The 2024 Levels Guide to ketosis and the keto diet
Ketosis is when your body is burning fat instead of glucose—so what does it have to do with the keto diet and metabolic health? And is it healthy?
You may know someone who "went keto" or have heard about the keto diet on health blogs and podcasts. But what does it mean to put your body into ketosis? Is it good for you? And are grocery items labeled "keto" healthier than other foods?
Ketosis is a metabolic state in which the body primarily burns fat for energy rather than glucose, and the production of ketones serves as an alternative fuel for the brain and other tissues. In addition to the well-established neurological benefits, some research suggests that keeping your body in a prolonged state of ketosis may help you lose weight and improve cardiometabolic health biomarkers. Emerging preclinical and clinical research suggests that a well-formulated ketogenic diet can be therapeutic for specific neurological disease, insulin resistance, diabetes, cardiovascular disease, and certain forms of cancer.
Developed as a medical therapy for epilepsy in the early 1920s, the modern keto diet has been described as a way of eating, even a lifestyle, designed to shift your metabolism physiologically. It's significantly higher in fat and lower in carbohydrates than a typical low-carb diet aimed at stabilizing blood sugar. Research suggests it has benefits such as reduced inflammation and increased focus and energy, but it can come with side effects such as "keto flu," and data about long-term safety and efficacy, outside of its clinical uses (such as for epilepsy treatment, is lacking. Because it is difficult for most to sustain the ketogenic pattern of eating, researchers are working on ways to induce and sustain "therapeutic ketosis" with exogenous ketone supplementation independent of dietary restriction. Ketogenic supplementation is a rapidly emerging area of basic science and clinical research, and dozens of large-scale studies are being done for a broad range of applications (see clinicaltrials.gov).
Here's a full explanation of what's happening in your body during ketosis and what we know about its effects on the body.
What is ketosis?
Under typical conditions, the body mostly burns glucose for energy. But when you consume very few carbohydrates and the body runs out of stored glucose, it transitions to fat and ketone metabolism as its primary energy source. This metabolic state is called ketosis or nutritional ketosis.
When in ketosis, triglycerides are broken down into fatty acids. The liver then turns these fatty acids into acidic compounds called ketone bodies, or ketones for short. The ketones travel to many tissues in the body and function as a form of alternative energy.
Although this is the primary way the body produces energy during ketosis, it also uses a process called gluconeogenesis, in which the liver (and, to a lesser extent, the kidneys) creates glucose to keep blood sugar stable and fuel cells that can't run on ketones. In the absence of carbohydrates, glucose production comes from amino acids and the glycerol backbone of triglycerides (fat).
The Full Physiology of Ketosis
Of course, the whole process is a bit more complicated. In ketosis, enzymes break down triglycerides into their component parts, including free fatty acids. The fatty acids travel through the blood and, after some modification, enter the mitochondria (the part of the cell that produces energy) in the liver. There, a process called beta-oxidation breaks them down to make a molecule heavily involved in metabolism: acetyl-CoA. (Some proteins are also converted into acetyl-CoA, but some are converted into glucose.)
Under normal conditions, acetyl-CoA directly produces energy through a cycle referred to as the tricarboxylic acid cycle (TCA) or Krebs cycle, which mainly occurs in the liver but can also occur in skeletal muscle and the outer layer of the kidney. But this cycle doesn't work normally during ketosis for two main reasons: 1) It can't handle the large amount of acetyl-CoA created in the liver during ketosis, and 2) decreased carbohydrate consumption and increased gluconeogenesis decreases the availability of a chemical component called oxaloacetate that the TCA cycle needs to run.
So, instead of going through the TCA cycle, the large amount of acetyl-CoA created during ketosis is turned into ketone bodies. This process, which occurs in liver mitochondria, is called ketogenesis.
