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Abstract

Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician's hand.

Keywords: ketogenic diet; cancer; diabetes; neurological diseases; obesity; cardiovascular diseases

Introduction

During recent years, an increasing amount of evidence has accumulated in the literature, suggesting that very-low-carbohydrate ketogenic diets (VLCKD) could have a therapeutic role in numerous diseases. The use of VLCKD in treating epilepsy has been well established for many decades and these diets have become even more widely known, as they became popular in the 1970s for weight loss - especially as the 'Atkins Diet'.[1] More recently, the therapeutic use of ketogenic diets in other diseases has been studied with positive results - it is an important direction for research because, clearly, if nutritional intervention can reduce reliance on pharmaceutical treatments it would bring significant benefits from an economic as well as a social point of view given the current US $750 billion annual cost of pharmaceuticals.[2]

Ketogenic diets are characterized by a reduction in carbohydrates (usually to less than 50 g/day) and a relative increase in the proportions of protein and fat.[3] The knowledge regarding the metabolic effects of classic ketogenic diets originates from the pioneering work of Cahill and colleagues in the 1960s,[4] but the realization of the importance of these diets from a clinical point of view can be traced back to the early 1920s when they began to be successfully used in the treatment of epilepsy.[5] [...]

What is ketosis?

Insulin activates key enzymes in pathways, which store energy derived from carbohydrates, and when there is an absence or scarcity of dietary carbohydrates the resulting reduced insulin level leads to a reduction in lipogenesis and fat accumulation. After a few days of fasting, or of drastically reduced carbohydrate consumption (below 50 g/day), glucose reserves become insufficient both for normal fat oxidation via the supply of oxaloacetate in the Krebs cycle (which gave origin to the phrase 'fat burns in the flame of carbohydrate') and for the supply of glucose to the central nervous system (CNS).[4]

The CNS cannot use fat as an energy source; hence, it normally utilizes glucose. After 3 - 4 days without carbohydrate consumption the CNS is 'forced' to find alternative energy sources, and as demonstrated by the classic experiments of Cahill and colleagues[4] this alternative energy source is derived from the overproduction of acetyl coenzyme A (CoA). This condition seen in prolonged fasting, type 1 diabetes and high-fat/low-carbohydrate diets leads to the production of higher-than-normal levels of so-called ketone bodies (KBs), that is, acetoacetate, β-hydroxybutyric acid and acetone - a process called ketogenesis and which occurs principally in the mitochondrial matrix in the liver.[6][...]

KBs are then used by tissues as a source of energy[3] through a pathway that leads to formation from β-hydroxybutyrate of two molecules of acetyl CoA, which are used finally in the Krebs cycle. It is interesting to note that the KBs are able to produce more energy compared with glucose because of the metabolic effects of ketosis - the high chemical potential of 3-β-hydroxybutyrate leads to an increase in the ΔG0 of ATP hydrolysis.[3] A further point to underline is, as shown in Table 1, that glycaemia, even though reduced, remains within physiological levels because of the fact that glucose is formed from two sources: from glucogenic amino acids and from glycerol liberated via lysis from triglycerides.[7]

We would like to emphasize that ketosis is a completely physiological mechanism and it was the biochemist Hans Krebs who first referred to physiological ketosis to differentiate it from the pathological keto acidosis seen in type 1 diabetes.[8] In physiological ketosis (which occurs during very-low-calorie ketogenic diets), ketonemia reaches maximum levels of 7/8 mmol/l (it does not go higher precisely because the CNS efficiently uses these molecules for energy in place of glucose) and with no change in pH, whereas in uncontrolled diabetic ketoacidosis it can exceed 20 mmol/l with a concomitant lowering of blood pH9[...]

