Hyperketosis Diet Explained: A Comprehensive Guide

Introduction

The saying "Diseases enter by the mouth," emphasizes the close association between dietary factors and many diseases. Dietary planning is increasingly popular as a way to maintain health and as a non-pharmaceutical option for fighting disease. Choosing a proper diet can have profound implications for health and may induce therapeutic effects. There are numerous types of diets, including low-carbohydrate diets (LCDs; e.g., ketogenic diet [KD]), paleo-type diets, plant-forward diets, intermittent fasting, clean eating, traditional regional diets (e.g., Mediterranean diet), and other specifically designed diets (e.g., dietary approaches to stop hypertension diet, Mayo Clinic diet), that diversify food patterns or fulfill specific purposes. The KD has a long history of clinical use and has recently gained considerable interest owing to its promising potential effects on a wide spectrum of diseases.

The KD comprises a high-fat component, very low carbohydrates, and adequate proteins and has been clinically used since the early 1920s to control seizures in patients with epilepsy, especially those who do not respond adequately to antiepileptic medication. In 1921, Russel Wilder first proposed that a ketone-producing diet could be as effective as fasting for the treatment of epilepsy, and coined the term “ketogenic diet”. In particular, the KD can mimic the metabolic effects of fasting without significant calorie deprivation. The KD re-emerged in the 1990s and became well established as an option for drug-resistant epilepsy. In the past few decades, the KD has received extensive interest because of its beneficial effects in a number of diseases, such as neurological disorders, obesity, type 2 diabetes mellitus (T2DM), cancer, intestinal disorders, and respiratory compromise. Here, we provide a comprehensive review of the KD, covering the therapeutic effects, relevant mechanisms, and clinical evidence underlying the implementation of the KD in various diseases.

What is Ketosis?

Ketosis is a metabolic state in which your body uses fat for fuel instead of carbs. It occurs when you significantly reduce your consumption of carbohydrates, limiting your body’s supply of glucose (sugar), which is the main source of energy for the cells. Normally, your body uses blood sugar (glucose) as its key energy source. You typically get glucose in your diet by eating carbohydrates (carbs) such as starches and sugars. Your body breaks the carbohydrates down into glucose and then uses the glucose as fuel. Your liver stores the rest and releases it as needed.

When your carb intake is very low, these glucose stores drain down. Since your body doesn’t have enough carbs to burn for energy, it burns fat instead. As your body breaks down fat, it produces a compound called ketones. The ketones, or ketone bodies, become your body and brain’s main source of energy. The fat your body uses to create ketones may come from your diet (nutritional ketosis), or it may come from your body’s fat stores. Your liver produces a small amount of ketones on its own, but when your glucose level decreases, your insulin level decreases. This causes your liver to ramp up the production of ketones to ensure it can provide enough energy for your brain. Therefore, your blood has high levels of ketones during ketosis.

Following a ketogenic diet is the most effective way to enter ketosis. Generally, this involves limiting carb consumption to around 20 to 50 grams per day and filling up on fats, such as meat, fish, eggs, nuts, and healthy oils. It’s also important to moderate your protein consumption, because protein can be converted into glucose if consumed in high amounts, which may slow your transition into ketosis. Practicing intermittent fasting could also help you enter ketosis faster.

Read also: Vibrant Health Through Diet

Blood, urine, and breath tests are available, which can help determine whether you’ve entered ketosis by measuring the amount of ketones produced by your body. Certain symptoms may also indicate that you’ve entered ketosis, including increased thirst, dry mouth, frequent urination, and decreased hunger or appetite.

Types of the Ketogenic Diet

The KD is characterized as a high-fat, very-low-carbohydrate diet. Several variant KD that show similar efficacy to that of the original form has been developed to date, and offer flexibility to increase compliance with the regimens. There are four major types of the KD with proven efficacy: the classic long-chain triglyceride (LCT) KD, medium-chain triglyceride (MCT) KD, modified Atkins diet (MAD), and low glycemic index treatment.

Classic Long-Chain Triglyceride (LCT) Ketogenic Diet

The classic LCT KD is the most traditional type of the KD, is widely used in the clinical setting, and incorporates a 4:1 ratio of fat (in grams) to protein plus carbohydrate (in grams). Fat provides 90% calories, and its predominant source is food-derived LCT, and a 3:1 or lower ratio may be used. Moreover, the low ratios are appropriate for the KD initiation in infants, whereas in older children, initiation with a 4:1 ratio, followed by a reduced ratio may be more effective. Furthermore, there is evidence that calorie and fluid restriction is unnecessary as no beneficial effect was proved with these two factors. Due to the severe carbohydrate restriction, the LCT KD is unpalatable, difficult to prepare, and, therefore, difficult to maintain.

