Ketosis: Reviewing the Research and the Fad

“Have you heard of this Bulletproof Coffee stuff?”

My cousin asked me while waiting for a flight at SFO two years ago.

“It’s this new coffee you drink with oil and butter that’s supposed to increase focus, brain function, and weight loss by putting you in ketosis.”

I first heard about ketosis when I did some research on the Dukan Diet that was popular in 2011.  Ketosis was referenced as the reason behind a fruity/acetone breath that may accompany the diet.  At the time I was somewhat horrified by the idea of actually trying to increase ketone production, as I had grown up with the very real threat of diabetic ketoacidosis (DKA) (a life-threatening condition in which high levels of ketones actually lower the pH of our blood).  Please note that the metabolic state of ketosis should not be confused with diabetic ketoacidosis, which I will explain later.

In the last two years, ketosis seems to be popping up everywhere.  Health blogs are touting it as the secret to increased cognitive function and weight-loss, researchers are examining its implications for a number of conditions, and a few clinicians are even prescribing it in very specific cases.  Many dietitians and clinicians however are still hesitant to advise a ketogenic diet .

As my readers may know, my biggest pet peeve is the vast amount of pseudoscience disseminated in the nutrition field.  So, as I was perusing the internet and reading a lot of personal testimonials and unsubstantiated claims of ketosis as a miracle cure-all, I decided that a look at the reputable peer-reviewed research on this topic was necessary.  Feel free to call me a skeptic, but I’m just a curious scientist.

What is Ketosis?

The first thing to mention, is that we typically discuss ketosis as a physiological adaptation to starvation.  Simply stated, ketosis is a metabolic state in which the liver produces ketone bodies.

After a few days of fasting, or a diet that drastically reduces carbohydrate intake (approximately <20 g/day)(1) the body’s glucose reserves become insufficient to supply glucose to the central nervous system including your brain (an extremely energy-greedy organ).

Fatty acids cannot be used as an energy source for the central nervous system, because they cannot cross the blood brain barrier.  Glucose is therefore the optimal fuel source for the brain.  After 3-4 days of starvation or a very low carbohydrate diet, however, glucose is no longer available, and your brain needs an alternative source of fuel.

Excess glucose is stored in the liver and in the muscles as glycogen.  Thankfully, glycogen is unable to enter the blood stream because muscles lack the enzyme glucose-6-phosphatase.  This protects the muscles from wasting away at an exponential rate during periods of starvation.  So, if we are deprived of dietary glucose, the liver rather than the muscles becomes the primary source, at least initially.

Most ketone bodies are derived from the partial degradation of long-chain fatty acids, which are liberated from white adipose tissue.  In the liver, when concentrations of circulating fatty acids are high, the body overproduces acetyl-CoA, which leads to the production of ketone bodies: acetoacetate, B-hydroxybutyric acid, and acetone (the fruity breath one).(2)

Glucose is also formed from two internal sources in the metabolic state of ketosis: glucogenic amino acids and glycerol (from triglycerides).  Initially (during the first few days), amino acids are the primary source of glucose, but as the fast continues, the amount of glucose from glycerol increases.

As mentioned previously, circulating fatty acids cannot be used by the brain for fuel (although they are used directly by skeletal muscle, myocardium, and liver).  Therefore, in positions of low glucose availability, ketone bodies are used by the brain once they reach a concentration of about 4 mmol/L or higher (for reference normal levels are typically <.3 mmol/L) (1)

Ketone bodies tend to be volatile compounds (particularly acetone), and have the potential to affect blood pH levels; however, the body works both to prevent change in blood pH through a buffer system, and also to rid itself of the compounds by use as an energy source and elimination.  The presence of ketone bodies in the blood and sub sequential elimination via urine causes ketonemia and ketonuria.  Acetone is primarily eliminated via respiration due to its volatility (hence the fruity breath).

Typically, in healthy people, ketone bodies do not exceed 8 mmol/L even during periods of fasting, because the brain is quickly utilizing these bodies for energy.  Levels in diabetic ketoacidosis can however exceed 20 mmol/L.(5)

Is Ketosis Effective for Weight loss?