Therapeutic roles of ketogenic diets

Strong evidence

Weight loss

[...] Here we can summarize (listed in order of importance and available evidence) that the weight-loss effect of VLCKD seems to be caused by several factors:

-Reduction in appetite due to higher satiety effect of proteins,[12, 22] effects on appetite control hormones[21] and to a possible direct appetite-suppressant action of the KBs.[23]
-Reduction in lipogenesis and increased lipolysis.[7, 10]
-Reduction in the resting respiratory quotient and, therefore, greater metabolic efficiency in consuming fats.[20, 24]
-Increased metabolic costs of gluconeogenesis and the thermic effect of proteins.[13, 18]

Cardiovascular disease

Several lines of evidence point to beneficial effects of VLCKD on cardiovascular risk factors. In the past, there have been doubts expressed about their long-term safety and increased effectiveness compared with 'balanced' diets,[25] and clearly negative opinions regarding possible deleterious effects on triglycerides and cholesterol levels in the blood.[26] However, the majority of recent studies seem instead to amply demonstrate that the reduction of carbohydrates to levels that induce physiological ketosis (see above 'What is ketosis?' section) can actually lead to significant benefits in blood lipid profiles.[15, 17, 27] [...]

Type 2 diabetes

Insulin resistance is the primary feature underlying type 2 diabetes (T2D) but it also exists across a continuum in the general population, and to varying extents it disrupts insulin action in cells, which can cause a wide spectrum of signs and symptoms. A primary feature of insulin resistance is an impaired ability of muscle cells to take up circulating glucose. A person with insulin resistance will divert a greater proportion of dietary carbohydrate to the liver where much of it is converted to fat (that is, de novo lipogenesis), as opposed to being oxidized for energy in skeletal muscle.[30] Although Hellerstein[31] has recently reported that de novo lipogenesis contributes only ~20% of new triglycerides, this greater conversion of dietary carbohydrate into fat, much of it entering the circulation as saturated fat, is a metabolic abnormality that significantly increases risk for diabetes and heart disease. Thus, insulin resistance functionally manifests itself as 'carbohydrate intolerance'. When dietary carbohydrate is restricted to a level below which it is not significantly converted to fat (a threshold that varies from person to person), signs and symptoms of insulin resistance improve or often disappear completely.

[...] Although significant reductions in fat mass often results when individuals restrict carbohydrate, the improvements in glycaemic control, haemoglobin A1c and lipid markers, as well as reduced use or withdrawal of insulin and other medications in many cases, occurs before significant weight loss occurs. Moreover, in isocaloric experiments individuals with insulin resistance showed dramatically improved markers of metabolic syndrome than diets lower in fat.[27] [...]

In summary, individuals with metabolic syndrome, insulin resistance and T2D (all diseases of carbohydrate intolerance) are likely to see symptomatic as well as objective improvements in biomarkers of disease risk if they follow a well-formulated very-low-carbohydrate diet. Glucose control improves not only because there is less glucose coming in, but also because systemic insulin sensitivity improves as well.

Epilepsy

[...] Although the mechanisms of action are not clear, the ketogenic diet is now considered an established part of an integrative approach, along with drug therapy, in the major epilepsy centres worldwide,[42] an important benefit being the reduction of drug use and concomitant reductions in severe side effects often associated with antiepileptic agents. The effectiveness of ketogenic diets is strongly supported in a recent Cochrane review where all studies showed a 30 - 40% reduction in seizures compared with comparative controls, and the review authors reported that in children the effects were 'comparable to modern antiepileptic drugs'. The main drawback with the ketogenic diet was difficult tolerability and high dropout rates - given the extremely positive results and the severe side effects common with antiepilepsy medication, the development of an easier-to-follow ketogenic diet would be a worthwhile goal.[5][...]

Emerging evidence

Acne

In recent years there have been an increasing number of studies published, suggesting that at least for certain food types there is a nutritional influence on the development of acne. The negative effects seem to lie in the capacity of some foods/nutrients to stimulate proliferative pathways that in turn stimulate development of acne - suspect foods include those with a high glycaemic load and milk.[11, 43, 44] [...] Various studies have provided evidence that high-glycaemic-load diets are implicated in the aetiology of acne through their capacity to stimulate insulin, androgen bioavailability and insulin-like growth factor-1 (IGF-1) activity, whereas the beneficial effects of low-glycaemic-load diets, apart from weight and blood glucose levels, also include improved skin quality.[44] [...]

