free fatty acids (FA).
Types of Ketogenic Diets
Several variations of the ketogenic diet exist, each with different macronutrient ratios and approaches:
- Standard Ketogenic Diet (SKD): A very-low-carbohydrate ketogenic diet (VLCKD) usually referred to as a standard ketogenic diet. The classic or standard long-chain triglyceride ketogenic diet contains high fat vs. low carbohydrate and low protein content with a 4:1 ratio of fat to protein plus carbohydrate (in grams).
- Cyclical Ketogenic Diet (CKD): Includes periods of higher carbohydrate intake, often strategically timed. Another strategy to improve adherence is to include days in which more carbohydrates are added to the diet (cyclical ketogenic diet).
- Targeted Ketogenic Diet (TKD): Carbohydrates are consumed specifically around exercise. Targeted ketogenic diet is similar to a standard ketogenic diet except that carbohydrates are consumed just before exercise.
- High-Protein Ketogenic Diet: Features a higher protein content compared to the standard ketogenic diet. Lower ratio with increase in protein content (high protein ketogenic diet) can also be helpful to increase adherence.
- Modified Atkins Diet (MAD): Adapted from Atkins weight reduction diet in which carbohydrate intake is restricted to 10-20 g/day. Ratio’s between fat to protein plus carbohydrate range typically between 1:1 and 1.5:1, but can reach 4:1.
- Medium-Chain Triglyceride (MCT) Diet: Utilizes medium-chain triglycerides, which are more ketogenic than long-chain triglycerides. The third type ketogenic diet is the medium-chain triglyceride (MCT) diet. It follows the outline of standard ketogenic diet, but instead of using long-chain triglycerides, medium chain (C6-C12) triglycerides are used since these triglycerides are more ketogenic. Calorie intake is calculated based on the percentage of energy derived from MCT.
- Low Glycemic Index Ketogenic Diet: A fourth strategy is to minimize glycemic increases by higher amounts of carbohydrates with low glycemic index (< 50).
Exogenous Ketone Supplementation
In recent years, the effectiveness of exogenous KB supplementation has been explored (15). Oral administered exogenous KB supplementation rapidly elevate plasma levels of KB during a ketogenic diet, but can also be taken as a supplement on top of a normal diet (see Table 1). The metabolic response, due to the presence of glucose, is however different. Exogenous KB lowers fasting glucose concentrations via attenuated hepatic glucose output (without increase in skeletal muscle glucose uptake). Dairy products are a natural source of β-hydroxybutyrate with concentration ranging from 10 to 631 μM (16-18). Beta-hydroxybutyrate and acetoacetate salts and/or amino acids, and esters, and MCT supplementation is commercially available and generally considered as safe. Ketone salts, consumed as sodium, potassium and/or calcium βHB, result in high levels of inorganic ion consumption. Ketone esters decrease blood pH and ketone salts increase urinary pH (19). Ketone formulations are racemic mixtures with equal amount of left- and right-handed enantiomers (D-βHB and L-βHB). In the body, D-enantiomers are the predominant circulating KB and is better oxidized than L-enantiomers. It is important to take into account when evaluating these effects of diets or supplementation, that commercial ketone meters and laboratory analysis only detect D-βHB and most do not test for acetoacetate.
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Forms of Exogenous Ketones
Exogenous ketones are available in various forms:
- Ketone Salts: These are βHB bound to minerals like sodium, potassium, and calcium. Ketone salts, consumed as sodium, potassium and/or calcium βHB, result in high levels of inorganic ion consumption.
- Ketone Esters: These are βHB linked to an ester, which the body breaks down to release the ketone. Ketone esters decrease blood pH and ketone salts increase urinary pH (19).
- MCT Oil: While not a ketone itself, MCT oil is readily converted into ketones by the liver.
Keto Pills
So-called “keto pills” are those that claim to boost ketosis, which is a process in which the body burns fat instead of carbohydrates for energy. A keto diet has a high fat requirement and followers eat fat at each meal.
Ingredients found in keto gummies
Most keto gummies typically contain medium-chain triglycerides (MCTs), a type of saturated fat that help give your body energy, in addition to exogenous ketones.“Sometimes, keto gummies may contain gelatin or natural sweeteners like Stevia,” notes Czerwony. “It’s not like eating a traditional gummy. It’s not going to have any additional sugars because if it did, then it would throw you out of ketosis.”So, what should you look for in a keto gummy?“There are a lot of options available and they all seem comparable,” says Czerwony. “I would suggest opting for something that fits in your budget and buy a small batch at first to make sure you like it.”
