What is the ketogenic diet?

The term ketogenic diet is used to define a dietary regimen based on a drastic reduction in carbohydrate intake, associated or not with a relative increase in protein and fat intake (24). The metabolic state of ketogenic diets is relatable in many ways to fasting; in fact, even in fasting, that particular metabolic state known under the name of ketosis is established. The first in-depth scientific studies on this metabolic condition were those conducted by Cahill's group in the 1960s starting precisely from the "fasted" or "fasting" condition (9, 22). That of fasting is in fact a practice, or rather a technique, used for millennia to achieve particular states of spiritual well-being during rituals or religious practices. Even in the Old Testament as well as in the Qur'an and the Mahabharata there is mention of this ascetic practice.

We can find a reference to fasting, for example, in Matthew (17:14-21) where, in the episode of the 'healed epileptic, it is said, "This race of demons is not cast out except by prayer and fasting"; and it is no coincidence that fasting is mentioned in connection with epilepsy since it has been known since the 1920s that ketosis ( and thus fasting) is able to improve some types of epilepsy (29). Of course, one of the problems with fasting is the progressive depletion of the body's protein reserves. Modern ketogenic diets, on the other hand, seek to induce a state of ketosis while providing adequate protein intake so as to maintain lean mass; in fact, they have also often been called modified fasting "modified fasting diets" (5) or low carbohydrate and protein-sparing "low carbohydrate protein sparing modified diets" (3).

Without carbohydrates, our body cannot follow the metabolic pathways it usually uses to assimilate fats. After a few days of fasting or a diet with drastic reduction of carbohydrates (less than 20 g per day), the body's reserve glucose becomes insufficient to allow both the normal oxidation of fats through the supply of oxaloacetate in the Krebs cycle and the supply of glucose to the CNS (central nervous system) (21, 22). Regarding the first point, namely, the supply of oxaloacetate to the Krebs cycle (which justifies the phrase : "fats burn at the flame of carbon hydrates"), it must be remembered how oxaloacetate is relatively unstable at body temperature and thus cannot be accumulated in the mitochondrial matrix. There is then a need to replenish the tricarboxylic acid cycle with oxaloacetate through the anaplerotic cycle that leads precisely from glucose to oxaloacetate, through ATP-dependent carboxylation of pyruvic acid by pyruvate-carboxylase (ATP-dependent biotin-enzyme) (29).

Regarding the second point, it is well known that since the CNS cannot use fats for energy purposes (since they cannot pass the blood-brain barrier), it normally uses glucose; therefore, after the first 3 to 4 days of the absence of carbohydrates in the diet, the CNS is "forced" to find alternative sources to replenish its energy supply, as demonstrated by the now-historic studies of Cahill's group (11). This alternative source of energy is the DCs produced from excess acetyl-CoA, DCs that the CNS is able to use for energy purposes. These ketone bodies produced under the particular metabolic conditions already listed (prolonged fasting, diabetes, lipid overeating, and verylowcarb diets), are more specifically: acetoacetic acid (AcAc); β-hydroxybutyric acid (3HB); and acetone. The production of ketone bodies is called ketogenesis and occurs specifically in the mitochondrial matrix of the liver.

La presenza in circolo dei CC e la loro eliminazione con le urine causano la chetonemia e la chetonuria. L’eliminazione dell’acetone, essendo un composto molto volatile, avviene prevalentemente con la respirazione polmonare. La via che porta alla formazione di HMG-CoA (idrossimetilglutarilcoenzimaA) da acetil-CoA è presente anche nel citosol delle cellule epatiche, dove viene invece utilizzato per la biosintesi del colesterolo. I CC derivano quindi da un processo che avviene nel fegato a carico dei grassi. In condizioni normali i CC sono in concentrazioni molto basse (<0,3 mmol) rispetto al glucosio (circa 4mmol). Dal momento che il glucosio ed i corpi chetonici hanno una KM (costante di Michaelis-Menten) simile per il trasporto del glucosio a livello cerebrale, i CC incominciano a venire utilizzati a livello del SNC quando arrivano ad un valore di circa 4 mmol/L , che è quello del trasportatore delle monocarbossilasi anche se i dati delle letteratura clinica ci dicono che i valori durante una dieta VLCKD si aggirino intorno ai 1-3 mmol/L di corpi chetonici ematici. Ci preme sottolineare come la chetosi sia un meccanismo del tutto fisiologico che ha permesso ai nostri antenati di sopravvivere e rimanere efficienti anche in caso di privazione di cibo (1). Il biochimico Hans Krebs fu il primo a parlare di chetosi fisiologica per distinguerla da quella patologica della cheto acidosi diabetica (18).

