For this article, we will refer to three different forms of ketosis: fasting ketosis, nutritional ketosis, and diseased ketosis. The different types of ketosis vary in their degree of ketone production, as well as their method of induction.
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 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 a point 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 0.3 mmol/L. Shorter fasts typically will not raise ketones above these levels because the rate of ketone metabolism matches ketone synthesis.
When oxaloacetate is removed from the cycle for gluconeogenesis, acetyl-CoA cannot enter the TCA cycle. It is instead used for the formation of ketone bodies.
Fasting ketosis can have an array of benefits, and has been used for the treatment of obesity, [2] and even as a method to induce ketosis prior to chemotherapy. [3] 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 levels of ketone production. This shift in fuel utilization is thought to be a survival mechanism that we have retained through our evolution, which is why prolonged fasts can often be tolerated by most individuals. Check out Dr. Jason Fung for more great information on fasting!
Nutritional ketosis is a state of ketosis that is induced by dietary modification. We will be dividing nutritional ketosis into three subcategories: carbohydrate-restricted ketosis, supplemental ketosis, and alcoholic ketosis.
Carbohydrate-restricted ketosis has been utilized for decades. In 1921, Woodyatt discovered that fasting or starvation resulted in the appearance of ketones in the blood.
Carbohydrate-restricted ketosis can occur through a well-formulated ketogenic diet. 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 can 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 previously discussed. Once an individual is adapted to the diet, the reason for ketone production could be increased fat oxidation, not oxaloacetate depletion. This, in turn, 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 regarding the production of ketones under various physiological conditions.
This state is a long-term, sustainable approach that can provide an array of health benefits, including stable blood sugar, increased weight loss, improved cognition, and the treatment of various diseases. [5]
Certain levels of ketosis can provide powerful therapeutic benefits, but this level of ketosis must 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. [6]
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 disease, [7] metabolic disorders, such as diabetes [8]; and cancer. [9] Additionally, since ketones are an alternative fuel source, supplemental ketones may provide performance benefits to athletes. [10]
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 are malnourished and drinking alcohol. Symptoms of alcoholic ketosis, depending on the severity, can include nausea and vomiting, fatigue, altered breathing, and abdominal pain.
Another change that accompanies alcohol consumption is suppressed insulin secretion, which provides an additional state in which ketones can be produced. 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.
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.
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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.
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.
Wheless, J. W. (2008). History of the ketogenic diet. Epilepsia, 49(s8), 3-5. Cahill Jr, G. F., & Aoki, T. T. (1980). Alternate fuel utilization by brain.Cerebral metabolism and neural function, 234-242.
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.
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.
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
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.
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.
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.
This is a great article. But I have one question. The list “Keto not Recommended for” lists gastric bypass as being contraindicated. I lam a 62 year old female who had the surgery in 2002. I lost weight but over the years regained some. I have been doing Keto with intermittent fasting and caloric restriction since July and have lost over 55 pounds so far. My labs and vitals are all excellent. Is there something I should watch out for or be concerned about?
Hello Carolyn, we are reaching out to Dr. Ryan Lowery to get you the best answer!
Not imparticular if its working fine for you and your vitals are fine keto on! We are talking to people who are starting keto after gastric and recommending they working closely with their doctors. Seems like you are doing great! Congrats!