Prescribing dietary fat: therapeutic uses of ketogenic diets
By Catherine Watkins
- The high-fat, adequate-protein, and very-low-carbohydrate way of eating known as the ketogenic diet (KD) has been used to treat epilepsy for almost 100 years.
- The therapeutic effects of KDs have been investigated in a number of diseases and disorders, including diabetes, obesity, cancer, cardiovascular disease, and neurological conditions such as Alzheimer's and Parkinson's disease.
- This article provides an overview of where the research stands.
One of the victims of the war against dietary fat has been the ketogenic (ketone-producing) diet. This high-fat, adequate-protein, and very-low-carbohydrate way of eating has been known for more than 100 years as an effective treatment for a number of disorders. William Banting published a monograph in 1863 titled Letter on Corpulence, which detailed the successful treatment of his own obesity with a low-carbohydrate diet. Severe childhood epilepsy has been treated since the 1920s with the ketogenic diet (KD), and some type 2 diabetics have achieved normal blood glucose levels without medication by following a high-fat, low-carbohydrate diet.
Despite an abundant anecdotal and scientific history, many modern-day physicians-often underschooled in nutrition and over-reliant on pharmacotherapy-have written off KDs as being unsustainable and unsafe, thanks in large part to the demonization of dietary fat. Now, however, after a significant increase in research on KDs and a shift in opinion regarding dietary fat, ketogenic diets are experiencing a comeback.
A recent review article co-written by Jeffrey S. Volek neatly summarizes a number of the conditions in which KDs appear to play a therapeutic role. These include a wide variety of neurological conditions such as epilepsy and Alzheimer's disease, diabetes, and certain cancers. In addition, KDs may improve cardiovascular risk parameters. The review, which appeared in the European Journal of Clinical Nutrition (Paoli, A., et al., http://dx.doi.org/10.1038/ejcn.2013.116, 2013), serves as the backbone of this feature article.
"There are so many exciting developments in nearly every chronic noncommunicable disease, especially type 2 diabetes and other diseases associated with insulin resistance such as heart disease and polycystic ovary syndrome," Volek wrote in an email. "The science supporting ketogenic diets for healthy weight loss is impressive, but equally exciting is the application in a number of other conditions." Volek is a registered dietitian and a professor in the Department of Human Sciences at The Ohio State University (Columbus, USA) and an associate professor in the Department of Kinesiology at the University of Connecticut (Storrs, USA).
What constitutes a ketogenic diet?
Researchers are still working to establish precisely why and how KDs lead to therapeutic outcomes, but the "what" of the matter is well understood.
At its simplest, there are two possible sources of fuel for most cellular functions-glucose or fat. However, cellular respiration (energy production in the presence of oxygen) using glucose has a weakness: The body can only bank about 1,000-1,600 calories of excess carbohydrate as glycogen-the storage form of glucose. Any excess glucose beyond that is converted via lipogenesis into fat and is stored. On the other hand, either dietary or stored fat can fuel cellular respiration using ketone bodies (a byproduct of the breakdown of fatty acids in the liver). Since many of us have too much of the latter and ready access to the former, fat-as-fuel is in plentiful supply. The advantage of metabolizing stored fat for the overweight and obese is obvious.
Once the body's glucose and glycogen stores are depleted, ketosis begins, and the body uses stored and/or dietary fat as energy. Generally, carbohydrate consumption must be below 50-60 g/day for ketosis to begin, although each person's metabolic requirement is unique. The popular and well-studied Atkins diet, which is a type of KD, calls for no more than 20 g of carbohydrate/day during its initial phase. To put that in perspective, there are about 7 g of carbohydrate in 100 g of raw broccoli and 31 g of carbohydrate in 100 g of cooked pasta. (See Table 1 for the macronutrient ranges of ketogenic diets.)
|TABLE 1. Macronutrient ranges and total grams for ketogenic diets
|Macronutrient||% of calories||Total grams*|
|Dietary fat||70-85%||178 g|
|*Based on 2,000 calories/day with 80% fat, 15% protein, 5% carbohydrate
Likewise, protein must be held at moderate levels-generally between 15-20% of total daily calories-because the liver will convert as much as 60% of excess protein into glucose via gluconeogenesis, thus stopping ketosis. Fats from sources such as butter, coconut oil, and extra virgin olive oil make up the remainder of the KD macronutrient equation (usually between 70-85% of daily calories).