In ketoacidosis, it is also possible to measure the blood (as well as urinary) concentration of Acetoacetate and 3-HydroxyButyrate. It is mainly used in the control of diabetic keto acidosis in conjunction with lactate/pyruvate ratio. The dual measurement of Lactate/Pyruvate and 3-HydroxyButyrate/Aceto-acetate ratio is also an index of the body's redox state related to the NAD+/NADH ratio.

However, 3-HydroxyButyrate appears to be a better indicator than Acetoacetate; and the ratio of CCs gives a very useful information in metabolic assessment. The normal 3HB / Aceto-acetate ratio is 3:1 but in ketosis there are values as high as 6:1 and up to 12:1.

In physiological ketosis (which is achieved during fasting and VLCKD diets) ketonemia reaches maximum levels of 7/8 mmol/L with unchanged pH, while in decompensated diabetes it reaches and exceeds 20 mmol/L with lowering of pH(28, 29). Blood values of DCs do not exceed 8 mmol/L in the healthy individual because the CNS precisely efficiently uses these molecules for energy purposes in place of glucose. As previously mentioned, blood values during a VLCKD are around 1-3 mmol/L while blood glucose around 4-4.4 mmol/dL.

It has been shown that CCs could increase the hydraulic efficiency of the heart by 28%, and this effect cannot be explained solely by changes in the glycolytic pathway, but rather by induced changes in mitochondrial ATP production by ketone bodies (17, 32). Another point to emphasize, as highlighted by Table 1, is that blood glucose, although lowering remains at physiological levels (29). In fact, glucose formed from gluconeogenetic amino acids and glycerol liberated from triglyceride lysis is sufficient for the maintenance of euglycemia (39).

It has to be said that ketosis is a phenomenon closely related to the human species (i.e., humans are easier to ketosis than other mammals), and this peculiarity is to be found in the brain/body mass ratio, which is significantly higher in humans than in other animals. This implies that the glucose produced by neoglucogenesis ( from amino acids) is not sufficient for both basic functions (brain and oxaloacetate) and therefore the CNS has been "forced" to make better use of an alternative fuel, namely ketone bodies; in this way the glucose produced through neoglucogenesis ( and as the days go by the glucose produced from triglyceride glycerol also gains importance; more than 16% of the glucose produced by the liver during a ketogenic diet and about 60% during a complete fast)(7, 37) .

There is much research confirming that ketogenic diets are more effective than classical low-calorie diets in fat loss, at least in the medium term (8, 23). The mechanisms underlying this effect are unclear but a number of causes can be hypothesized: one of these is the suggestive hypothesis that there is metabolic advantage that could explain the important effect of VLCKDs on weight loss. Authors espousing this line of thought hypothesize that the utilization, for energy purposes, of protein in VLCKDs is an "expensive" process for the body and therefore may lead to a" waste of calories" (12). In a very low-carbohydrate diet, in fact, our body needs in the first phase about 60-65grams of glucose per day, which is derived to a lesser extent (16%) from glycerol and for the most part from gluconeogenesis of dietary or tissue proteins.

The role of energy expenditure for gluconeogenesis in VLCKDs has been confirmed by several authors (19, 39, 41, 42), and the cost of this process (from endogenous and dietary proteins) has been calculated to be approximately at 400-600Kcal/day (10). Although there are actually no definitive data on this aspect (29). Another factor to consider is the specific dynamic action of foods now called the thermogenic effect of nutrients (thermogenicresponse to food). This parameter calculates the energy expenditure that our body must incur to absorb and metabolize nutrients. This energy expenditure amounts, averaging the literature, to 7%, 2.5% and 27% of the calories contributed by, respectively, CHO, fat and protein (16).