Potential Benefits of Nutritional Ketosis
Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Caloric restriction and various forms of fasting (intermittent fasting, time restricted eating, periodic fasting) showed extension of lifespan in animals and reduced rates of several diseases, especially metabolic diseases, and cancers (1, 2). Fasting elicits evolutionarily conserved, adaptive cellular responses that reduce free-radical production, improves glucose regulation, increases stress resistance, suppresses inflammation, and causes weight loss. In recent years carbohydrate restriction is gaining popularity and attention. Benefits for general health can be weight loss and improved glucose tolerance, but also better blood pressure control and cholesterol profile (3).
Weight Loss
The ketogenic diet has been shown to produce beneficial metabolic changes in the short-term. Along with weight loss, health parameters associated with carrying excess weight have improved, such as insulin resistance, high blood pressure, and elevated cholesterol and triglycerides. A meta-analysis of 13 randomized controlled trials following overweight and obese participants for 1-2 years on either low-fat diets or very-low-carbohydrate ketogenic diets found that the ketogenic diet produced a small but significantly greater reduction in weight, triglycerides, and blood pressure, and a greater increase in HDL and LDL cholesterol compared with the low-fat diet at one year. A study of 39 obese adults placed on a ketogenic very low-calorie diet for 8 weeks found a mean loss of 13% of their starting weight and significant reductions in fat mass, insulin levels, blood pressure, and waist and hip circumferences. Their levels of ghrelin did not increase while they were in ketosis, which contributed to a decreased appetite. However during the 2-week period when they came off the diet, ghrelin levels and urges to eat significantly increased. A study of 89 obese adults who were placed on a two-phase diet regimen (6 months of a very-low-carbohydrate ketogenic diet and 6 months of a reintroduction phase on a normal calorie Mediterranean diet) showed a significant mean 10% weight loss with no weight regain at one year. The ketogenic diet provided about 980 calories with 12% carbohydrate, 36% protein, and 52% fat, while the Mediterranean diet provided about 1800 calories with 58% carbohydrate, 15% protein, and 27% fat. Eighty-eight percent of the participants were compliant with the entire regimen.
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Appetite Suppression
A systematic review of 26 short-term intervention trials (varying from 4-12 weeks) evaluated the appetites of overweight and obese individuals on either a very low calorie (~800 calories daily) or ketogenic diet (no calorie restriction but ≤50 gm carbohydrate daily) using a standardized and validated appetite scale. None of the studies compared the two diets with each other; rather, the participants’ appetites were compared at baseline before starting the diet and at the end. Despite losing a significant amount of weight on both diets, participants reported less hunger and a reduced desire to eat compared with baseline measures. The authors noted the lack of increased hunger despite extreme restrictions of both diets, which they theorized were due to changes in appetite hormones such as ghrelin and leptin, ketone bodies, and increased fat and protein intakes. The authors suggested further studies exploring a threshold of ketone levels needed to suppress appetite; in other words, can a higher amount of carbohydrate be eaten with a milder level of ketosis that might still produce a satiating effect? This could allow inclusion of healthful higher carbohydrate foods like whole grains, legumes, and fruit.
