The ketogenic diet (or keto diet) has been touted for its many potential health benefits such as weight loss, cognitive enhancement, and prevention of neurodegenerative diseases and cancer. In this post, we cover: Different ways to get into ketosis
Physiology and pathways that are changed when you are in ketosis, which explains how the ketogenic diet may derive its benefits
Genetic factors that may affect the safety and effectiveness of ketosis
Health conditions that may be helped by the ketogenic diet
Negative effects of ketosis and how to mitigate them
What Is the Keto Diet?
Keto diets are defined by a low-carbohydrate (typically under 50 grams/day) and high-fat intake, leading to an elevation of free fatty acids and ketone bodies in the blood [ 1 ].
The first ketogenic diets in the medical literature are noted in publications from the 1920s, although wider popularity and increased research was not observed until the 1960s [ 1 ].
Variations of this diet have remained popular for the past 20-30 years, with proponents claiming that these diets boost weight loss and energy while protecting from certain metabolic diseases [ 1 ].
A ketogenic diet and fasting seem to affect the body similarly. Both deplete the body’s glucose reserves, so the body may start turning fatty acids into ketones [ 2 ]. The Physiology of Ketosis
Beta-hydroxybutyrate is a signaling molecule that can activate HDACs and thereby increase or decrease important genes during ketosis [ 3 ]. Biochemical Pathway, Hormones, or Benefits Ketogenic Diet Calorie Restriction or Fasting References How to Get Into Ketosis
When the body doesn’t have enough carbohydrates from food, it burns fat to produce energy. This results in the production of ketones or ketone bodies [ 17 ].
In non-diabetics, ketosis can be achieved through 4 ways: Prolonged physical exercise in a fasted state, depending on intensity and duration [ 19 , 20 ]
Nutritional ketosis, i.e. by consuming a very low carbohydrate diet
Supplementation, such as with medium-chain triglycerides or exogenous ketones (ketone esters or ketone ester salts) [ 21 ]
There are 3 different types of ketone bodies, including [ 22 ]: Beta-hydroxybutyrate, the main ketone body that circulates in the blood
Acetoacetate , the main ketone body produced by the liver
Acetone , a very volatile ketone that is generally eliminated through exhalation and is what gives the sweet ketone breath in people in ketosis
In rats, acetoacetate concentration in the blood and brain is very low. A study found that its concentration in the brain was less than 4% of that in the whole blood and 2.6% of that in plasma. However, the brain/blood ratio was highest in starved rats [ 23 ].
In this study, the concentration of beta-hydroxybutyrate in the blood and brain was 5-10 times greater than that of acetoacetate [ 23 ]. Exogenous Ketones
Ketone body supplements can provide 8-12 grams of beta-hydroxybutyrate and 1 gram of sodium per serving, which can rapidly increase ketone body availability.
While a ketogenic diet or fasting can take days to raise blood ketone levels, exogenous ketones can reach peak levels in 1-2 hours.
Upon ingestion, ketone esters, such as (R)-3-hydroxybutyl and (R)-3-hydroxybutyrate, have emerged as a more practical and applicable way to increase ketone bodies, especially for athletes.
Ketone esters are cleaved and absorbed in the gut, from where they can either enter circulation or undergo first-pass metabolism in the liver [ 24 ]. Keto-Adaptation
Keto-adaptation refers to the process where cells transition from relying on glucose to relying on fat burning for energy production [ 25 ].After prolonged fasting (over 2 weeks) or diet-induced ketosis, cells adapt to using fatty acids and ketone bodies (keto-adaptation), resulting in a significant reduction in glucose requirement [ 26 ].Typically, ketone bodies are present in low amounts in the blood. After the first 2-3 days of fasting or being on a very low-carbohydrate diet, the liver starts to produce ketones so ketone levels remain around 2-3 mM [ 25 ].Keto-adaptation is complete when, after weeks of carbohydrate depletion, cells in the body cut down their uptake of ketone bodies. This results in an increase of ketone body concentration in the blood to ~8 mM [ 27 ].Keto-adaptation allows the brain to effectively take up and use the ketone bodies because the protein that transports them through the blood-brain barrier is more effective at higher concentrations (Km = 7 mM) [ 28 ]. Nutritional Ketosis vs Diabetic Ketoacidosis Nutritional ketosis is very different from diabetic ketoacidosis .In non-diabetics, blood sugar remains normal during ketosis. When the carbohydrate stores are depleted by the end of the first day on a ketogenic diet, the liver starts to produce glucose from other sources, such as pyruvate, glycerol, and amino acids. This helps maintain normal blood sugar levels [ 26 ].In healthy people eating a ketogenic diet or fasting for long periods of time, ketone levels can reach up to 8 mmol/L, which is a safe level [ 18 ].Ketone bodies can inhibit their own production, typically preventing these substances from building up to levels that cause ketoacidosis in type 1 diabetics (approximately 20 mmol/L) [ 29 , 18 ]. Genetic Factors that Determine Whether You Should Adopt a Ketogenic Diet PPAR-alpha activity is required for ketosis. Mice lacking PPAR-alpha have reduced ability to enter ketosis [ 9 , 8 ].People with ApoE 3 (CT for RS429358 ) and ApoE4 genotypes (CC for rs7412 ) may have very high cholesterol when they consume a diet high in saturated fat . The keto diet is contraindicated in this case, since it increases their risk of heart disease [ 30 ].Epileptic patients with certain variants at KCNJ11 (rs8175351, rs5219 , rs5215 ) and BAD (rs34882006, rs2286615) genes had lower responses to ketogenic diet treatments after three months in a study on over 500 people [ 31 ]. Snapshot Proponents Often prescribed to reduce seizures in people with epilepsy May help lose weight May lower blood fat levels May improve blood sugar […]