Did you know that some people purposely skip meals? Hard to imagine, I know. No, we are not talking about eating disorders here, although I suppose eating a diet that is made up of 85-90% fat would sound disordered to some...Today we are talking about one of the hottest topics on the interwebs: fasting (on purpose). I just want to emphasize that part. Not eating breakfast, or second breakfast....or lunch...or dinner...or snacks...or anything in between because you chose to. Specifically, today's post digs into fasting as it relates to the ketogenic diet. We are digging into what ketosis is, how it works, and most importantly, why you should care. Hold onto your hats, down the rabbit hole we go.

Why should you give a rat's a$$ about ketosis?

You'd like to jump right in wouldn't you. Let's back up and start with the bigger picture: how did the ketogenic diet come to be?

Early in the 20th century, starvation was introduced as a treatment for children with epilepsy (Wheless, 2008). Notice the nice person-first language there? We don't say "epileptics", we say kids with epilepsy. It may seem insignificant but putting the person ahead of their disease helps us remember that it is people we are treating, not diseases. People are more than their diagnosis reduces them to be. Rant over. Back to the story.

In the early 1920's, two physicians at Harvard Medical School were the first to document an improvement in seizures after 2-3 days of fasting. They reported that fasting changed the body's metabolism. In the absence of food, the body was forced to burn acid-forming fat (Wheless, 2008).

If you're thinking what I'm thinking, that making kids starve for 2-3 days to induce ketosis is pretty extreme, it was! Thankfully it was discovered that ketosis could be induced by a diet very low in carbohydrate and very, very high in fat (Wheless, 2008 & Woodyatt, 1921). The prescription was simple: 1 g of protein per kilogram of body weight in children, 10–15 g of carbohydrates per day, and the remainder of the calories in fat (Peterman, 1925). The "ketogenic diet" (KD) was born. Though widely used in the 1920s and 30s, the KD's popularity fell with the discovery of anti-epileptic drugs in the late 1930s. Over the past few decades, the KD has seen a resurgence in the medical community for the treatment of drug-resistant epilepsy. More to our interest though, the KD has received a lot of attention in the cancer, weight-loss, and performance-enhancement fields. Let's dig in.

So we know how to get into ketosis...but what actually is ketosis?

Ketosis occurs when the body produces excessive ketone bodies (Seeley, Stephens, & Tate, 2008). Don't you love when someone uses the word they are defining in the definition? Bear with me, let's get a lesson in physiology...

If you just want the juicy gossip on ketosis, scroll down and ignore the really cool and important physiology lesson below...

Your body stores 99% of its energy as triglycerides in adipose tissue (aka fat). The other 1% of your energy is stored in the form of glycogen mostly in the liver and skeletal muscle tissues. The difference being, glycogen is a short-term energy storage molecule that can only be stored in the body in limited amounts while fat can be stored in much larger amounts for a longer period of time (Seeley et al., 2008). The energy your body can derive from one gram of triglyceride is more than twice what it can get from a gram of carbohydrate (Seeley et al., 2008).

Even though the body gets more bang for its buck from triglycerides, it will preferentially convert stored glycogen into glucose for fuel. Ever heard someone say that your body stores excess carbs as fat? Well, it's true. When you consume more carbohydrates than your body needs for fuel, it will store as much as it can in the form of glycogen but as we discussed above, these stores are limited and the excess is converted into fat and stored in our adipose tissue. Guess what? The same goes when you eat more triglycerides (fat) than your body needed replenishing....the excess is stored in our adipose tissue.

Between meals, triglycerides are broken down into free fatty acids that can be used as energy by your liver and skeletal muscles. It is normal for your body to use glycogen and triglycerides for fuel on an "as needed" basis. Your body will use protein for fuel if it has to, but it means losing molecules with other important functions in the body.

Where does ketosis come in? And seriously, what is it?!

When your body first enters "starvation mode"...no diet jargon to sell products here...we are talking about actual starvation....blood glucose levels are maintained by breaking down glycogen. Unfortunately, your body only stores enough glycogen in the liver to last you a few hours (Seeley et al., 2008). Your body is not a quitter though, once it runs out of glycogen it will start breaking down protein and fat. At all costs, the body will protect the brain. In a heroic fashion, the body will convert stored triglycerides into fatty acids that can be used by the skeletal muscle for energy to spare glucose for the brain. Protein will be broken down into amino acids, some of which will be used directly for energy.

After a few days, fats become your body's primary energy source. Your liver metabolizes fatty acids into ketone bodies (yay! we found our way back to ketosis) which are used as a source of energy (Seeley et al., 2008). After one week, your brain ditches its exclusive glucose diet and starts using ketone bodies for energy. The demand for glucose is reduced and the rate of protein breakdown slows but does not stop.