Medium-Chain Triglyceride (MCT) Ketogenic Diet

In 1971, the MCT (C6-C12) KD was devised. The dietary use of MCT oil is more acceptable and is more ketogenic than LCTs. The MCT KD has better flexibility in diet ratios than the LCT KD, and the calorie intake is calculated based on the percentage of energy derived from MCT. In addition, there is clinical evidence of the equivalent efficacy of the MCT and LCT KD. However, the MCT KD is frequently associated with gastrointestinal side effects.

Modified Atkins Diet (MAD)

The MAD is based on the Atkins diet, which was popularly used in weight loss and shares similar food choices with the classic KD, but without the need for precise weighing of ingredients. The MAD does not have a strict ketogenic ratio, which typically ranges from 1:1 to 1.5:1 and, sometimes, can reach 4:1. Moreover, the MAD does not include protein, fluid, or calorie restrictions. Carbohydrate intake in the MAD is restricted to 10-15 g/day in the first month and can be subsequently increased to 20 g/day. There is clinical evidence supporting the efficacy of the MAD in children with intractable epilepsy.

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Low Glycemic Index Treatment

The low glycemic index treatment is based on the concept that the protective effect of the KD relies on stable glucose levels, but has a liberalized regimen with low-carbohydrate composition to minimize glycemic increases (glycemic indices <50), and is an effective antiepileptic intervention in children with intractable epilepsy. Despite the abovementioned evidence that suggests the similar efficacy of the four types of KD, it is unclear whether the mechanisms of action of these diets differ.

The Impact of the Ketogenic Diet on Metabolism

The ketogenic diet has a significant impact on various aspects of metabolism, including lipid and glucose metabolism, and the ketogenic process itself.

Lipid Metabolism

The metabolism of blood lipids during KD is often a concern. In the presence of oxygen, most cellular energy originates, through glycolysis, from glucose-metabolized pyruvate, which then undergoes oxidative phosphorylation within mitochondria. In the absence of glucose, cellular energy is produced by the degradation of fatty acids. A low-carbohydrate, high-protein, and high-fat diet can be unhealthy as it may lead to an increase in the circulating low-density lipoprotein (LDL), cholesterol, and triglyceride (TG) concentrations. As for liver fat metabolism, from the perspective of diet metabolism, a low total and saturated fat/high-carbohydrate diet can effectively manage liver fat storage by limiting exogenous fats.

However, the KD has potential health benefits with regard to these cardiovascular risk factors, and recent animal and clinical studies provided ample evidence that cutting carbs can actually lower total cholesterol, increase high-density lipoprotein (HDL), and reduce blood TG levels. With the premise of ensuring constant total calorie intake, the KD reduces carbohydrate intake, lowers serum insulin levels, increases insulin sensitivity, and enhances fat catabolism, thus reducing blood lipids. Due to increased de novo lipogenesis and decreased fatty acid oxidation and/or ketone production, higher carbohydrate intake may be detrimental to the net loss of liver fat. In contrast, low-carbohydrate/high-fat KD significantly increases the rate of whole-body fatty acid oxidation and liver ketogenesis. Therefore, KD has been shown to reduce liver fat. Moreover, the KD induces the expression of fibroblast growth factor-1 and promotes the hepatic clearance of TGs. In addition, the KD can increase the size and volume of LDL-C particles, which is believed to reduce the risk of cardiovascular disease, as smaller LDL particles have higher atherogenic activity. Furthermore, the KD affects endogenous cholesterol synthesis. β-Hydroxy β-methylglutaryl-CoA reductase, a key enzyme in cholesterol biosynthesis, is activated by insulin. Therefore, increased blood glucose concentrations and higher insulin levels lead to increased endogenous cholesterol synthesis. Thus, reducing dietary carbohydrates and proper cholesterol intake will lead to the inhibition of cholesterol biosynthesis.

