Obesity remains a significant global health challenge, contributing to millions of deaths annually. It is closely associated with chronic diseases such as diabetes, hypertension, and heart disease, often stemming from unhealthy lifestyles and poor dietary habits. Implementing tailored dietary regimens for weight reduction can help mitigate the obesity epidemic. One such regimen is the very low-carbohydrate, high-fat ketogenic diet.
Introduction to the Ketogenic Diet
The ketogenic, or keto, diet is a dietary approach characterized by high fat and low carbohydrate intake, aiming to facilitate weight loss, enhance mental clarity, and boost energy levels. By significantly reducing carbohydrate consumption and increasing fat and protein intake, this diet induces a metabolic state called ketosis, where the body utilizes fat as its primary fuel source instead of carbohydrates. The primary goal of the ketogenic diet is to decrease overall body fat and improve metabolic health. Recent research indicates potential benefits in reducing the risk of certain diseases, including type 2 diabetes, hyperlipidemia, heart disease, and cancer.
Function and Mechanisms of the Ketogenic Diet
A ketogenic diet primarily consists of high fat intake, moderate protein consumption, and low carbohydrate intake. The macronutrient distribution typically ranges from approximately 55% to 60% fat, 30% to 35% protein, and 5% to 10% carbohydrates. Carbohydrates typically serve as the main source of energy production in the body's tissues. However, when carbohydrate intake is restricted to less than 50 grams daily, insulin secretion decreases significantly, leading the body into a catabolic state. As a result, glycogen stores are depleted, triggering a series of metabolic changes. Two prominent metabolic processes come into play when carbohydrates are limited in body tissues: gluconeogenesis and ketogenesis.
Gluconeogenesis
Gluconeogenesis is the process by which the body produces glucose internally, primarily in the liver, using substrates such as pyruvate, lactic acid, glycerol, and specific amino acids classified as glucogenic. When glucose availability drops, the endogenous breakdown of glucose cannot provide sufficient energy, ie, adenosine triphosphate (ATP). The metabolic pathway switches to ketogenesis to provide an alternate energy source in the form of ketone bodies. Ketone bodies replace glucose as a primary source of energy.
Ketogenesis
During ketogenesis, insulin secretion is low due to feedback from blood glucose levels, leading to a decrease in the stimulation of fat and glucose storage. Other hormonal changes may contribute to the increased fat breakdown resulting in fatty acids. Fatty acids are metabolized to acetoacetate, later converted to beta-hydroxybutyrate and acetone. These primary ketone bodies (ie, acetoacetate, beta-hydroxybutyrate, and acetone) accumulate in the body as the ketogenic diet is sustained and serve as an alternative energy source for the body. This metabolic state is referred to as "nutritional ketosis." As long as the body is deprived of carbohydrates, the metabolism remains ketotic. Nutritional ketosis is generally considered safe since it involves the production of ketone bodies in moderate concentrations without significantly impacting blood pH. Nutritional ketosis differs from ketoacidosis, a severe and life-threatening condition characterized by excessively high levels of ketone bodies, leading to acidosis in the blood.
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Ketone bodies synthesized within the body can be effectively utilized as an energy source by vital organs such as the heart, muscle tissue, and kidneys. Ketone bodies can also cross the blood-brain barrier to provide an alternative energy source for the brain. RBCs and the liver do not utilize ketones due to a lack of mitochondria and enzyme diaphorase.
Ketone body production depends on several factors, such as resting basal metabolic rate (BMR), body mass index (BMI), and body fat percentage. Ketone bodies, often referred to as a "super fuel," produce a greater amount of ATP than glucose. When comparing energy production, 100 grams of acetoacetate generates 9,400 grams of ATP, 100 grams of beta-hydroxybutyrate yields 10,500 grams of ATP, while 100 grams of glucose produces only 8,700 grams of ATP. Ketone bodies enable the body to maintain efficient fuel production even when experiencing a caloric deficit.