It is intuitive that by changing nutrient ratios we could act on this aspect of daily caloric expenditure. Another aspect that seems to have recently emerged is the minor influence that ketogenic diets seem to have on the mediators of hunger (ghrelin) and satiety (PYY, CCK, etc.).; in fact, it seems that low-calorie diets cause an increase in hunger signals and reduction in satiety signals even months after the end of the diet while ketogenic diets seem to have less influence on this scenario (34, 35). Finally, there are preliminary data that seem to indicate that ketogenic diets act on metabolism by lowering the respiratory quotient (ratio of exhaled CO2 to consumed O2) thus indicating a favored use of fats over sugars (25, 27, 36).

In summary, we can therefore say that the effect on weight loss of VLCKD diets seems to be caused by several factors:

• appetite reduction through the action of proteins and ketone bodies, although the mechanism of the latter has not yet been well understood;
• Less influence on "signals" related to hunger and satiety compared to classical low-calorie diets;
• Reduction of liposynthesis mechanisms and increase of lipolytic mechanisms;
• Decrease in the respiratory quotient at rest. The respiratory quotient or QR represents the ratio of CO2 produced to O2 consumed (CO2/O2); the QR of sugars is 1, while for a fatty acid mixture it is 0.7;
• Increased metabolic expenditure caused by gluconeogenesis and protein thermal action.

It has been widely demonstrated how the ketogenic diet can be useful in improving the outcomes of metabolic syndrome and type 2 diabetes. The mechanisms are generally related to a reduction in circulating insulin levels, a consequent reduction in blood glucose, and an improvement in the lipemic profile, especially a reduction in triglycerides and an increase in HDL with a consensual reduction in LDL and an increase in LDL size, a factor that contributes to a reduction in atherogenic risk (26, 33, 40, 43). The reduction in insulin not only acts on the decrease in circulating glucose but also on endogenous cholesterol production. In fact, low circulating levels of insulin reduce the activation of HMGCa reductase with a consequent reduction in cholesterol production (30).

Insulin resistance thus seems to be the key factor on which VLCKDs act, not only in prediabetes or type 2 diabetes conditions but also in the general population. The efficacy of insulin action on cells may show varying degrees of dysfunction in turn related to varying degrees of symptoms and signs. In the case of insulin resistance, subjects have difficulty utilizing glucose at the muscle level but also reduce hepatic glucose release. Subjects with insulin resistance use a greater proportion of glucose at the liver level where it is converted to fat (de novo lipogenesis) instead of being oxidized at the muscle level. These fats mostly enter the bloodstream as saturated fats increasing the risk of diabetes and cardiovascular disease. This condition, more widely known as impaired glucose tolerance can be significantly reduced by reducing carbohydrate intake to a level where it is not converted into fat.

Molti studi ben controllati hanno valutato la risposta di soggetti con diabete di tipo 2 a diete chetogeniche nel breve e nel lungo periodo, dimostrando anche un'elevata compliance dei pazienti. In un lavoro oramai storico Bistrian e colleghi hanno dimostrato un calo dell'insulina ed una significativa perdita di peso nei soggetti affetti da diabete di tipo 2 durante una VLCKD ipocalorica (4). Stessi risultati ottenuti da Gumbiner (15) qualche anno più tardi in due gruppi con identica quantità di proteine ma uno in dieta chetogenica l'altro in dieta non chetogenica. Il gruppo a bassi carboidrati (con una concentrazione di corpi chetonici di circa 3 mmol/L ) aveva dimostrato un miglioramento di tutti gli outcomes collegati al metabolismo del glucosio.  Più recentemente Boden (6) ha studiato pazienti diabetici di tipo 2 sottoposti ad una dieta con meno di 20 grammi al giorno di carboidrati per 2 settimane.

Blood glucose dropped from 7.5 to 6.3 mmol/L and hemoglobin A1c from 7.3 to 6.8 percent with a dramatic improvement (75 percent) in insulinemic sensitivity as measured by the calmopeuglycemiciperinsulinemic. In a longer study Dashti studied type 2 diabetic and obese subjects on a ketogenic diet for 56 weeks demonstrating significant weight loss and metabolic improvement as early as 12 weeks. This improvement continued throughout the 56 weeks leading to improvements in fasting blood glucose (-51%), total cholesterol (-29&), HDL-C (+63%), LDL-C (-33%) and triglycerides (-41%). Other studies confirm the effectiveness of a ketogenic diet in treating complications of type 2 diabetes (20, 44). The effects of ketogenic diets are not only related to weight loss; in fact, positive metabolic effects occur even in the absence or equivalence of weight loss (13, 14).