Glucose Metabolism

There are two sources of glucose in humans: glycogenic amino acids and glycerol that are released by TG lysis. The importance of the latter source increases during ketosis. In the first few days of the KD, glycogenesis from amino acids is the main source of glucose. Subsequently, the contribution of amino acids is reduced, whereas the amount of glucose obtained from glycerol increases. In fact, TG-hydrolysis-induced glycerol can generate more than 16% glucose in the liver during the KD, compared to 60% glucose after several days of complete fasting.

Read also: Understanding the Ketogenic Diet

The effect of the KD on blood sugar levels remains controversial. After fasting for several days or restricting carbohydrate intake, the glucose reserves in the body are insufficient to produce oxaloacetate in the Krebs cycle for normal fat oxidation and supply of glucose to the central nervous system. Thus, most studies believe that the KD leads to decreased blood sugar concentration and a lower insulin-to-glucagon ratio, which is beneficial for glycemic control in individuals with diabetes. Elevated glucagon levels are associated with hepatic glucose mobilization. A recent study analyzed the effects of KDs in exercising and sedentary rats. After 6 weeks, KD decreased insulin levels by 80%, blood sugar by 50%, TGs by 55%, and cholesterol by 20%, compared to the standard feed, whereas exercising did not bring benefits. Furthermore, a 5-year prospective study that included a total of 27,799 men and 36,875 women in Japan showed that LCDs are significantly associated with a reduced risk of type 2 diabetes in women, whereas high-fat and high-protein diets are protective factors against diabetes in Japanese women. However, Delahanty et al. arrived at the opposite conclusion. Independent of exercise and body mass index, patients with type 1 diabetes who consume high fat and LCDs have higher glycosylated hemoglobin and poorer blood sugar control. Some animal experiments have shown that glucose tolerance decreases in mice that are fed KD for 22 weeks. The KD did not prevent the decline in β-cell function, nor did it improve insulin secretion. Therefore, individual differences and treatment conditions should be considered in the clinical application of the KD.

Ketogenic Process

In the liver, excessive production of acetyl coenzyme A (acetyl-CoA) and oxidation of fatty acids leads to the production of Ketone Bodies (KBs). The acetyl-CoA molecule can be utilized in the Krebs cycle or to produce acetoacetate, which is then spontaneously converted to acetone or 3-β-hydroxybutyrate by 3-β-hydroxybutyrate dehydrogenase. The KBs then enter the bloodstream and can be utilized by the brain, heart, and muscle, where they produce cellular energy in mitochondria. Higher circulating KB levels lead to ketonemia and ketonuria. Under physiological conditions, the blood concentration of KBs during prolonged fasting usually is 5-7 mM, while the glucose concentration could be lowered to below 1 mM without either convulsions or any impairment of cognitive function. In diabetic ketoacidosis, the plasma KB levels can increase up to 25 mM due to insulin deficiency, with a consequent increase in the plasma glucose concentration and decreased blood pH.

The KBs constitute a more efficient energy source than glucose, metabolize faster than glucose, and can bypass the glycolytic pathway by directly entering the Krebs cycle, whereas glucose needs to undergo glycolysis. Moreover, KBs cause fatty acid-mediated activation of peroxisome proliferator-activated receptor α as well as the inhibition of glycolysis and fatty acids. Therefore, KBs reduce the production of glycolytic adenosine triphosphate (ATP) and increase mitochondrial oxidation-induced ATP generation, thereby promoting mitochondrial oxidative metabolism, with resultant beneficial downstream metabolic changes.

Ketogenic Diet and Gut Microbiota

The effects of the KD on the gut microbiome have been reported in many murine and human studies. Mice that were fed a 4-day KD showed significant changes in gut bacterial composition, which was characterized by an increase in Akkermansia and Parabacteriodes populations that induced an anti-seizure effect in germ-free or antibiotic-treated mice. The increased gut populations of these two bacterial genera decrease the γ-glutamyl transpeptidase level, which catalyzes the transfer of functional groups of γ-glutamyl from glutathione to an amino acid acceptor that may produce glutamate. In addition, ketogenic γ-glutatamylated amino acids decreased in the gut and in the blood, which supports the key anti-seizure effects of KD-associated microbiota. In the human gut, the post-KD production of KB by the host can partially drive gut microbial shifts, which reduces the number of intestinal Th17 cells. Similarly, using a murine model, Kong et al. demonstrated that an increase in Akkermansia muciniphila, Lactobacillus, and Roseburia following a KD plays a potential anti-colitis effect. The potential protective effects on intestinal barrier function may be related to the production of RORγt+CD3- group 3 innate lymphoid cells and related inflammatory cytokines (IL-17α, IL-18, IL-22, CCL-4). Another study of a 16-week KD revealed beneficial effects of the ketogenic-induced microbiota, including improved neurovascular functions in mice and reduced risk of Alzheimer’s disease. These beneficial effects may be related to changes in the gut microbiota composition, including an increase in the beneficial bacteria Akkermansia muciniphila and Lactobacillus, which produce short-chain fat.