The ketones travel via the bloodstream to the mitochondria of organs throughout the body. In these organs, the ketones are processed to become, once again, acetyl-CoA. There, acetyl-CoA has two potential fates, both of which produce energy. It can either 1) go through the TCA cycle to make energy or 2) be converted to oxaloacetate and used to make energy via gluconeogenesis. (The TCA cycle in organs other than the liver isn't limited by an overwhelming amount of acetyl-CoA, or by a dearth of oxaloacetate, since gluconeogenesis doesn't occur outside of the liver and kidneys.)
Despite how complicated it may seem to create energy in ketosis, creating energy from glucose is even more complex. As a result, ketone bodies are more efficient than glucose at creating energy. In other words, with all the chemical processes involved, each ketone body produces more energy during ketosis than the equivalent amount of glucose under normal conditions.
Many organs, such as the heart, brain, muscles, and kidneys, can use ketone bodies for fuel. Researchers from Harvard, Oxford, and NIH have proposed that beta-hydroxybutyrate (BHB), the principal "ketone," is a "super fuel" more efficiently producing ATP energy than glucose or fatty acid. However, not every part of the body can metabolize ketones, including red blood cells and the liver. That's because they lack an enzyme that is necessary to create energy from ketones, respectively. Instead, these tissues use glucose derived from the small amounts of carbohydrates you eat while on the keto diet and from gluconeogenesis.
It's important to note that ketones don't only provide energy when you're in nutritional ketosis from following the keto diet. For instance, some newborns are in ketosis for the first few days of their lives. Adults may enter ketosis when fasting, post-exercise, or during pregnancy. Beyond metabolism, ketone bodies like BHB have many other functions, including anti-inflammatory, anti-cancer, and epigenetic signaling.
What is the keto diet?
The keto diet is a high-fat, low-carbohydrate diet designed to trigger and maintain ketosis. For the typical 2,000 calorie diet, it includes eating 20 to 50 grams of carbohydrates per day, around 165 grams of fat, and 75 grams of protein. About 70% to 85% of calories come from fat, 10% to 20% from protein, and 5% to 10% from carbohydrates. You're essentially starving the body of glucose as a fuel source and instead providing ample fat to burn.
The keto diet typically requires cutting out all added sugars, bread, cereal, and other grains, and eating vegetables and fruit sparingly. Foods on the keto diet primarily consist of meat, fish, eggs, nuts and seeds, dairy products, and oils. Given these restrictions, it can be challenging to maintain. It's often meant to be a temporary diet, lasting a minimum of two to three weeks, up to 6 to 12 months --- partly because of a lack of research on its long-term risks and partly because it's challenging to stick to. The duration of the ketogenic diet for epilepsy is typically 2 to 3 years, but this can vary based on individual circumstances. In metabolic disorders, the diet is often used for a decade or more as metabolic therapy with no cardiovascular risks. However, as cardiologist Dr. Paolo Raggi put it in a 2020 review paper, "Many may find this restriction too limiting and unpalatable, despite the freedom to ingest as much butter and bacon as desired and may deviate from such enforcement with the simple ingestion of one apple a day." Therefore, many researchers are investigating less restrictive forms of the ketogenic diet.
The four main subtypes of the keto diet differ based on their macronutrient components. The most popular type---and the one you probably think of when you think of the keto diet---is called the "classical ketogenic diet" or "long-chain triglyceride" (LCT) ketogenic diet. It's categorized by a 4:1 ratio of grams of fat to grams of carbohydrate and protein, although some people use a 3:1 ratio because it's easier to maintain. The name of this subtype comes from LCTs, which are the types of fats predominantly found in food. An alternative is the medium-chain triglyceride (MCT) ketogenic diet. This subtype involves adding a significant percentage (>30%) of MCT oil to the diet, usually derived from coconut or palm kernel oil, to the diet. Because MCTs are more ketogenic than LCTs, this subtype allows you to maintain ketosis while eating more protein and carbohydrates. There are fewer clinical trials with the MCT keto diet, and this version of the diet is associated with more gastrointestinal side effects.
