Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets
By A Paoli A Rubini JS Volek and KA Grimaldi
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.
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.
The knowledge regarding the metabolic effects of classic ketogenic diets originates from the pioneering work of Cahill and colleagues in the 1960s. There even appears to be a reference to its use in the Bible in the story of the cured epileptic (New• Testament, Matthew 17:14-21). There is also ample evidence to support the notion that a low-carbohydrate diet can lead to an improvement in some metabolic pathways and have beneficial health effects.
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).
The characteristic ‘sweet breath’ odour of ketosis is caused by acetone which, being a very volatile compound, is eliminated mainly via respiration in the lungs.
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.
There is no doubt that there is strong supportive evidence that the use of ketogenic diets in weight-loss therapy is effective; however, there are contrasting theories regarding the mechanisms through which they work. Some researchers suggest that there are not in fact any metabolic advantages in lowcarbohydrate diets and that weight loss results simply from reduced caloric intake, probably due to the increased satiety effect of protein.
The first law of thermodynamics, also known as the law of conservation of energy, has controlled the concepts for the basis of weight loss for over a century – resulting in a difficulty in accepting other ways of thinking. Adhering to these traditional concepts the US Department of Agriculture has concluded that diets, which reduce calories, will result in effective weight loss independent of the macronutrient composition, which is considered less important, even irrelevant.
In contrast with these views, the majority of ad-libitum studies demonstrate that subjects who follow a low carbohydrate diet lose more weight during the first 3-6 months compared with those who follow balanced diets.
A simpler, perhaps more likely, explanation for improved weight loss is a possible appetite-suppressant action of ketosis. The mechanism for this is not established but evidence supports direct action of KBs together with modifications in levels of hormones, which influence appetite, such as ghrelin and leptin.
Here we can summarize (listed in order of importance) that the weight-loss effect of VLCKD* seems to be caused by several factors:
1. Reduction in appetite due to higher satiety effect of proteins, effects on appetite control hormones and to a possible direct appetite-suppressant action of the KBs.
2. Reduction in lipogenesis and increased lipolysis.
3. Reduction in the resting respiratory quotient and, therefore, greater metabolic efficiency in consuming fats.
4. Increased metabolic costs of gluconeogenesis and the thermic effect of proteins.
*Very Low Calorie Ketogenic Diet
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, and clearly negative opinions regarding possible deleterious effects on triglycerides and cholesterol levels in the blood. 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?’ ) can actually lead to significant benefits in blood lipid profiles.
The VLCKD effect seems to be particularly marked on the level of blood triglycerides, but there are also significant positive effects on total cholesterol reduction and increases in high-density lipoprotein.
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.
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.
Bistrian et al reported withdrawal of insulin and major weight loss in a matter of weeks in T2D individuals who were fed a very-low-calorie and -carbohydrate diet.
Interestingly, there was a strong inverse correlation between circulating ketones and hepatic glucose output, suggesting that higher levels of ketones are associated with more favourable effects on glycaemic control in diabetics.
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.
It is interesting in this respect that a recent extremely large epidemiological study reported that diabetes risk is directly correlated, in an apparently causative manner, with sugar intake alone, independently of weight or sedentary lifestyle.
Since 1920, the ketogenic diet has been recognized as an effective tool in the treatment of severe childhood epilepsy, but following the introduction of anticonvulsant drugs, the interest in ketogenic diet treatment waned until the 1990s, with subsequent research and clinical trials demonstrating its practical usefulness.
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, 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.
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.
In summary, there is persuasive, although not yet conclusive, clinical and physiological evidence that the ketogenic diet could be effective in reducing the severity and progression of acne and randomized clinical trials will be required to resolve the issue.
It seems a reasonable possibility that a very-lowcarbohydrate diet could help to reduce the progression of some types of cancer, although at present the evidence is prellminary.
Perhaps through glucose ‘starvation’ of tumour cells and by reducing the effect of direct insulin-related actions on cell growth, ketogenic diets show promise as an aid in at least some kind of cancer therapy and is deserving of further and deeper investigation.
It is evident that any interventions that improve insulinaemia and reduce body weight may also be effective in reducing hyperandrogenism, normalizing ovulation and reducing the various symptoms of PCOS.
Emerging data suggest a possible therapeutic utilization of ketogenic diets in multiple neurological disorders apart from epilepsy, including headache, neuro-trauma, Alzheimer’s and Parkinson’s disease, sleep disorders, brain cancer, autism and multiple sclerosis. 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.
KBs were recently reported to act as neuro-protective agents by raising ATP levels and reducing the production of reactive oxygen species in neurological tissues, together with increased mitochondrial biogenesis, which may help to enhance the regulation of synaptic function.
Moreover, the increased synthesis of polyunsaturated fatty acids stimulated by a KD may have a role in the regulation of neuronal membrane excitability: it has been demonstrated, for example, that polyunsaturated fatty acids modulate the excitability of neurons by blocking voltage-gated sodium channels. Another possibility is that by reducing glucose metabolism, ketogenic diets may activate anticonvulsant mechanisms, as has been reported in a rat model.
Patients affected with Alzheimer’s disease show a higher incidence of seizures compared with unaffected people, and it has recent been reported that neuronal excitability is enhanced and neuronal circuits and mitochondrial homeostasis are altered.
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.
The possible beneficial effects of ketogenic diets on mitochondrial activity has also been proposed to explain the improved scores on a standard gravity scale of Parkinson’ disease exhibited by some patients.
Traumatic brain injury may lead over time to epilepsy. Because of the effective use of the ketogenic diet in reducing seizures, 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.
Dysfunction in energy production, that is, mitochondrial function impairment, is likely to have a role in the pathogenesis of many neuro-degenerative diseases, perhaps including amyotrophic lateral sclerosis. On this basis, a ketogenic diet has been proposed as a collateral therapeutic approach in this disease.
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.
These findings at least suggest potential useful effects of this diet in patients with increased carbon dioxide, arterial partial-pressure values as a consequence of respiratory failure.
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 hyper-filtration. There is not wide agreement between studies however, some infer the possibility of renal damage from animal studies, 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. In subjects with intact renal function, higher dietary protein levels caused some functional and morphological adaptations without negative effects. There may actually be renal-related effects, but on blood pressure rather than morphological damage.
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.