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. As the fast continues, the rate of ketone production exceeds ketone clearance, resulting in an increase in blood ketone levels. 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 fasts as fasting ketosis. This response to fasting and starvation is a protective mechanism used to maintain energy balance and avoid a loss in body mass.
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 the TCA cycle intermediate
oxaloacetate. Oxaloacetate is required for the first step of the TCA cycle to occur and, without it, a build-up of acetyl-CoA occurs. Excess 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: 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, or 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.
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, and even as a method to induce ketosis prior to chemotherapy. 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 Jimmy Moore and 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. He discovered that this could 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. 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.
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.
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. While it is possible to produce such levels following a carbohydrate-restricted ketogenic diet, those levels are difficult to achieve and maintain on the diet. This is where the importance of supplemental ketosis comes in. Ketosis can be achieved through the consumption of supplements, such as medium-chain triglycerides (MCTs) 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 than other ketone supplement variations. Supplemental ketosis can be coupled with carbohydrate-restricted ketosis, but does not necessarily have to be.
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 disease7, metabolic disorders, such as diabetes; and cancer. Additionally, since ketones are an alternative fuel source, supplemental ketones may provide performance benefits to athletes.
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. 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 (See figure below). Due to the redox state that accompanies AKA, BHB tends to be the ketone body that is elevated the most. 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. 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.
The 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 such a bad stigma surrounding it. Diseased ketosis occurs due to uncontrolled rates of ketogenesis (10-15 mmol), leading to much greater levels of ketones than carbohydrate-restricted or supplemental ketosis. This sharp increase in ketones can cause acidity in the blood, thus lowering blood pH from 7.35 to less than 7.30. Furthermore, diabetic ketoacidosis is accompanied by high blood glucose levels that can be greater than 2250 mg/dL! DKA typically occurs in type I diabetics, but also can occur in type II. Type I diabetics do not produce enough insulin, so glucose is left in the blood, rather than being taken up and utilized for energy by 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.
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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