The two other subtypes---the Modified Atkins diet (MAD) and Low glycemic index treatment (LGIT)---are more flexible in their carbohydrate intake. Both MAD and LGIT have been used for seizure disorders. They are being studied for autism spectrum disorders (ASD), Alzheimer's disease, migraines, and potentially aiding in conditions like Type 2 diabetes or insulin resistance.
How does the keto diet lead to ketosis?
When you severely cut back on eating carbohydrates, your body quickly burns through your stored glucose, called glycogen. After this, blood glucose levels decrease, leading to a decrease in insulin levels, the hormone that allows glucose to enter cells. Low insulin levels signal the liver to increase fat oxidation and ketone production.
Although insulin suppression is the major player in initiating and maintaining ketosis, increases in other hormones, some of which are affected by following the keto diet, can also regulate ketosis. The hormone glucagon normally stimulates insulin secretion, but when insulin is low, it can instead stimulate fat breakdown, called lipolysis, and enhances the liver's production of ketones in the short term. The stress hormone cortisol can have similar effects, though the interactions are more complex. Growth hormone can also enhance lipolysis when insulin levels are low. Catecholamines, which act as hormones and neurotransmitters, stimulate lipolysis and fatty acid mobilization, even in the presence of insulin.
When eating less than 50 grams of carbohydrates per day, it usually takes two to four days to transition into ketosis, but it can take a week or longer, depending on factors such as age, macronutrient intake, physical activity, metabolism, sleep, and stress. Additionally, if you ate a lot of carbohydrates before beginning the keto diet, it can take longer to use up your body's liver glycogen stores and enter ketosis.
The keto diet, however, isn't the only safe way to enter ketosis. Intermittent fasting can trigger it, too, sometimes even faster. Some people even enter ketosis after 12 hours of fasting---for example, during a fast between dinner and breakfast. Fasting for more extended periods could prolong ketosis and be more beneficial. Some evidence suggests that intermittent fasting while on the ketogenic diet could augment the beneficial effects of the diet by further increasing ketone levels.
Indeed, many benefits of the ketogenic diet and fasting, like suppressed inflammation, have been linked to elevated ketone levels.
Is going keto good for you?
One of the biggest draws of the keto diet is weight loss. A 2022 meta-analysis found that following a low-calorie keto diet led to significant weight loss and reductions of waist circumference in people with overweight and Type 2 diabetes. In a 2020 meta-analysis, following a very low-calorie keto diet (less than 800 calories per day) for at least four weeks (preceded by a phase-in period) led to an average weight loss of 34.4 pounds in people with overweight and obesity. Although quantitative analysis was inconclusive statistically, it appeared that weight stayed off during a two-year follow-up period in which they returned to a balanced diet without extreme calorie restriction. And a 2013 meta-analysis showed that a very low-carbohydrate keto diet was more effective for weight loss than a conventional low-fat diet over a year.
Although much research supports that a keto diet without calorie restriction drives weight loss, some analyses conflict with this. Exactly how a version that doesn't restrict calories would lead to weight loss is unclear. Some experts suggest that keto dieters eat fewer calories because the relatively higher protein content of the diet leads to greater satiety. It could also be due to direct appetite-suppressing effects of the diet on appetite-control hormones (e.g., GLP-1). It is generally accepted that higher ketone levels suppress appetite and ghrelin levels and protect against hypoglycemia-induced food cravings. Another possibility is that it could cause a small but significant increase in how many calories you burn at rest.
It's also important to note that not all weight lost on the keto diet is from fat mass. Much of the initial weight loss is water weight, and if dietary protein is insufficient, it can also include the loss of lean mass like muscle. Therefore, ensuring sufficient hydration, electrolytes, and protein is essential, especially during the transition into ketosis.
There isn't enough evidence to determine whether the keto diet is superior for prolonged weight loss, although there do seem to be advantages for some. Researchers have mainly investigated the short- and medium-term effects of following the keto diet for up to a year, with study follow-up periods as long as two years. And the limited evidence that does exist on weight loss during this period is mixed. Many studies that follow up on it after two years don't compare the effects of the keto diet to that of other diets. More trials are in the works that may provide more long-term data. The success of the ketogenic diet for long-term weight loss appears to be due, in part, to diet formulation, compliance issues, recruiting participants motivated enough to adhere to this restrictive diet, and concerns with elevated LDL-C levels.