Cancer

Carcinogenesis is a complex process involving multiple sequential mutations, which occur randomly in the DNA of normal cells over many years, even decades, until finally specific genes are mutated and cell growth becomes out of control resulting in the full neoplastic phenotype and often metastasis. There is evidence that hyperinsulinaemia, hyperglycaemia and chronic inflammation may affect the neoplastic process through various pathways, including the insulin/IGF-1 pathway, and most cancer cells express insulin and IGF-1 receptors. Insulin has been shown to stimulate mitogenesis (even in cells lacking IGF-1 receptors)[50] and it may also contribute by stimulating multiple cancer mechanisms, including proliferation, protection from apoptotic stimuli, invasion and metastasis.[51] [...] Considering the obvious relationship between carbohydrates and insulin (and IGF-1) a connection between carbohydrate and cancer is a possible consequence, and some links have been recognized since the 1920s when the Russo-German physician Dr A Braunstein observed that glycosuria falls off notably in diabetic patients who developed cancer.[54] Later Warburg et al.[55] of the Kaiser Wilheim Institute fur biologie described what was later known as the Warburg effect - where energy is predominantly generated by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, even in the presence of plentiful oxygen.[51, 55] The Warburg effect has been confirmed in many studies and today is a well-established hallmark of many types of cancers, and rapidly growing tumour cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin.[56] [...] In the 1980s, seminal animal studies by Tisdale and colleagues[62, 63] demonstrated that a ketogenic diet was capable to reduce tumour size in mice, whereas more recent research has provided evidence that ketogenic diets may reduce tumour progression in humans, at least as far as gastric and brain cancers are concerned.[...]

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in females, with a high prevalence (6 - 10%);72 symptoms include hyperandrogenism, ovulatory dysfunction, obesity, insulin resistance and subfertility. Insulin resistance and related hyperinsulinaemia is actually a very common feature affecting about 65 - 70% of women with PCOS[...]

Neurological diseases 

Emerging data suggest a possible therapeutic utilization of ketogenic diets in multiple neurological disorders apart from epilepsy,[78] including head ache, neurotrauma, Alzheimer's and Parkinson's disease, sleep disorders, brain cancer, autism and multiple sclerosis.[79] Although these various diseases are clearly different from each other, a common basis potentially explaining ketogenic diet efficacy could be a neuroprotective effect in any disease in which the pathogenesis includes abnormalities in cellular energy utilization, which is a common characteristic in many neurological disorders.[79] The exact mechanism(s) by which a ketogenic diet may act is still poorly understood; however, some published reports can provide useful suggestions. For example, KBs were recently reported to act as neuroprotective agents by raising ATP levels and reducing the production of reactive oxygen species in neurological tissues,[80] together with increased mitochondrial biogenesis, which may help to enhance the regulation of synaptic function.[80] [...]

Alzheimer's disease

Patients affected with Alzheimer's disease show a higher incidence of seizures compared with unaffected people,84 and it has recently been reported that neuronal excitability is enhanced[,85, 86] and neuronal circuits and mitochondrial homeostasis are altered.[87]

On the basis of the reports described above, these results indicate a possible role of the ketogenic diet in the treatment of Alzheimer's disease in the clinic. Supporting evidence is provided by a study, which reported that at least in selected conditions a significant clinical improvement was observed in Alzheimer's patients fed a ketogenic diet.88 It was suggested that this was, at least in part, related to improved mitochondrial function secondary to the reported protective effects of KBs against the toxic consequences of the exposure of cultured neurons to β-amyloid.[...]