Although the body needs small amounts of glucose to function, dietary carbohydrate in and of itself is not an essential nutrient. When ketosis begins, fat-whether stored or consumed-becomes the primary metabolic fuel in the form of ketone bodies (KBs). The three KBs produced by the liver from fatty acids are acetone, acetoacetic acid, and β-hydroxybutyric acid (BHB). Acetoacetate and BHB can be converted into acetyl-CoA and burned for energy through the citric acid cycle. Acetone can be converted into pyruvate, although it generally is excreted as waste; in some circumstances, it can be metabolized into glucose. The heart favors the use of fatty acids for energy in normal conditions, and it has no problem using KBs under ketotic conditions. The brain requires some glucose under both normal and ketotic conditions; this is readily produced by the liver in ketosis through gluconeogenesis using substrates such as pyruvate, lactate, glycerol, and glucogenic amino acids.
Clearly, the biochemistry of KDs is much more complicated than this bare-bones description suggests. The focus of this article, however, is on research regarding therapeutic uses of KDs and not on the cellular mechanisms at play.
Ketosis vs. ketoacidosis: are KDs safe?
Nutritional ketosis is a normal, strictly benign, and tightly regulated physiological process. Yet, medical practitioners often confuse it with ketoacidosis, a pathological condition seen in some insulin-dependent diabetics (type 1, or T1D) when they are under stress and/or have failed to administer enough insulin. This confusion has led to the mistaken idea that KDs and nutritional ketosis are inherently dangerous.
"Ketogenic diets are metabolically regulated and are far outside the danger range of ketoacidosis," said Richard D. Feinman, a professor of cell biology and medical researcher at the State University of New York Downstate Medical Center in Brooklyn (USA). Feinman is the author of The World Turned Upside Down: The Second Low-Carbohydrate Revolution (2014) and a pioneer in incorporating nutrition into the biochemistry curriculum.
"The low-carbohydrate way of eating in general is probably the safest thing you can do to improve your diet," he continued. "It is not really a joke to say that we know that low-carbohydrate diets are safe because the medical establishment has spent 40 years trying to find something wrong with them, and they never come up with anything. Of course, most of the 'concerns' are just mindless fear of doing something different, but there have been serious tests of potential risks, particularly in cardiovascular disease. In fact, [KDs] usually prove to be beneficial-they lower triglycerides dramatically and increase high-density lipoprotein (HDL), the so-called good cholesterol. The low-fat message never had a scientific foundation and is finally being recognized as a mistake."
KDs are not without side effects in some individuals, particularly as their metabolisms transition from burning glucose to running primarily on fat and KBs. These side effects can include kidney stones, diarrhea, dizziness, fatigue, tachycardia, and thirst. No one way of eating is ideal for everyone, and some conditions such as hypothyroidism and adrenal fatigue may preclude the use of therapeutic KDs. However, Volek suggests that the majority of side effects can be eliminated by properly formulating the ketogenic diet.
Research led by Amisha Patel of Johns Hopkins University in Baltimore, Maryland, USA, found that KDs are safe over the long term (Epilepsia, http://dx.doi.org/10.1111/j.1528-1167.2009.02488.x, 2010). "Despite its temporary side effects, we have always suspected that the ketogenic diet is relatively safe long term, and we now have proof," said Eric Kossoff, a co-author on the study and director of the ketogenic diet program at Johns Hopkins Children's Center, in a news release. "Our study should help put to rest some of the nagging doubts about the long-term safety of the ketogenic diet," he added.
"It turns out that when a person's metabolism runs on these small molecules [ketone bodies], there is a host of positive effects, including decreased oxidative stress and inflammatory markers and improved tolerance to stress," said Volek.
"Basic and applied scientists are studying the mechanisms of how this fat-burning state improves a variety of different cancers, wound healing, post-traumatic stress disorder, the aging process, and much more," he added. "Research is not just focused on weight loss and clinical applications. Recreational and elite athletes and soldiers are also using ketogenic diets to enhance their physical and mental performance and speed recovery from exercise."
Below are summaries of some of the conditions and disorders in which the well-formulated KD shows promise, as identified by Paoli et al. The list undoubtedly will grow over time. Wouldn't it be ironic if, after decades of demonizing fat, it turns out to be among the best of all dietary prescriptions for a number of diseases and disorders?