Types of Ketogenic Diets
Four types of ketogenic diets are categorized based on the percentage of macronutrients they contain, allowing for increased compliance with the regimens. The ketogenic diet's short-term effects (up to 2 years) are well-reported and established. However, the long-term health implications are unknown due to limited literature. 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. 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.
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. The medium-chain triglyceride diet (MCTD) guarantees faster absorption of triglycerides into the bloodstream, which results in the formation of more ketone bodies per kilocalorie. Higher efficiency of this process allows for using less fat in the diet and thus allows for more carbohydrate and protein to be consumed, which facilitates long-term maintenance of the diet. In addition, this type of diet improves mitochondrial function.
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Modified Atkins Diet (MAD)
The MAD is based on the Atkins diet, which was popularly used in. The MAD is based on a high content of fats relative to other macronutrients, but the ratio of fats varies within much wider boundaries. The ratios of these compounds are not strictly maintained and can range from 1:1 to 4:1. In the MAD, it is assumed that the ratio of fats to carbohydrates and protein combined is 1:1 or 2:1. During the first month of the diet, carbohydrate intake is limited to 10-15 g/day and then increased to 20 g/day.
Low Glycemic Index Treatment
Interest in this type of diet has been growing intensely for many years. Moreover, trends of creating new forms of the KD can be observed, and there have been reports about the ketogenic Mediterranean diet. The Mediterranean ketogenic diet (MMKD) is based on the Mediterranean diet, which emphasizes healthy fats such as olive oil, lean protein sources like fish and lean meat, and limited consumption of fruits and vegetables
Potential Benefits of the Ketogenic Diet
Weight Loss
A ketogenic diet may help you lose more weight in the first 3 to 6 months than some other diets. This may be because it takes more calories to change fat into energy than it does to change carbs into energy. It’s also possible that a high-fat, high-protein diet satisfies you more, so you eat less, but that hasn’t been proved yet. Over the past century, the prevalence of obesity has increased, leading to the emergence of various diet programs. Among them, the ketogenic diet has shown significant benefits compared to other diets. A meta-analysis of 11 studies found that the low-carbohydrate diet group experienced considerable weight reductions compared to the low-fat diet group. Individuals assigned to a very low-carbohydrate ketogenic diet (VLCKD) experienced decreases in body weight, triglycerides, and diastolic blood pressure, as well as increases in HDL-C and LDL-C. Moreover, the VLCKD resulted in more significant long-term weight loss compared to a low-fat diet, suggesting it is a potential alternative option for obesity management. Similarly, a meta-analysis of randomized controlled trials (RCTs) revealed that the ketogenic diet is particularly effective in improving metabolic parameters related to glycemic control, weight management, and lipid control in obese individuals, particularly those with preexisting diabetes. Compared to low-fat diets, the ketogenic diet demonstrated superior outcomes in terms of glycemic control, weight loss, and lipid markers. The ketogenic diet also showed positive effects on insulin resistance and lipid markers, suggesting it can improve metabolic markers independent of weight loss.
Diabetes Management
Low-carb diets seem to help keep your blood sugar lower and more predictable than other diets. A recently published randomized crossover trial comparing the effects of ketogenic and Mediterranean diets revealed that patients who adhered to a well-formulated ketogenic diet experienced improved glucose control and reduced body weight. Although the blood sugar levels were reduced, the decrease in HbA1c levels was modest, with a reduction of less than 20%. Additionally, study participants had difficulty adhering to the strict dietary regimen. These findings have led to debates, as some argue that any restriction on carbohydrate intake would inevitably lead to a reduction in blood sugar and HbA1c levels. Minimizing the intake of carbohydrates results in the reduced absorption of simple sugars, thereby decreasing blood glucose levels and fluctuations of glycaemia in diabetes.