Ketogenesis is the process by which ketone bodies are formed. When triglycerides are broken down into their component parts (glycerol + fatty acids), the fatty acids are metabolized through a process called beta-oxidation. Beta-oxidation strips a fatty acid chain of its carbon atoms two at a time until the acid chain is converted into acetyl-CoA molecules, some of which then enter the citric acid cycle to generate ATP (energy) for the body. When large amounts of acetyl-CoA are produced, not all of the acetyl-CoA molecules will enter the citric acid cycle. Instead two acetyl-CoA molecules will combine to form aceotoacetic acid which is converted into b-hydroxybutryic acid and acetone, aka ketone bodies! These ketone bodies are released into the blood to provide energy for other tissues, mainly skeletal muscle. Once inside, these ketone bodies are converted back into acetyl-CoA and now have their chance to enter the citric acid cycle to make ATP! It's a beautiful thing. Acidosis however, is not. If the number of acidic ketone bodies produced exceeds the body's blood buffering systems, a dangerous decrease in blood pH can occur. Fruity smelling breath, nausea, vomiting, dehydration, and shortness of breath are all symptoms of acidosis. Check with your doctor before you purposely mess with your body's metabolism. Back to the story...

Ketosis, as mentioned above, refers to a state of excessive production of ketone bodies. Starvation (or fasting), untreated diabetes mellitus, and very low carbohydrate diets can all lead to an increase in fat metabolism and thus an increase in ketone body formation.

So why would someone want to be in ketosis?

Welcome back article skimmers...

A great question. The KD has been explored in several new and exciting ways since its discovery for the treatment of epilepsy. Namely, using the KD to treat cancer and enhance performance (not necessarily simultaneously though...)

Cancer

First off let's make two important points:

1) The KD is an adjunct i.e. not a standalone or complete treatment by any means
2) The KD as an adjunct treatment for cancer is under study in animal models, so what we know is based on rats....now you know why you should give a rat's a$$ about ketosis.....bahahaha.

The associations between dietary restriction (including intermittent fasting, caloric restriction, and the KD) and cancer were the subject of a recent systematic review (Lv, Zhu, Wang, & Guan, 2014). In total, 59 studies on caloric restriction (in animal models) were included in the review. The authors analyzed the tumour incidence rate (primary outcome) in 21 studies of the included studies. The general theory behind caloric restriction is to "starve" the cancer cells. By restricting access to glucose for short periods (intermittent fasting) or reducing the availability of glucose for longer durations (the KD) metabolism is slowed, oxidative damage is reduced, and tumour growth is postponed (Lv et al., 2014).

Included in the review were 44 studies examining caloric restriction, 9 on the KD, and 8 on intermittent fasting (IF). The most common cancer types studied were: mammary, prostate, brain, pancreatic, hepatic, colonic, gastric, and metastatic. The diets used in the KD studies ranged from 0-20% carbohydrate contribution, IF protocols ranged from 24 to 72 hours, and the periods of caloric restriction ranged from 1-3 weeks followed by an equal period of ad libitum eating. An overwhelming 91% of studies supported the conclusion that caloric restriction is preventive of cancers. The authors conclude that the KD has the potential to prevent cancer although the pooled data was not significant. There was no evidence to support the preventive effect of IF, in fact 37.5% of the studies provided negative results. The authors caution the reader against the limitations of the literature: there are few studies, many without control groups, a lack of evidence from human trials, and many protocols involve short-term dietary regimens that would be difficult to adhere to long term.

A 2017 systematic review explored the relationship between isocaloric (a maintenance level of calories) KDs and cancer in humans (Erickson, Boscheri, Linke, & Huebner, 2017). 15 studies of 330 patients were included in the review, of which 5 were case reports, 8 were prospective cohort studies, and two were retrospective studies. The authors rated the methodological quality of all of the studies as low. Comparison of results in a meta-analysis was not possible as studies differed in type, location and stage of cancer. No study used the same dietary protocol. Only 53% of patients followed a KD at any point during the intervention period while only 37% actually adhered to the diet for the duration of the study. Only 6 of the 15 studies had a dietary intervention that lasted longer than 3 months. Some of the studies did not have a dietitian supervising the patients' diets, instead patients were given brochures with sample recipes and facts. I bet you see where this is going....of the few studies that evaluated anti-tumour effects of the KD, results were not statistically significant. The authors conclude that evidence to support the KD as a tool for the prevention and treatment of cancer in humans is lacking.