Level of Evidence-STRONG
Cardiovascular risk parameters
Contrary to popular opinion about the dangers of dietary fat in general and saturated fat in particular, the high-fat ketogenic diet has been shown to have favorable effects on cardiovascular risk factors.
"The [KD] effect seems to be particularly marked on the level of blood triglycerides, " Paoli et al. write, adding that "there are also significant positive effects on total cholesterol reduction and increases in high-density lipoprotein. Furthermore, [KDs] have been reported to increase the size and volume of low-density lipoprotein-cholesterol particles, which is considered to reduce cardiovascular disease risk . . . ."
Research that has evaluated well-formulated very-low-carbohydrate diets and documented high rates of compliance in individuals with type 2 diabetes (T2D) indicates that KDs have the potential to reverse symptoms of the disease. Given that diabetes-whether T2D or T1D-is a disease characterized by carbohydrate intolerance-the results are not surprising.
Type 2 diabetics exhibit insulin resistance, in which high levels of insulin released after ingestion of carbohydrates cause a greater diversion of carbohydrate to the liver, where much of it is converted into fat. This increases the level of serum triglycerides, largely as saturated fat (mainly palmitoleic acid [C16:1n7]), which in turn increases the risk of cardiovascular disease. By greatly lowering dietary carbohydrate through ketogenic eating, diabetics often lose weight and can lower or stop the use of insulin and other medications.
One study reported by Paoli et al. found "significant improvements in both weight loss and metabolic parameters . . . seen at 12 weeks and continued throughout the 56 weeks" of the research. Subjects exhibited improvements in fasting circulating glucose (-51%), total cholesterol (-29%), HDL-cholesterol (63%), low-density lipoprotein-cholesterol (-33%), and triglycerides (-41%).
Fasting and other dietary modifications have been used to treat epilepsy for several thousand years. In the 1920s, the KD was introduced for the treatment of intractable childhood epilepsy. With the advent of antiseizure drugs in 1938, however, KDs fell out of favor until the 1990s. Since then, research has proliferated and the KD (in several different formulations) remains an effective therapeutic tool, particularly for children who do not respond to drug therapy. In fact, a recent Cochrane review led by R.G. Levy found that all studies reviewed "showed a 30-40% reduction in seizures compared with comparative controls."
Recent work in rats by a group led by Katja Kobow at University Hospital Erlangen in Germany points to a possible mechanism (Kobow et al., Acta Neuropathol., http://dx.doi.org/10.1007/s00401-013-1168-8, 2013). Animals fed a normal diet exhibited an increased level of methylation (the addition of a CH3 group) in their DNA compared with rats on the KD. The alteration in methylation could be linked to deactivation of the genes responsible for epilepsy. Other research suggests alternative mechanisms such as the anti-convulsant effects of KBs as well as a KB-induced reduction of neuronal excitability.
Ketogenic diets, beginning with William Banting's in the 1860s, have a long history of efficacy in weight loss. As Paoli et al. indicate, "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."
But what about the suggestion, made by the Mayo Clinic and others, that ". . . most studies have found that at 12 or 24 months, the benefits of a low-carb diet are not very large"?
"In most longer-term studies of low-carbohydrate diets, rather than encouraging subjects to consume more fat in the later phases of the diet, [researchers] often reintroduce high-carbohydrate foods," Jeff Volek writes. "Thus, it is not surprising in randomized clinical trials that weight loss at six months is higher in groups assigned to a low-carbohydrate diet than to a low-fat diet, but the effect is diminished at 12 months. Nevertheless, weight loss is at least as good and some cardiovascular risk markers improve to a greater extent, especially in subjects with insulin resistance."
Volek also points to a clinical practice in Kuwait that adopted a low-carbohydrate, moderate-protein, high-fat diet to deal with the dramatically increased incidence of obesity and T2D in that region (Dashti, et al., Mol. Cell Biochem., http://dx.doi.org/10.1007/s11010-005-9001-x, 2006). This research concerns a cohort of 66 subjects (35 with T2D) who were instructed to maintain a total daily carbohydrate intake under 50 g/day; 49 achieved a mean weight loss of 27 kg in a year, Volek said, with dramatic improvements in dyslipidemia, and normalization of blood glucose among the diabetics. "Given that intensive pharmaceutical management of T2D to achieve normoglycemia consistently leads to weight gain (as opposed to the marked weight loss in this study)," Volek added, "it is hard to believe that any potential (but as yet undemonstrated) risks of long-term carbohydrate restriction outweigh the benefits of this dietary approach in this group of patients."