Therapeutic Applications
Nutritional ketosis seems an interesting and promising strategy to increase the health status of healthy individuals and to serve as a therapeutic intervention in several diseases. Insights in these mechanisms will lead to precision nutrition for these diseases (56). KD is a well-established, effective non-pharmacologic treatment for intractable childhood epilepsy. Its history dates back to 500 years BC when fasting was already was recognized as an effective therapy against epilepsy; a finding that was also mentioned in Hippocrates …
Physical Performance
Physical performance and fatigue are dependent on substrate availability to working muscles. As exercise intensity increases, there is a shift in the contribution of different substrates to energy provision from free fatty acids and glucose in the blood toward intramuscular triglycerides and glycogen. At moderate-to high intensity exercise (> 75% of maximal oxygen uptake, VO2max), muscle glycogen is the main energy source (22). KB have the potential to be used as an alternative fuel source to carbohydrates and fat during endurance exercise and can lower the exercise-induced rise in plasma lactate (see Figure 1) (26), amongst other metabolic effects (6). The potential ergogenic effects of KB supplementation has therefore attracted a lot of scientific interest. Habitual consumption of a ketogenic diet, which is high in fat (∼80% total kcal), very low in carbohydrate (∼5% total kcal), and moderate in protein (∼15% total kcal), augments circulating KB and enhances fat oxidation while sparing carbohydrate oxidation during endurance exercise (28-30). Yet benefits of ketogenic dieting for performance remain equivocal, possibly attributed to a low muscle glycogen content at the start of exercise due to severe carbohydrate restriction and impaired glycolytic flux during high-intensity exercise (31-33). This has led to the exploration of means to achieve acute nutritional ketosis that bypass the undesirable effects of carbohydrate restriction. Acute exogenous ingestion of KB in the form of βHB salts or ketone esters has sparked the interest to enhance performance and recovery in athletes (34, 35). The latter ketone supplements can induce acute ketosis as evidenced by > 0.5 mM βHB in the blood for up to 3 h after consumption of an acute dose, without the necessity to modify dietary intake (19, 36). Hence, they could serve as an attractive strategy to supply the working muscle with extra energy, while sparing muscle glycogen stores (35).
From a performance point of view, the effect of exogenous KB supplementation as an ergogenic aid, especially in the acute form, is not ambiguous. A recent meta-analysis (13 studies) (37) and systematic review (10 studies) (38) both failed to show consistent effects of exogenous KB supplements on physical performance (both endurance and power outcomes). Except for the seminal study of Cox et al. (39), the remainder of the studies failed to show any benefit of acute KB supplementation on performance (40-46), and some even reported detrimental effects (47, 48). The various KB supplements in combination with their pharmacokinetics as well as the variation in gastrointestinal distress between supplements is likely to affect the performance outcome measures. That is, the type of supplement (ketone ester vs. ketone salt) and the nutritional status (fed vs. fasted state) seems to determine the level of circulating βHB concentrations, and hence explain a lot of the variance between studies (37, 38). Providing ketone monoesters in the fasted state maximizes the state of ketosis, reaching peak circulating βHB concentrations above 2 mM (19, 39, 40, 49), which are blunted in the fed state (19). Ingestion of ketone salts (46, 48), ketone diesters (47), ketone precursors (44, 45), or ketone monoesters (41) in the fed state induce acute ketosis (βHB > 0.5 mM), yet fail to reach the 2 mM cutoff. The difference in peak βHB concentrations between ester and salt supplements are likely mediated by the βHB isoform present in the drinks. In contrast to ketone esters, which are composed of D-βHB, ketone salts are often a racemic mixture of both D-βHB and L-βHB isoforms of βHB, even though the metabolism and metabolic fate of L-βHB being less well understood (50, 51). The L-βHB isoform seems less readily oxidized and does not seem to contribute a lot to energy supply, and hence may accumulate upon repeated ketone salt drinks (19). Furthermore, it is documented that food in the gut can delay or prevent the uptake of small hydrophilic carbons such as βHB (52, 53), probably explaining the lower circulating βHB following food consumption (19). KB supplementation is also associated with symptoms of gastrointestinal distress, which can range in severity. Symptoms including nausea, diarrhea, constipation, vomiting and abdominal pain have been reported (36). Another factor that may likely influence the performance benefit is the type of test chosen. As KB have been suggested to exert antiglycolytic effects (39), KB may especially work advantageous during low-to-moderate intensity endurance exercise (35). That is, KDs have shown to be beneficial during a long duration (≥ 12 h), low-intensity ultra-endurance-type event, where mitochondrial beta-oxidation can match lower rates of ATP demand, whereas the combination of nutritional ketosis and high carbohydrate intake may confer performance benefits in endurance events of moderate intensity and durations of ≥ 8 h (54). In summary, even though there is a clear biological rationale to support a performance enhancing effect of acute exogenous KB supplementation, to date there is not sufficient evidence to support a clear ergogenic effect.
Potential Risks and Side Effects
Following a very high-fat diet may be challenging to maintain. Some negative side effects of a long-term ketogenic diet have been suggested, including increased risk of kidney stones and osteoporosis, and increased blood levels of uric acid (a risk factor for gout). Possible nutrient deficiencies may arise if a variety of recommended foods on the ketogenic diet are not included. It is important to not solely focus on eating high-fat foods, but to include a daily variety of the allowed meats, fish, vegetables, fruits, nuts, and seeds to ensure adequate intakes of fiber, B vitamins, and minerals (iron, magnesium, zinc)-nutrients typically found in foods like whole grains that are restricted from the diet.