Benefits of Ketosis

Research has shown that ketosis may have several health benefits.

Weight Loss

One of the biggest benefits of ketosis may be weight loss. The process can help you feel less hungry, which may lead to eating less food. It can help you lose belly fat (visceral fat) while maintaining a lean mass. A ketogenic diet can help you lose slightly more weight than a low fat diet. This often happens with less hunger. One review of 13 studies found that following a very low carb, ketogenic diet was slightly more effective for long-term weight loss than a low fat diet. People who followed the keto diet lost an average of 2 pounds (0.9 kg) more than the group that followed a low fat diet. Another study in 34 older adults found that those who followed a ketogenic diet for 8 weeks lost nearly five times as much total body fat as those who followed a low fat diet.

Treating and Managing Diseases

Other possible benefits of ketosis include treating and managing diseases such as:

• Epilepsy: Healthcare providers often put children with epilepsy on the keto diet to reduce or even prevent seizures by altering the “excitability” part of their brain. The ketogenic diet, described initially as a successful treatment for epilepsy, has regained attention through numerous studies showcasing its effectiveness in patients with drug-resistant epilepsy and certain pediatric epilepsy syndromes.
• Other neurologic conditions: Research has shown the keto diet may help improve neurological conditions such as Alzheimer’s disease, autism and brain cancers such as glioblastoma. A ketogenic diet regulates brain metabolism, mitochondrial homeostasis, and inflammation in Alzheimer disease by increasing mitochondrial function and reducing oxidative stress.
• Type 2 diabetes: The keto diet can help people with Type 2 diabetes lose weight and manage their blood sugar levels. The ketogenic diet can boost insulin sensitivity and cause fat loss, leading to significant health benefits for people with type 2 diabetes or prediabetes. One older study found that the ketogenic diet improved insulin sensitivity by a whopping 75%. A small study in women with type 2 diabetes also found that following a ketogenic diet for 90 days significantly reduced levels of hemoglobin A1C, which is a measure of long-term blood sugar management.
• Heart disease: The keto diet may lower your risk of developing cardiovascular disease by lowering your blood pressure, improving your HDL (“good”) cholesterol levels and lowering your triglycerides. The ketogenic diet can help improve risk factors like body fat, HDL (good) cholesterol levels, blood pressure, and blood sugar.
• Metabolic syndrome: The keto diet may reduce your risk of developing metabolic syndrome, which is associated with your risk of heart disease.
• Polycystic ovarian syndrome (PCOS): The ketogenic diet can help reduce insulin levels, which may play a key role in polycystic ovary syndrome. A crossover study compared the effects of a standard diet and a low-carbohydrate diet on PCOS and showed that the low-carbohydrate diet decreased glycemia, fasting serum insulin, and testosterone and increased insulin sensitivity.
• Parkinson disease: A pilot RCT compared the effect of a low-fat diet versus the ketogenic diet in Parkinson's disease. The study had 47 patients, and both groups showed a decrease in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS). However, the group on the ketogenic diet showed a more significant reduction than the low-fat diet group. Also, the ketogenic group showed more significant improvements in nonmotor symptoms.
• Cancer: The therapeutic impact of the ketogenic diet on tumors, such as neuroblastoma, acute myeloid leukemia, and glioblastoma, is attributed to its ability to downregulate GPR109A expression, activate mTORC1, and reduce glucose uptake at the tumor site. This results in suppressed tumor growth, improved survival rates, and enhanced efficacy of chemotherapy.

Ketosis has also been shown to increase your focus and energy. The keto diet delivers your body’s energy needs in a way that reduces inflammation. Research suggests your brain works more efficiently on ketones than on glucose.

Foods to Eat and Avoid on a Ketogenic Diet

Adhering to a ketogenic diet requires careful selection of foods to ensure that carbohydrate intake remains low while fat intake is high.