Level of Evidence-EMERGING
"The Warburg effect is the single most common malady expressed in all cancers," noted Thomas N. Seyfried, a professor of biology at Boston College and author of Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer.
"The Warburg effect" refers to Otto Warburg, the German Nobel laureate and physician who hypothesized that cancer arises largely from impaired energy metabolism (mitochondrial dysfunction), which then produces genetic instability.
"The mitochondrial defects force cancer cells to use fermentation as a major source of energy production for growth and survival," Seyfried wrote in an email. "Consequently, the restriction of fermentable fuels (primarily glucose and glutamine) will target cancer cell growth and survival."
Indeed, tumor cells often have "glycolytic rates up to 200 times higher than those of their normal tissues of origin," Paoli et al. write. Further, "there is evidence that hyperinsulinemia [excess levels of serum insulin], hyperglycemia [excess levels of serum glucose], 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."
A search in December 2015 for phase 1 clinical trials on KDs and cancer returned 14 results. Eight of the studies are in the recruitment phase; one of the 14 has been completed, with results reported in 2014 (Rieger, J., et al., Int. J. Oncol., http://dx.doi.org/10.3892/ijo.2014.2382). The researchers, led by Johannes Rieger of the University Hospital Frankfurt, concluded that the KD is both feasible and safe "but probably has no significant clinical activity when used as a single agent in recurrent glioma."
Until the clinical trials are reported, Seyfried noted, "Lipid biochemists are ideally positioned to help unravel the mechanisms underlying the therapeutic action of the KD."
Research on KDs and Alzheimer's disease is in the beginning stages. Because Alzheimer's patients exhibit an increased incidence of seizures compared with those not affected by the disease-along with impaired glucose metabolism and poor mitochondrial function-investigation of KDs and Alzheimer's makes sense.
Preliminary data in humans suggest that dietary ketosis "can provide neurocognitive benefit for older adults with early memory decline and increased risk for neurodegeneration," according to researchers led by Robert Krikorian at the University of Cincinnati (Ohio, USA). Their study appeared in Neurobiology of Aging (http://dx.doi.org/10.1016/j.neurobiolaging.2010.10.006, 2012). Additional work in humans found significant clinical improvement in subjects with mild to moderate Alzheimer's disease (Henderson et al., Nutr. Metab., http://dx.doi.org/10.1186/1743-7075-6-31, 2009). "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," Paoli et al. note (Kashiwaya, Proc. Natl. Acad. Sci., http://dx.doi.org/10.1073/pnas.97.10.5440, 2000).
Research has also been conducted into KDs and headache, neurotrauma, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, sleep disorders, brain cancer, and autism. "Although these various diseases are clearly different from each other," Paoli et al. write, "a common basis potentially explaining KD 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."
Catherine Watkins is a freelance writer based in Champaign, Illinois, USA. She can be reached at email@example.com.
- Banting, W. (1863) A Letter on Corpulence Addressed to the Public.
- Dashti, H.M., Al-Zaid, N.S., Mathew, T.C., Al-Mousawi, M. Talib, H., Asfar, S.K., Behbahani, A.I. (2006) "Long term effects of ketogenic diet in obese subjects with high cholesterol level." Mol. Cell Biochem. 286:1-9; http://dx.doi.org/10.1007/s11010-005-9001-x.
- Feinman, R.D. (2014) The World Turned Upside Down: The Second Low-Carbohydrate Revolution, NMS Press, Brooklyn, New York, USA, and Duck in a Boat LLC, Snohomish, Washington, USA; ISBN 978-0979201820.
- Feinman, R. D., Pogozelski, W.K., Astrup, A., Bernstein, R.K., et al. (2015) "Dietary carbohydrate restriction as the first approach in diabetes management: Critical review and evidence base." J. Nutr. 31:1-13; http://dx.doi.org/10.1016/j.nut.2014.06.011.
- Henderson, S.T., Vogel, J.L., Barr, L.J., et al. (2009) "Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: A randomized, double-blind, placebo-controlled, multicenter trial." Nutr. Metab. (Lond) 6:31; http://dx.doi.org/10.1186/1743-7075-6-31.