Regardless of whether you lose weight, the keto diet may improve metabolic health, according to a 2023 review. This is because it can lead to lower glucose and insulin levels while you're following it, which would cause the body to become more sensitive to insulin in the long run. (Some research, however, suggests that it doesn't have a greater effect on fasting glucose and insulin compared to other diets, and any benefits may fade in the long term.) Ketone bodies may also directly affect insulin signaling by enhancing insulin sensitivity and improving metabolic flexibility, particularly in insulin-resistant people.
Additionally, the keto diet decreases liver fat, which improves insulin sensitivity through several mechanisms, including enhancing mitochondrial efficiency and reducing inflammation and oxidative stress. The diet also increases the volume and efficiency of mitochondria in skeletal muscle, improving metabolic health, muscle fat oxidation, and overall energy production.
Expert opinion on whether the keto diet primarily benefits or harms cholesterol profiles is mixed; some worry that it may worsen total cholesterol and LDL cholesterol levels, while others argue that the emphasis on LDL levels is overhyped when viewed in the context of improved cardiometabolic biomarkers like HDL cholesterol, triglycerides, and small dense LDL particle count (a more damaging form of LDL cholesterol).
The keto diet also protects the heart in other ways, such as improving the function of the layer of cells that line blood vessels, called the vascular endothelium, which performs many important jobs, including blood flow regulation. People on the keto diet often consume high levels of heart-healthy omega-3s. The keto diet often improves blood pressure, but perhaps not more so than other diets.
Research also suggests that the keto diet is anti-inflammatory, enhances antioxidants, and improves the body's defenses against oxidative stress, which causes cell damage.
Finally, there's growing evidence that the keto diet may be particularly beneficial for people with certain conditions in either improved quality of life or in conjunction with other treatments. The ketogenic diet can be an effective stand-alone therapy for conditions like drug-resistant epilepsy or even Type 2 diabetes, but it appears most effective as an integrative or adjuvant therapy when combined with more conventional therapies.
- Epilepsy: The keto diet was first developed to help manage epilepsy. Shifting the brain's energy source from glucose to ketone bodies reduces its excitability, helping limit seizures. However, the exact mechanisms are poorly understood and a topic of intense investigation.
- Cancer: Cancer cells have altered metabolism, including a high demand for glucose. Reducing glucose and insulin signaling are proposed mechanisms for how ketosis could aid in cancer outcomes. Evidence in clinical settings is mixed and limited as to its effectiveness. However, it looks promising in mouse studies that keto may enhance treatments like chemo or radiation, and in humans there's evidence it can aid in quality of life for cancer patients. In addition, ketones may have direct anti-cancer and anti-catabolic effects (muscle sparing).
- Type 2 diabetes: The keto diet can reduce the need for insulin treatment and other antidiabetic drugs in people with Type 2 diabetes, and it may improve quality of life.
- Non-alcoholic fatty liver disease (NAFLD): A small body of evidence suggests that the keto diet in the short- and medium-term may help NAFLD by improving mitochondria, oxidative stress, and inflammation. However, in people with existing liver damage (e.g., hepatitis), the keto diet can put additional stress on the liver, so it is crucial to get routine liver function tests when used long term.
- Polycystic ovarian syndrome (PCOS): Preliminary evidence suggests that a very low-calorie keto diet in the short term can improve PCOS by improving body weight and composition, metabolic profile, and insulin resistance.
- Neurodegenerative disorders: The keto diet may benefit people with Alzheimer's disease by improving mitochondrial function, optimizing the gut microbiome, and reducing oxidative stress and inflammation in the brain. It could also help those with Parkinson's disease, multiple sclerosis, and migraines. There's even some evidence that the ketogenic diet may benefit psychological conditions like schizophrenia. The use of ketogenic diets in the relatively new field of metabolic psychiatry is rapidly emerging for a broad range of psychiatric diseases.
