Before reading this, if you haven’t already, I suggest reading What is a Ketogenic Diet and Understanding Ketosis so you will have a stronger understanding of what it means to be in a state of ketosis. The next step necessary in comprehending the ketogenic diet is learning the different types of ketosis that can occur. For this article, we will refer to three different forms of ketosis: fasting ketosis, nutritional ketosis, and pathological ketosis. The different types of ketosis vary in their degree of ketone production as well as their method of induction.

Fasting Ketosis

waking-up-ketones

The idea of fasting has been around for hundreds of years and played a major part in the origins of the ketogenic diet. In fact, many great philosophers, such as Hippocrates, Socrates, and Aristotle, all praised the many benefits of fasting. Paracelsus, physician and father of toxicology, was quoted saying, “Fasting is the greatest remedy—the physician within.” While these early scientists and philosophers were definitely ahead of the game in recognizing the potential of fasting, the mechanisms were still yet to be understood.  Ketosis tends to occur when insulin and blood glucose levels decrease to an extent that allows for increased fat oxidation, which is ultimately followed by greater ketone production. A minor state of ketosis can occur following periods of complete food restriction, such as an overnight fast. This may produce ketone levels around 0.1 mmol/L to 0.03 mmol/L. Shorter duration fasts typically will not raise ketone levels above these levels because the rate of ketone metabolism matches ketone synthesis. As the fast continues, the rate of ketone production exceeds ketone clearance, resulting in an increase in blood ketone levels (1). While a minor state of ketosis can occur during a short fast, the fasts that early philosophers were referring to were much longer than an overnight fast. We will refer to these longer duration fasts as starvation, or fasting ketosis. This response to fasting and starvation is a protective mechanism used to maintain energy balance and avoid a loss in body mass.

When oxaloacetate is removed from the cycle for gluconeogenesis, acetyl-CoA can not enter the TCA cycle. It is instead used for the formation of ketone bodies.

When oxaloacetate is removed from the cycle for gluconeogenesis, acetyl-CoA can not enter the TCA cycle. It is instead used for the formation of ketone bodies.

During a fast, depletion of stored glucose (glycogen) in the liver triggers certain chemical signals in the body to start burning more fat, causing the production of more ketones. As the fast continues, blood glucose continues to drop, and the degree of ketogenesis can become much greater due to the depletion of TCA cycle intermediate oxaloacetate for gluconeogenesis. Oxaloacetate is required for the first step of the TCA cycle to occur, and without it, a build up of acetyl-CoA occurs. If you recall from Understanding Ketosisexcess acetyl-CoA is required for ketone production. The removal of oxaloacetate from the TCA cycle prevents acetyl-CoA (stemming from fatty acid oxidation) from entering the cycle, which results in the ketone-producing buildup of acetyl-CoA. There are two primary ways in which oxaloacetate can become depleted. One is through its removal from the cycle for gluconeogenesis, which can be the primary cause of ketone production under fasting conditions in an attempt to regulate blood glucose levels. The other way in which oxaloacetate can become depleted is through over-production of ATP.  If further ATP production is not required, oxaloacetate may be removed to aid in the synthesis of glucose, amino acids, and other beneficial substrates. It is possible that this may be the cause of ketosis under fed conditions, which we will discuss in the next section.

Adapted from George Cahill's 40 day fast study

Adapted from George Cahill’s 40 day fast study

Fasting ketosis can have an array of benefits and has been used for the treatment of epilepsy (2), obesity (3), and even as a method to induce ketosis prior to chemotherapy (4). In the graph below you can see the relationship between glucose, free fatty acids, and ketones during a fast. This is a representation of what could occur during an extended day fast; however, similar occurrences happen during overnight fasts, intermittent fasting, and alternate day fasting but at much lower rates of ketone production. This shift in fuel utilization is thought to be a survival mechanism that we have retained throughout our evolution, which is why prolonged fasts can often be tolerated by most individuals. Check out Jimmy Moore and Dr. Jason Fung for more great information on fasting!

Nutritional Ketosis

Nutritional ketosis is a state of ketosis that is induced by dietary modification.We will be dividing nutritional ketosis into three subcategories: carb-restricted ketosis, supplemental ketosis, and alcoholic ketosis.