Performance

Your body has a hierarchy of energy demands depending on the intensity of the activity you are performing. At rest, your body uses circulating free fatty acids and glucose as fuel. During moderate to high intensity exercise (>75% of V02 max) your body preferentially selects glycogen as its primary energy source (Egan & D’Agostino, 2016). As a consequence, nutrition strategies to enhance athletic performance have focused on optimizing carbohydrate intake before and during exercise. Exploring ketosis as a means of enhancing performance is a relatively new concept. The trouble is, to produce its own ketone bodies your body must endure a period of extreme caloric or carbohydrate restriction...not exactly what every coach wants to put their athlete through.

To circumvent the challenges and impracticality of traditional fasting approaches to entering ketosis, Cox et al. (2016) examined the effects of ketone supplementation prior to and during intense cycling exercise on fuel selection and time-trial performance. Consuming exogenous ketones reduced carbohydrate metabolism and increased fat oxidation (even in the presence of normal muscle glycogen....i.e. glycogen stores were not depleted as is the case when fasting), reduced lactate production during exercise, and led to a 2% improvement in 1 hour time-trial cycling performance. It is not clear whether these adaptations would occur in an untrained population or during purely anaerobic (sprint) or intermittent bursts of high-intensity exercise whereby the body relies on carbohydrates for fuel. Though it may seem like a modest increase in performance, a 2% improvement for elite athletes can be the difference between winning a gold medal and not breaking the top 10. The evidence body for ketosis and sport performance is limited but growing. For now, exciting discoveries are challenging traditional paradigms of exercise metabolism (Egan & D’Agostino, 2016).

Is it safe?

Though exciting evidence is emerging for the therapeutic use of the KD, we still do not know enough to draw strong conclusions about the most appropriate dietary protocol or duration to achieve specific outcomes (Paoli, Rubin, Volek, & Grimaldi, 2014). Research on the safety and efficacy of the KD is underway. For now, keep reading and keep asking questions using your keen skeptical intellect and the advice of your physician to make informed choices about your metabolic health.

Super fun fact:

Hibernating bears do not enter ketosis. Strangely, despite burning nearly 4000 kcal a day, black bears do not eat, drink, urinate, or defecate for 4-7 months while hibernating (Nelson, 1983). Though black bears rely on fat for hibernation metabolism, ketosis does not occur! It is hypothesized that fatty acids are prevented from entering the blood stream during hibernation and instead glycerol is converted into glucose for energy (Hellgren, 1998). This is very important as a bear that is not urinating would not be able to buffer the acid-base imbalance that occurs when the body produces an excess number of ketone bodies (aka ketosis)! Nerd alert: anyone else think that is fascinating?!

In conclusion...

Ketosis is cool, bears are cool, and fasting sounds hard. I hope you learned something in today's article, if so give it a share or at the very least validate the year (week) I spent writing this and like or comment below!

Cheers,

Coach P.

References

Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., …Clarke, K. (2016). Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metabolism, 24(2): 256-268.

Egan, B., & D’Agostino, D. (2016). Fueling performance: Ketones enter the mix. Cell Metabolism, 24(3): 373-375.

Erickson, N., Boscheri, A., Linke, B., & Huebner, J. (2017). Systematic review: isocaloric ketogenic dietary regimes for cancer patients. Medical Oncology, 34(5), doi: 10.1007/s12032-017-0930-5.

Hellgren, E.C. (1998). Physiology of hibernation in bears. Ursus, 10: 467-477

Lv, M., Zhu, X., Wang, H., & Guan, W. (2014). Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis. PLoS One, 9(12, doi:10.1371/journal.pone.0115147

Nelson, R.A., Folk, G.E., Pfeiffer, E.W., Craighead, J.J., Jonkel, C.J., & Steiger, D.L. (1983). Behavior, biochmeistry, and hibernation in black, grizzly, and polar bears. Ursus, 5: 284-290

Paoli, A., Rubin, A., Volek, J.S., & Grimaldi, K.A. (2014). Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. European Journal of Clinical Nutrition, 67: 789-796

Peterman MG. (1925) The ketogenic diet in epilepsy. JAMA 84:1979–1983

Seeley, R.R., Stephens, T.D., & Tate, P. (2008). Nutrition, Metabolism, and Temperature Regulation. Anatomy & Physiology (8th ed.), pp. 927-960. New York, NY: McGraw-Hill.

Wheless, J.W. (2008). History of the ketogenic diet. Epilepsy, 49(8): 3-5.

Woodyatt RT. (1921) Objects and method of diet adjustment in diabetics. Arch Intern Med 28:125–141

Fasting and ketogenic diets: what you need to know