- Kashiwaya, Y., Takeshima, T., Mori, N., Nakashima, K., et al. (2000) "D-β-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease." Proc. Natl. Acad. Sci. USA 97:5440-5444; http://dx.doi.org/10.1073/pnas.97.10.5440.
- Kobow K., Kaspi, A., Harikrishnan, K.N., et al. (2013), "Deep sequencing reveals increased DNA methylation in chronic rat epilepsy." Acta Neuropathol. 126:741-756; http://dx.doi.org/10.1007/s00401-013-1168-8.
- Krikorian, R., Shidler, M.D., Dangelo, K., Couch, S.C., Benoit, S.C., Clegg, D.J. (2012), "Dietary ketosis enhances memory in mild cognitive impairment." Neurobiol. Aging 33:425 e19-425.e27; http://dx.doi.org/10.1016/j.neurobiolaging.2010.10.006.
- Levy, R.G., Cooper, P.N., Giri, P., Weston, J. (2012), "Ketogenic diet and other dietary treatments for epilepsy." Cochrane Database of Systematic Reviews 2012, Issue 3; http://dx.doi.org/10.1002/14651858.CD001903.pub2.
- Paoli, A., Rubini, A., Volek, J.S., and Grimaldi, K.A. (2013) "Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets." Eur. J. Clin. Nutr. 67:789-796; http://dx.doi.org/10.1038/ejcn.2013.116.
- Patel, A., Pyzik, P. L., Turner, Z., Rubenstein, J. E. and Kossoff, E. H. (2010) "Long-term outcomes of children treated with the ketogenic diet in the past." Epilepsia 51:1277-1282; http://dx.doi.org/10.1111/j.1528-1167.2009.02488.x.
- Rieger, J., Bähr, O., Maurer, G.D., et al. (2014) "ERGO: a pilot study of ketogenic diet in recurrent glioblastoma." Int. J. Oncol. 44:1843-1852; http://dx.doi.org/10.3892/ijo.2014.2382.
- Seyfried, T.N. (2012) Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer; A. John Wiley & Sons, Inc., Hoboken, New Jersey, USA; ISBN 978-0470584927.
- Volek, J. S. and Phinney, S.D. (2011) The Art and Science of Low Carbohydrate Living, Beyond Obesity, LLC, Miami, Florida, USA; ISBN 978-0983490708.
The beginning of the Letter on Corpulence
Of all the parasites that affect humanity I do not know of, nor can I imagine, any more distressing than that of Obesity, and, having emerged from a very long probation in this affliction, I am desirous of circulating my humble knowledge and experience for the benefit of other sufferers, with an earnest hope that it may lead to the same comfort and happiness I now feel under the extraordinary change, which might almost be termed miraculous had it not been accomplished by the most simple common-sense means.
-William Banting, 1863, who lost 50 pounds on a low-carbohydrate diet.
Defining a "well-formulated ketogenic diet"
"A well-formulated ketogenic diet is one personalized to the individual, and it addresses more than just carbohydrate restriction," says Jeff Volek, who is the co-author-along with Stephen D. Phinney-of The Art and Science of Low Carbohydrate Living. "The level of carb restriction required to become keto-adapted varies from person to person, but most people will find they get the best results at levels below 50 g/day . . . but it may vary from 30 to 100 g/day.
Volek notes that it is important not to overdo protein on a low-carbohydrate diet because an excess of protein can interfere with ketosis. "The best approach is to experiment with finding the right amount of carbs and protein, coupled with regular monitoring of blood (not urine) ketones," using a simple finger-stick instrument.
"Given that this diet is low in carbs and moderate in protein, the majority of calories need to come from fat," he says, with a limited amount of those rich in polyunsaturated fat (e.g., corn, soybean, safflower, cottonseed, and peanut oils).
"You don't need to worry about increasing saturated fat intake. We have repeatedly shown that on a ketogenic diet, blood levels of saturated fat actually decrease as the fat-adapted body prefers to burn them as fuel," Volek says.
In the fat-adapted body, the kidneys tend to discard more water and salt, which can result in reduced plasma volume, fainting, and a general "washed-out" feeling (sometimes called the "Atkins flu"). "An easy solution," Volek says, "is to take an extra 1-2 g of sodium/day as broth, bouillon, or soup. And in particular, on days you exercise, be sure to take 1 gram of sodium to prime your circulation 30 minutes before your workout."