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Adverse reaction during initiation of the diet as a result of the low glucose levels is termed “keto-flu” and consists of headache, weakness, irritability, constipation, nausea, and vomiting. Symptoms can vary and often diminish after a week of diet. Due to reduction of total calorie intake, since high fat diet is less palatable and fat has a weak effect on satiation, weight loss and anorexia often occur. Polyunsaturated fatty acid intake and reduced intake of cholesterol is important to prevent elevated cholesterol and triglycerides levels associated with atherogenic risk, especially during long-term use of the ketogenic diet (9). Supplementation of omega 3-fatty acids can prevent hyperlipidemia and improve fatty acid profile (10). Gut microbiome alterations in its composition can result in gastrointestinal discomfort, and certain species (Akkermansia, Bacteroidetes, Firmicutes, Muciniphila, Lactobacillus) increase production of short-chain FAs like acetate, propionate and butyrate (11). It is important to avoid malnutrition and include an adequate intake of macro- and micronutrients. Low-carbohydrate diets are often low in thiamin, vitamin B6, folates, vitamin A, vitamin E, calcium, magnesium, iron or vitamin K. There is a reduced bone- and calcium (Ca) metabolism and a risk for developing hypercalciuria and kidney stones (12). Urine analysis and urine calcium creatinine ratio should be analyzed during KD. Good hydration minimizes the risk of stone formation.
Ketoacidosis
Excessive ketone bodies can produce a dangerously toxic level of acid in the blood, called ketoacidosis. During ketoacidosis, the kidneys begin to excrete ketone bodies along with body water in the urine, causing some fluid-related weight loss. Ketoacidosis most often occurs in individuals with type 1 diabetes because they do not produce insulin, a hormone that prevents the overproduction of ketones. However in a few rare cases, ketoacidosis has been reported to occur in nondiabetic individuals following a prolonged very low carbohydrate diet.
Potential risks of keto gummies
Are keto gummies safe? Before you decide to try keto gummies, it’s also worth understanding the potential risks.Czerwony says those potential risks include:Nausea and vomiting.Gastrointestinal issues, like diarrhea.Low blood sugar.“You run the risk of GI issues if your keto gummies use sorbitol, which is known as a laxative,” warns Czerwony. “You should be cautious if you’re going try it. Slowly introduce keto gummies to see how you do because you don’t want to all sudden just kind of overdo it and have those side effects and not be very happy.”And while some people with Type 2 diabetes, high blood pressure and kidney issues may opt to go on the keto diet, Czerwony cautions against adding keto gummies to the mix.“The keto diet - and the addition of a keto supplement like gummies - can potentially lower your…
Considerations and Recommendations
Available research on the ketogenic diet for weight loss is still limited. Most of the studies so far have had a small number of participants, were short-term (12 weeks or less), and did not include control groups. A ketogenic diet has been shown to provide short-term benefits in some people including weight loss and improvements in total cholesterol, blood sugar, and blood pressure. However, these effects after one year when compared with the effects of conventional weight loss diets are not significantly different. Eliminating several food groups and the potential for unpleasant symptoms may make compliance difficult. An emphasis on foods high in saturated fat also counters recommendations from the Dietary Guidelines for Americans and the American Heart Association and may have adverse effects on blood LDL cholesterol. A ketogenic diet may be an option for some people who have had difficulty losing weight with other methods. The exact ratio of fat, carbohydrate, and protein that is needed to achieve health benefits will vary among individuals due to their genetic makeup and body composition. Therefore, if one chooses to start a ketogenic diet, it is recommended to consult with one’s physician and a dietitian to closely monitor any biochemical changes after starting the regimen, and to create a meal plan that is tailored to one’s existing health conditions and to prevent nutritional deficiencies or other health complications. A modified carbohydrate diet following the Healthy Eating Plate model may produce adequate health benefits and weight reduction in the general population.
Given the potential risks and side effects, it is crucial to consult with healthcare professionals before starting a ketogenic diet or using ketone supplements. This is especially important for individuals with pre-existing medical conditions, such as diabetes, kidney disease, or heart disease.