The first reports of studies indicating that the fasting or fasting-mimicking diet may have a beneficial effect on certain medical conditions were published at the beginning of the 20th century. The ketogenic diet (KD) was first used in order to reduce the incidence of epileptic seizures [1
] and, over time, its application in other diseases was studied, including such medical conditions as amyotrophic lateral sclerosis (Charcot’s disease) [3
], traumatic brain injury [5
], cerebral ischemia [6
], and neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease [7
]. The use of KD enables fasting mimicking. This diet is characterized by a high fat content, few carbohydrates, and normal protein content. Whereas carbohydrates constitute approximately 55% of the energy value in the traditional diet, with approximately 30% of fat and 15% of protein, these proportions in classical KD are up to 8% for carbohydrates, 90% for fat, and approximately 7% for protein [8
]. The most frequent KD form includes mainly long-chain fatty acids (which was proposed by Doctor Wider in 1921 to treat children with drug-resistant epilepsy. In Dr. Wilder’s diet, fats provided approximately 90% of energetic diet value, with very limited volumes of carbohydrates and protein) [10
]. Although the diet proved to be an effective therapy for epilepsy in a considerable number of patients, adherence to the diet’s rules may pose a number of problems. To follow KD, it is necessary to introduce drastic changes in eating habits, which are unpalatable and difficult to maintain, especially from a long-term perspective. These problems may particularly be a concern for teenagers, adults, and families with many children, as well as individuals who are not fond of such a diet. Thus, a more attractive variety of this diet has been devised that allows users to achieve a similar metabolic effect. A diet based on medium-chain triglycerides (MCT) was applied as a form of therapy in the 1950s [11
], which led to an increase in the concentration of ketone bodies in the blood, even if carbohydrates were present in the diet; thus, this version of KD enables the production of ketone bodies without drastic changes in diet composition [12
]. However, its use is associated with the occurrence of dyspeptic conditions, limiting its more widespread application. In addition, it is not more effective than the traditional KD. Another version of KD was a combination of the traditional diet version and an MCT-based diet, but its effectiveness was similar to that of the traditional KD [11
]. Another form of KD is a modified version based on the Atkins diet, which was proposed in 2003. In this version, carbohydrates are limited to up to 5% of energy in the diet, whereas neither the general energetic value of the diet nor its protein content undergoes any modification [10
]. See Table 1
for the characteristics of various forms of KD.
Stubbes et al. [14
] ordained 16 healthy non-obese volunteers following an overnight fast. Subjects consumed 395 mg/kg ketone ester on an empty stomach or immediately following a standard meal. The serum BHB (beta-hydroxybutyrate) level was tested one hour after administration of ketone ester. Serum BHB was lower in the group that consumed the standard meal versus the “empty stomach” group (2.1 mM ± 0.2 mM versus 3.1 mM ± 0.1 mM). These extreme doses convert to 31.6 grams of ketone ester for an 80 kg person, and were well-tolerated. In another study [15
] using an oral dose of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a monoester of the BHB molecule was quantified at 714 mg/kg body weight. This high dose was administered for five days, three times per day. The maximum plasma ketones were achieved within 2 h (3.30 mM BHB and 1.19 mM acetoacetate). These doses convert to 57.1 grams of ketone ester for an 80 kg (176 lb) person, and were well-tolerated also.
Very promising data about the ketogenic diet comes from an observation by Murray et al. [16
] of rats. They investigated the effects of the novel ketone ester diet on the physical and cognitive performance of animals. In the novel ketone ester diet, 27% of energy came from protein, 39% from carbohydrates, and 34% from total fat, but the diet was supplemented with (R)-3-hydroksybutyl (R)-3-hydroksybutytate as 30% of calories. This is very interesting, because this proportion of macronutrients is similar to fat-rich Western diets. They concluded that the novel ketone diet improved physical and cognitive functions in animals, and its energy-sparing proportions suggest that it may help to treat a range of human conditions with metabolic abnormalities.