There is a lot of evidence supporting ketogenic diets for weight-loss. (4)  There is still, however,  a number of contrasting theories regarding the mechanisms through which ketosis works. The following are  a few predominant theories:

1. Ketosis provides a distinct metabolic advantage. (6) Specifically, greater metabolic efficiency in consumption of fats and also increased metabolic costs of gluconeogenesis, resulting in greater weigh-loss per calorie consumed.(9) (12) Note that other studies, however, can be cited to discount this theory. (13)
2. Weight-loss results from decreased caloric intake due to the satiety effects of protein.(7)
3. Ketogenic diets suppress appetite- CCK (cholecystokinin), a hormone that assists in satiety is typically reduced in diets involving caloric restriction; however, these levels remain normal in ketogenic diets according to a number of studies.  Furthermore, ghrelin (an appetite hormone) is suppressed in mildly ketotic participants. (9)

Of course it’s important to remember that ketogenic diets are not 100% effective.  A number of studies report statistically significant weight-loss in response to a low-carbohydrate ketogenic diet, and studies report greater weight loss than in fat-reduction diets.(4)  Not all studies, however, show that a ketogenic diet results in greater amounts of weight loss than other diets with higher carbohydrate composition. (8)

Does it sound confusing?  That’s because it is.  Studies in nutrition often have contradictory results, because often studies are only published if they match the hypothesized results.  Because clinical studies use human participants, results can be difficult to replicate.  Welcome to the world of nutrition!  

What about weight maintenance?

Here’s where the research is truly lacking.  Unfortunately, there are very few studies on the maintenance of weight loss, and the few studies that have examined weight maintenance typically only tracked participants for a year or less post weight-loss.

One study provided evidence for long term weight-loss maintenance by following a ketogenic diet with a Mediterranean (not low-carb) diet.(14)  Another study suggested that ketogenic diets provided no benefit in weight maintenance, due to adherence issues. (13)

Is Ketosis safe?

Again there is some controversy.  Ketosis is generally considered safe for “healthy” individulals; however, there are a number of concerns regarding both blood lipids and potential negative renal effects associated with ketosis.

If we look back at the Atkin’s Diet, a large amount of criticism of this diet surrounded the potentially negative impact on cholesterol levels among other cardiometabolic risk factors.  Again there is controversy.  Some studies have shown increase in cardiovascular factors,(16) while other recent studies have actually shown improvement (increase in HDL and decrease in triglycerides) as a result of ketogenic diets.(5)

In terms of renal effects, high levels of nitrogen excretion as a result of protein metabolism can cause an increase in glomerular pressure and hyper filtration.(1) (15)

In clinic, ketogenic diets are not typically advised for those with diabetes or renal disease due to the potential risks associated; however, a lot of research is exploring ketosis for diabetes (both type 2 and type 1).

 

Discussion

It is clear from the research that there are a number of potential benefits associated with the state of ketosis and ketogenic diets.  Many dietitians, however, hesitate to suggest ketogenic diets, due to the difficulty in maintaining them, potential risks, and the yo-yo effect.

I personally have some doubts when it comes to ketogenic diets.  First, I want to make it clear that not all ketogenic diets will cause ketosis.  The exact amount of carbohydrates in the diet and time required to induce ketosis differs depending on the person.  In fact, it is clear from a number of studies I have cited below that participants were not always tested for ketones, so it is unclear whether participants were in this metabolic state.

Recent fad diets suggest consumption of coconut oil to induce ketosis and there is some supporting research that suggests that lauric acid- rich medium chain fatty acids (such as those found in coconut oil) can actually drive ketone body production.(17)  This mechanism again requires further study and clarification, and there remains some concern over the saturated fat in coconut oil (see my post on coconut oil).  Furthermore, the mechanism of ketosis for weight loss is not entirely clear.

Also, the safety of these diets remains a concern, particularly for those with type 1 diabetes.  My personal experience on a ketogenic diet in 2011 for two months resulted in a rapid increase in LDL and total cholesterol (I had never before had high cholesterol) even with a five pound weight loss.  I also remember feeling irritable, depressed, and foggy (sometimes called the brain fog) for a significant period of time.

Although, my cholesterol and weight are now in the normal range (due to a balanced whole diet), I personally will not be experimenting with a ketogenic diet again.  By nature, I dislike any diet that restricts intake of whole foods, and would like to remind my readers that most vegetables contain carbohydrates.  If you do consider a ketogenic diet, please be aware of your micronutrient needs, and know that supplementation may be necessary.

Although I didn’t get into this in this post, ketosis has some very clear implications for the treatment of Epilepsy and even Alzheimers among other conditions.  I do believe that in some cases ketogenic diets can be a useful clinical treatment; however, I believe this approach should be applied with careful consideration of potential risks and benefits.