Parkinson's disease

The possible beneficial effects of ketogenic diets on mitochondrial activity described above has also been proposed to explain the improved scores on a standard gravity scale of Parkinson' disease exhibited by some patients.[91] In addition, the typical mitochondrial respiratory chain damage that occurs in animal models of Parkinson's disease was reduced by a ketogenic diet;[89] however, the real utility of this diet remains largely speculative and uncertain.

Brain trauma

Traumatic brain injury may lead over time to epilepsy. Because of the effective use of the ketogenic diet in reducing seizures (see above), it has been suggested that it may also improve the clinical status in brain injury, especially by reducing the incidence of long-term consequences, such as epilepsy.[79] Positive effects of a ketogenic diet have also been reported in reducing the cortical contusion volume in an age-dependent manner in an animal model of cortical injury, which is related to the maturation-dependent variability in brain ketone metabolism.[92] These findings were also supported by the demonstration that a ketogenic diet reduced post-traumatic cognitive and motor function impairment, at least in a rat model.[93][...]

Amyotrophic lateral sclerosis

Dysfunction in energy production, that is, mitochondrial function impairment, is likely to have a role in the pathogenesis of many neurodegenerative diseases, perhaps including amyotrophic lateral sclerosis.On this basis, a ketogenic diet has been proposed as a collateral therapeutic approach in this disease.[95] Studies by Zhao et al.[96] revealed both histological and functional improvements in an animal model of amyotrophic lateral sclerosis when a ketogenic diet was given compared with when given a control diet.[...]

The effect of a ketogenic diet on respiratory function

The metabolic effects of a ketogenic diet imply a higher-than-usual oxidation of fats, which leads in turn to reduced respiratory exchange ratio values.[20, 97] [...] Hence, following a ketogenic diet-induced decrement of the respiratory exchange ratio and of metabolic carbon dioxide output, a decrease in arterial carbon dioxide partial pressure or of pulmonary ventilation, or of both, is expected. If verified, these effects might be useful in the treatment of patients with respiratory failure; however, this aspect of the ketogenic diet remains to be investigated. [...]

Potential risks of ketogenic diets

If we equate de facto ketogenic diets with high-protein diets (which is not always correct) then the risks proposed by critics of this type of dietary approach are essentially those of possible kidney damage due to high levels of nitrogen excretion during protein metabolism, which can cause an increase in glomerular pressure and hyperfiltration.[12] There is not wide agreement between studies; however, some infer the possibility of renal damage from animal studies,[99, 100] whereas others, looking at both animal models, meta-analyses and human studies, propose that even high levels of protein in the diet do not damage renal function.[101, 102] In subjects with intact renal function, higher dietary protein levels caused some functional and morphological adaptations without negative effects.[103] There may actually be renal-related effects, but on blood pressure rather than morphological damage. The amino acids involved in gluconeogenesis and/or production of urea in general have blood-pressure-lowering effects, whereas acidifying amino acids tend to cause a rise in blood pressure. Subjects with renal insufficiency, even subclinical, kidney transplant patients and people with metabolic syndrome or other obesity-related conditions, will be more susceptible to the hypertensive effect of amino acids, especially of the sulphated variety.[...]

Moreover, it should be noted that ketogenic diets are only relatively high in protein[18, 106] and that some recent studies have demonstrated that VLCKD can even cause a regression of diabetic nephropathy in mice.[109] With regard to possible acidosis during VLCKD, as the concentration of KBs never rises above 8 mmol/l10 this risk is virtually inexistent in subjects with normal insulin function.

Conclusions

Ketogenic diets are commonly considered to be a useful tool for weight control and many studies suggest that they could be more efficient than low-fat diets, although there is not concordance in the literature about their absolute effectiveness and even some doubts raised about safety. But there is a 'hidden face' of the ketogenic diet: its broader therapeutic action. There are new and exciting scenarios about the use of ketogenic diets, as discussed in this review, in cancer, T2D, PCOS, cardiovascular and neurological diseases. Further studies are warranted to investigate more in detail the potential therapeutic mechanisms, its effectiveness and safety, and we would invite all researchers to face this challenge without prejudice.