Potential drawbacks of the keto diet
In the first few days to weeks of beginning the keto diet, many people experience the "keto flu," which includes symptoms like fatigue, headache, dizziness, insomnia, nausea, vomiting, constipation, and reduced exercise tolerance. Staying hydrated and getting ample electrolytes (salt) is key to avoiding this side effect. Going keto can also cause bad breath that smells fruity or sweet due to the production of a ketone body called acetone; this usually clears up in a few weeks.
Possible long-term side effects observed in clinical studies include nutritional deficiencies, digestive issues, and kidney stones. These side effects have been reported primarily in studies using the classical LCT ketogenic diet. Rapid introduction to high fat consumption can result in fat intolerance, nausea, and GI issues. This can typically be mitigated with caloric restriction for the first few weeks, and then calories can be adjusted to meet energy demands and stabilize weight. In the context of obesity, weight loss can be favorable but can also be associated with fatigue and altered electrolytes. Consuming too much saturated fat and too little fiber is also a concern for some people. The keto diet may be dangerous for people with certain conditions, such as liver, kidney, and respiratory insufficiency. Getting routine comprehensive bloodwork and consulting your doctor is advised before attempting a keto diet since the metabolic changes can influence many parameters, including the metabolism of many prescription drugs.
What is ketoacidosis?
Ketoacidosis is a dangerous condition that occurs when the concentration of ketones in the blood rises too high, making the blood overly acidic. This can, for example, cause inflammation or swelling in the brain, disruptions in the blood-brain barrier, and impair the heart's ability to contract. It is a medical emergency that may lead to fluid buildup in the brain, cardiac arrest, and kidney failure.
However, ketoacidosis rarely occurs in metabolically healthy people as a result of the keto diet or fasting to induce ketosis. This is because metabolically healthy people can increase the levels of bases in the blood to buffer the increased blood acidity from ketones and keep it from rising too high. Ketoacidosis is most likely to occur in people with Type 1 diabetes and occasionally in people with Type 2 diabetes. In these cases, the condition is referred to as diabetic ketoacidosis (DKA).
Ketone concentration in the blood is typically between 0.5mmol/L and 3 mmol/L during nutritional ketosis and between 5 mmol/L and 10 mmol/L during prolonged fasting. Ketoacidosis is characterized by levels anywhere from 3 mmol/L to about 16 mmol/L or more, so there is overlap between healthy and dangerous blood levels of ketones. But if you're in the keto/fasting range, don't have diabetes, and don't have ketoacidosis symptoms, it's unlikely that your blood is too acidic.
Symptoms of DKA include:
- Extreme thirst
- Frequent urination
- Vomiting or feeling the need to vomit
- Stomach pain
- Shortness of breath
- Weakness or tiredness
- Sweet or fruity-scented breath
- Confusion
Conclusion
The keto diet has a range of clinically proven benefits, especially for the brain, cardiovascular system, and in emerging applications, and even exercise. Several systematic reviews and meta-analyses of randomized clinical trials have reported the benefits of ketogenic diets, but whether they are stronger than the benefits of other diets---and whether the benefits outweigh the risks---is largely unclear and highly dependent on the context. Crucially, many people find such a restrictive diet a burden to maintain continuously. As cardiologist Dr. Raggi wrote, "Adopting the keto diet beyond the scope of weight loss begs the question of its sustainability and long-term safety, but also enjoyment in life." On the other hand, some people find ketogenic diets indulgent since it allows them to enjoy higher-fat foods that have greater satiety. Ongoing research on modified ketogenic diets, MCT, and exogenous ketone supplementation shows alternative approaches to inducing nutritional and therapeutic ketosis. Additional clinical trials with long-term follow-up are needed to determine whether long-term beneficial outcomes in weight loss, and metabolic, cardiovascular, and neurological health endure.
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