As I have discussed previously, there is not always one diet that works for everyone.  What has worked for me is balance and moderation.  I feel good and maintain my weight-loss with both carbohydrates and fats, which is why I know I will not be dumping grass-fed butter and coconut oil into my coffee every morning in an attempt to push my body into ketosis.

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1. Paoli A. Ketogenic Diet for Obesity: Friend or Foe? International Journal of Environmental Research and Public Health. 2014;11(2):2092-2107. doi:10.3390/ijerph110202092.
2. Fukao T., Lopaschuk G.D., Mitchell G.A. Pathways and control of ketone body metabolism: On the fringe of lipid biochemistry. Prostaglandins Leukot. Essent. Fatty Acids. 2004;70:243–251. doi: 10.1016/j.plefa.2003.11.001.
3. Bueno N.B., de Melo I.S., de Oliveira S.L., da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. Low-fat diet for long-term weight loss: A meta-analysis of randomised controlled trials. Br. J. Nutr. 2013;110:1178–1187. doi: 10.1017/S0007114513000548.
4. Bueno N.B., de Melo I.S., de Oliveira S.L., da Rocha Ataide T. Very-low-carbohydrate ketogenic diet v. Low-fat diet for long-term weight loss: A meta-analysis of randomised controlled trials. Br. J. Nutr. 2013;110:1178–1187. doi: 10.1017/S0007114513000548.
5. Paoli A., Rubini A., Volek J.S., Grimaldi K.A. Beyond weight loss: A review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur. J. Clin. Nutr. 2013;67:789–796. doi: 10.1038/ejcn.2013.116.
6. Feinman RD, Fine EJ. Nonequilibrium thermodynamics and energy efficiency in weight loss diets. Theor Biol Med Model. 2007;4:27.
7. Westerterp-Plantenga MS, Nieuwenhuizen A, Tome D, Soenen S, Westerterp KR. Dietary protein, weight loss, and weight maintenance. Annu Rev Nutr. 2009;29:21–41
8. Sacks FM, Bray GA, Carey VJ, et al. Comparison of Weight-Loss Diets with Different Compositions of Fat, Protein, and Carbohydrates. The New England journal of medicine. 2009;360(9):859-873. doi:10.1056/NEJMoa0804748.
9. Sumithran P., Prendergast L.A., Delbridge E., Purcell K., Shulkes A., Kriketos A., Proietto J. Ketosis and appetite-mediating nutrients and hormones after weight loss. Eur. J. Clin. Nutr. 2013;67:759–764. doi: 10.1038/ejcn.2013.90.
10. Paoli A., Cenci L., Fancelli M., Parmagnani A., Fratter A., Cucchi A., Bianco A. Ketogenic diet and phytoextracts comparison of the efficacy of mediterranean, zone and tisanoreica diet on some health risk factors. Agro Food Ind. Hi-Tech. 2010;21:24–29.
11. Tagliabue A., Bertoli S., Trentani C., Borrelli P., Veggiotti P. Effects of the ketogenic diet on nutritional status, resting energy expenditure, and substrate oxidation in patients with medically refractory epilepsy: A 6-month prospective observational study. Clin. Nutr. 2012;31:246–249. doi: 10.1016/j.clnu.2011.09.012.
12. Feinman R.D., Fine E.J. Nonequilibrium thermodynamics and energy efficiency in weight loss diets. Theor. Biol. Med. Model. 2007;4 doi: 10.1186/1742-4682-4-27.
13.  Johnston CS, Tjonn SL, Swan PD, White A, Hutchins H, Sears B. Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets. Am J Clin Nutr 2006;83:1055–1061
14. Paoli A., Bianco A., Grimaldi K.A., Lodi A., Bosco G. Long term successful weight loss with a combination biphasic ketogenic mediterranean diet and mediterranean diet maintenance protocol. Nutrients. 2013;5:5205–5217. doi: 10.3390/nu5125205.
15. Westerterp-Plantenga M.S., Nieuwenhuizen A., Tome D., Soenen S., Westerterp K.R. Dietary protein, weight loss, and weight maintenance. Annu. Rev. Nutr. 2009;29:21–41. doi: 10.1146/annurev-nutr-080508-141056.
16. Nordmann AJ, Nordmann A, Briel M, Keller U, Yancy WSJr, Brehm BJ et al. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch Intern Med 2006; 166: 285–293.
17. McCarty MF, DiNicolantonio JJ. Lauric acid-rich medium-chain triglycerides can substitute for other oils in cooking applications and may have limited pathogenicity. Open Heart. 2016;3(2):e000467. doi:10.1136/openhrt-2016-000467.