Foods to Avoid

Here’s a list of foods that need to be reduced or eliminated on a ketogenic diet:

• Sugary foods: soda, fruit juice, smoothies, cake, ice cream, candy, etc.
• Grains or starches: wheat-based products, rice, pasta, cereal, etc.
• Fruit: all fruit, except small portions of berries or strawberries
• Beans or legumes: peas, kidney beans, lentils, chickpeas, etc.
• Root vegetables and tubers: potatoes, sweet potatoes, carrots, parsnips, etc.
• Low fat or diet products: low fat mayonnaise, salad dressings, and condiments
• Some condiments or sauces: barbecue sauce, honey mustard, teriyaki sauce, ketchup, etc.
• Unhealthy fats: processed vegetable oils, mayonnaise, etc.
• Alcohol: beer, wine, liquor, mixed drinks
• Sugar-free diet foods: sugar-free candies, syrups, puddings, sweeteners, desserts, etc.

Avoid carb-based foods like grains, sugars, legumes, rice, potatoes, candy, juice, and even most fruits.

Foods to Eat

You should base the majority of your meals around these foods:

• Meat: red meat, steak, ham, sausage, bacon, chicken, and turkey
• Fatty fish: salmon, trout, tuna, and mackerel
• Eggs: pastured or omega-3 whole eggs
• Butter and cream: grass-fed butter and heavy cream
• Cheese: unprocessed cheeses like cheddar, goat, cream, blue, or mozzarella
• Nuts and seeds: almonds, walnuts, flaxseeds, pumpkin seeds, chia seeds, etc.
• Healthy oils: extra virgin olive oil, and avocado oil
• Avocados: whole avocados or freshly made guacamole
• Low carb veggies: green veggies, tomatoes, onions, peppers, etc.
• Condiments: salt, pepper, herbs, and spices

It’s best to base your diet mostly on whole, single-ingredient foods. Base the majority of your diet on foods such as meat, fish, eggs, butter, nuts, healthy oils, avocados, and plenty of low carb veggies.

Potential Side Effects of Ketosis

The keto diet has many benefits, but it may come with some side effects. One of the signs of ketosis may include “keto flu,” which includes symptoms such as upset stomach, headache and fatigue. Though it may seem newer to your newsfeed, the ketogenic diet has been around since the 1920s.

The "Keto Flu"

Although the ketogenic diet is usually safe for most healthy people, there may be some initial side effects while your body adapts. There’s some anecdotal evidence of these effects often referred to as the keto flu. Based on reports from some on the eating plan, it’s usually over within a few days. Reported keto flu symptoms include diarrhea, constipation, and vomiting. Other less common symptoms include:

• Poor energy and mental function
• Increased hunger
• Sleep issues
• Nausea
• Digestive discomfort
• Decreased exercise performance

To minimize this, you can try a regular low carb diet for the first few weeks. This may teach your body to burn more fat before you completely eliminate carbs. A ketogenic diet can also change the water and mineral balance of your body, so adding extra salt to your meals or taking mineral supplements may help. Talk to your doctor about your nutritional needs. At least in the beginning, it’s important to eat until you’re full and avoid restricting calories too much. Usually, a ketogenic diet causes weight loss without intentional calorie restriction.

Long-Term Risks

While the keto diet has its benefits, staying on it in the long term may have some negative effects, including risks of the following:

• Low protein in the blood
• Extra fat in the liver
• Kidney stones
• Micronutrient deficiencies

A type of medication called sodium-glucose cotransporter 2 (SGLT2) inhibitors for type 2 diabetes can increase the risk for diabetic ketoacidosis, a dangerous condition that increases blood acidity. Anyone taking this medication should avoid the keto diet. More research is being done to determine the safety of the keto diet in the long term. Keep your doctor informed of your eating plan to guide your choices.

Supplements for a Ketogenic Diet

Although no supplements are required, some can be useful.

• MCT oil: Added to drinks or yogurt, MCT oil provides energy and helps increase ketone levels.
• Minerals: Added salt and other minerals can be important when starting out due to shifts in water and mineral balance.
• Caffeine: Caffeine can have benefits for energy, fat loss, and performance.
• Exogenous ketones: This supplement may help raise the body’s ketone levels.
• Creatine: Creatine provides numerous benefits for health and performance. This can help if you are combining a ketogenic diet with exercise.
• Whey: Use half a scoop of whey protein in shakes or yogurt to increase your daily protein intake.

Certain supplements can be beneficial on a ketogenic diet. These include exogenous ketones, MCT oil, and minerals.

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