Carb-Restricted Ketosis

Carb-restricted ketosis has been utilized for decades. In 1921, Woodyatt discovered that fasting or starvation resulted in the appearance of ketones in the blood. He discovered that this presence of ketones in the blood could also occur in individuals who were restricting carbohydrates, and from this, the ketogenic diet was born. Dr. Russell Wilder of the Mayo Clinic, who is credited with naming the diet, proposed that the ketogenic diet undergo testing in patients with epilepsy (5). The diet proved to have a very positive effect on childhood epilepsy and was considered the gold standard for seizure treatment until the development of anti-epileptic drugs soon thereafter.

ketosis-definition

Carb-restricted ketosis can occur through a well-formulated ketogenic diet or even a “fat fast.” This approach is the most commonly used method for achieving a state of ketosis and typically results in a greater increase in ketones compared to an overnight fast. High fat, low carbohydrate (typically below 30 grams), and “moderate” protein intake is generally accepted as the best method for achieving carbohydrate-restricted ketosis.  However, macronutrient distribution and the subsequent degree of ketosis can drastically vary between individuals. Ketone production during carbohydrate-restricted ketosis may vary slightly from ketone production during fasting ketosis. When consuming a high-fat diet and restricting carbohydrates, we see an increase in fat oxidation, which results in an increase in ATP production. If sufficient enough to meet energy demands of the cell, this increase can result in a number of events that regulate the TCA cycle, including the removal of oxaloacetate from the TCA cycle, as discussed previously. While ketone production at the beginning of a ketogenic diet may be due to the removal of oxaloacetate for gluconeogenesis, it has been shown that ketones aid in the maintenance of blood glucose, thus lowering rates of gluconeogenesis (6). This means that, once an individual is adapted to the diet, the reason for elevated ketone production could be increased fat oxidation, not just oxaloacetate depletion. This, in turn, just like fasting ketosis, would result in a buildup of acetyl-CoA and the production of ketone bodies. There is still much more work to be done on the production of ketones under various physiological conditions.

After a week of carbohydrate-restricted ketosis, circulating ketones can elevate to levels between 2-5 mmol (7). This state is a long-term, sustainable approach that can provide an array of health benefits, including stable blood sugar, increased weight loss, enhanced sports performance, improved cognition, and the treatment of various diseases (8).

Supplemental Ketosis

exogenous-ketones

Certain levels of ketosis can provide powerful therapeutic benefits, but this level of ketosis may need to be even greater than what is typically seen with fasting and carbohydrate-restricted ketosis. Although the reported level of ketone production required to achieve therapeutic ketosis varies, some studies have demonstrated ketone levels greater than 4 mmol (9). While it is possible to produce such levels following a carbohydrate-restricted ketogenic diet, it may be more difficult to achieve and maintain these levels than the levels that are normally maintained in carbohydrate-restricted ketosis. This is where the importance of supplemental ketosis comes in. Ketosis can also be achieved through the consumption of ketogenic supplements, such as medium-chain triglycerides (MCT’s), or exogenous ketones, such as ketone esters or mineral bound ketone salts. Some data suggests that the use of ketone esters can increase ketone levels and maintain that elevation for a longer period (10). This form of ketosis can be coupled with carbohydrate-restricted ketosis but does not necessarily have to be. It is no surprise why there is a great demand for this type of ketosis, as some individuals may struggle with adherence to a diet when trying to manage a disease or disorder.

There are several chronic conditions that have demonstrated great benefit from supplemental ketosis, with the most researched condition being drug-resistant childhood epilepsy. We are starting to gather more data on supplemental ketosis aiding in the treatment of neurological disorders such as Alzheimer’s (10); metabolic disorders such as diabetes (11); cancer (12); and even certain forms of cardiovascular disease (13). Additionally, since ketones can provide an alternative fuel source, supplemental ketones can provide benefit to athletes (14).

Alcoholic Ketosis

Alcoholic ketosis, or alcoholic ketoacidosis (AKA), can technically be classified as a variation of nutritional ketosis since it occurs due to a dietary intervention. Like its name implies, this form of ketosis is a result of alcohol consumption and causes an acidic internal environment due to the drastic increase in ketone bodies. AKA can occur in those who frequently drink or those who are malnourished and drinking alcohol. Symptoms of alcoholic ketosis, depending on the severity, can include nausea and vomiting, fatigue, altered breathing, and abdominal pain. AKA typically occurs the day after drinking and is characterized by increased ketone production in conjunction with a mild elevation in blood glucose levels, making it much different than other variations of ketosis. Ketone bodies B-hydroxybutyrate (BHB) and acetoacetate (AcAc) are formed via alcohol metabolism in the liver. Due to the redox state that accompanies AKA, BHB tends to be the ketone body that is elevated to the greatest extent. Additionally, due to the dehydrated state that typically accompanies alcohol consumption, the kidneys fail to excrete these extra ketones. Under normal conditions, our bodies may shut down ketone production when they become elevated to dangerously high levels. However, during AKA, hormonal changes (cortisol and catecholamines) occur that promote further lipolysis, which provides more substrate for additional ketone production. An additional change that accompanies alcohol consumption is suppressed insulin secretion, which provides an additional state in which ketones can be produced.

Alcohol-Induced-Ketones

There are several treatment options for AKA including intravenous fluid and vitamin administration. These fluids typically contain glucose as an attempt to increase insulin secretion. This form of ketosis is not recognized as safe and is not a recommended variation of ketosis.

infographic-remake

Pathological Ketosis

A final form of ketosis that can occur is pathological ketosis and in particular diabetic ketoacidosis (DKA). DKA, also characterized by an acidic internal environment, is one of the reasons why ketosis has a bad stigma surrounding it. Pathological ketosis occurs due to uncontrolled rates of ketogenesis (10-15mmol), leading to much greater levels of ketones compared to carbohydrate-restricted or supplemental ketosis. This sharp increase in ketones can cause acidity in the blood, thus lowering the pH to seven or lower. Furthermore, diabetic ketoacidosis is accompanied by high blood glucose levels that can be greater than 200! DKA typically occurs in Type I diabetics but also can occur in Type II. Type I diabetics do not produce enough insulin, leaving glucose in the blood rather than shuttling it towards the cells. This convinces the body that it is starved of energy, leading to increased ketone production. Subsequently, high blood glucose and high blood ketone levels occur simultaneously. This is much different than the state of ketosis that occurs during fasting, carbohydrate restriction, or supplementation in healthy individuals who have regulatory systems that prevent such large increases in both ketones and glucose.

levels-of-ketosis

Fasting and nutritional ketosis each have unique benefits, but those benefits can certainly overlap. Given the current research, both are considered to be safe and well-tolerated by the majority of individuals (7). However, we still lack a universal consensus among physicians and scientists about the safety and efficacy of being in a state of ketosis and the ideal level of blood ketones. There are certain metabolic and health disorders that may contraindicate ketogenic dieting and ketosis. Below is a list of conditions that should prevent someone from attempting nutritional ketosis.

Ketosis Contraindications

 

Keto Conclusions

  • Ketosis can be achieved through fasting, nutritional modification, and certain pathological conditions.
  • Fasting ketosis typically results in a much lower level of ketone producting compared to nutritional ketosis but this is dependent on the duration of the fast.
  • Nutritional ketosis can be achieved through carbohydrate restriction, supplementation, or increased alcohol consumption.
  • Fasting and nutritional ketosis are safe and effective strategies with a variety of body composition and therapeutic benefits.
  • Pathological variations of ketosis are different from fasting and nutritional ketosis.
keto-conclusions-bar

References

  1. Hall S. E., Wastney M. E., Bolton T. M., Braaten J. T., Berman M. (1984). Ketone body kinetics in humans: the effects of insulin-dependent diabetes, obesity, and starvation. J. Lipid Res. 25 1184–1194
  2. Varady, K. A., Bhutani, S., Church, E. C., & Klempel, M. C. (2009). Short-term modified alternate-day fasting: a novel dietary strategy for weight loss and cardioprotection in obese adults. The American journal of clinical nutrition, 90(5), 1138-1143.
  3. Lee, C., Raffaghello, L., Brandhorst, S., Safdie, F. M., Bianchi, G., Martin-Montalvo, A., ... & Emionite, L. (2012). Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Science translational medicine, 4(124), 124ra27-124ra27.
  4. Wheless, J. W. (2008). History of the ketogenic diet. Epilepsia, 49(s8), 3-5.
  5. Cahill Jr, G. F., & Aoki, T. T. (1980). Alternate fuel utilization by brain.Cerebral metabolism and neural function, 234-242.
  6. Veech, R. L. (2004). The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins, leukotrienes and essential fatty acids, 70(3), 309-319.
  7. Hasselbalch S. G., Knudsen G. M., Jakobsen J., Hageman L. P., Holm S., Paulson O. B. (1995). Blood-brain barrier permeability of glucose and ketone bodies during short-term starvation in humans. Am. J. Physiol. 268(6 Pt 1), E1161–E1166.
  8. Paoli, A., Rubini, A., Volek, J. S., & Grimaldi, K. A. (2013). Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. European journal of clinical nutrition, 67(8), 789-796.
  9. D'Agostino, D. P., Pilla, R., Held, H. E., Landon, C. S., Puchowicz, M., Brunengraber, H., ... & Dean, J. B. (2013). Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 304(10), R829-R836.
  10. Newport, M. T., VanItallie, T. B., Kashiwaya, Y., King, M. T., & Veech, R. L. (2015). A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease. Alzheimer's & Dementia, 11(1), 99-103
  11. Westman, E. C., Yancy, W. S., Mavropoulos, J. C., Marquart, M., & McDuffie, J. R. (2008). The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutrition & metabolism, 5(1), 1.
  12. Poff, A. M., Ari, C., Arnold, P., Seyfried, T. N., & D'Agostino, D. P. (2014). Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International journal of cancer, 135(7), 1711-1720.
  13. Labarthe, F., Gélinas, R., & Des Rosiers, C. (2008). Medium-chain fatty acids as metabolic therapy in cardiac disease. Cardiovascular drugs and therapy, 22(2), 97-106.
  14. Cox, P. J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., ... & King, M. T. (2016). Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metabolism, 24(2), 256-268.