Heart Disease Risk Reduction
Research suggests that a ketogenic diet can reduce the risk of heart disease. A systematic review published in the American Journal of Clinical Nutrition in 2019 found that a ketogenic diet can lower markers of inflammation, which is associated with a decreased risk of heart disease. Furthermore, a study published in Circulation in 2020 demonstrated that a low-carbohydrate, high-fat ketogenic diet could reduce low-density lipoprotein (LDL) cholesterol levels, a significant risk factor for heart disease. These findings indicate that a ketogenic diet may effectively reduce the risk of heart disease. It seems strange that a diet that calls for more fat can raise “good” cholesterol and lower “bad” cholesterol, but ketogenic diets are linked to just that. It may be because the lower levels of insulin that result from these diets can stop your body from making more cholesterol. That means you’re less likely to have high blood pressure, hardened arteries, heart failure, and other heart conditions. It's unclear, however; how long these effects last.
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Management of Neurological Disorders
Every therapeutic action taken in diseases of the nervous system is aimed at slowing down or completely stopping the process that leads to the degeneration and death of neurons (neuroprotective actions). The beneficial effects of the ketogenic dietary therapy on neurological diseases result, inter alia, from the reconstruction of neuronal myelin sheaths, in the reduction of neuron inflammation, reduction of reactive oxygen species (ROS) production, promotion of dopamine production, repair of damaged mitochondria (which affect the disturbed neuronal metabolism in the course of numerous neurological diseases) and formation of new ones. Additionally, the ketogenic dietary therapies provides neurons with an alternative energy source in the form of ketone bodies, which is extremely important because glucose absorption, transport and metabolism are most often impaired in neurological diseases.
Epilepsy
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. Ketogenic diets have helped control seizures caused by this condition since the 1920s. But again, it’s important to work with your doctor to figure out what’s right for you or your child. The KD has been used as a treatment option for drug-resistant epilepsy in children ever since.
Alzheimer's Disease
A ketogenic diet regulates brain metabolism, mitochondrial homeostasis, and inflammation in Alzheimer disease by increasing mitochondrial function and reducing oxidative stress. These affect your brain and spine, as well as the nerves that link them together. Scientists aren’t sure why, but it may be that the ketones your body makes when it breaks down fat for energy help protect your brain cells from damage. It has been demonstrated that the KD can have a beneficial effect on AD, affecting many bodily processes. Consumption of high-glycaemic-index foods promotes the accumulation of β-amyloid in the brain; hence, the KD may have a neuroprotective effect in AD.
Parkinson's 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.
Other Potential Benefits
Nonalcoholic Fatty Liver Disease (NAFLD): The ketogenic diet induces a shift in the gut microbiome, resulting in increased folate production and reduced inflammation and oxidative stress. Furthermore, the ketogenic diet promotes a sense of satiety and induces epigenetic modifications that play a role in the pathogenesis of NAFLD and allows the expression of antiinflammatory markers at the genetic level.
Polycystic Ovarian Syndrome (PCOS): 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. PCOS is related to increased insulin resistance, hyperinsulinemia, T2DM, dyslipidemia, and hyperandrogenism. The mechanism by which a ketogenic diet helps PCOS is unclear. However, many theories postulate lowering insulin resistance helps with improving androgen levels. High levels of insulin can cause it. Ketogenic diets, which lower both the amount of insulin you make and the amount you need, may help treat it, along with other lifestyle changes, like exercise and weight loss.
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. Insulin is a hormone that lets your body use or store sugar as fuel. Ketogenic diets make you burn through this fuel quickly, so you don’t need to store it. This means your body needs -- and makes -- less insulin. Those lower levels may help protect you against some kinds of cancer or even slow the growth of cancer cells.
Acne: Carbohydrates have been linked to this skin condition, so cutting down on them may help. And the drop in insulin that a ketogenic diet can trigger may also help stop acne breakouts. (Insulin can cause your body to make other hormones that bring on outbreaks.)
Exercise: A ketogenic diet may help endurance athletes -- runners and cyclists, for example -- when they train. Over time, it helps your muscle-to-fat ratio and raises the amount of oxygen your body is able to use when it’s working hard. But while it might help in training, it may not work as well as other diets for peak performance.
Potential Risks and Side Effects
The ketogenic diet may present some common and generally mild short-term adverse effects, known as the "keto flu." These symptoms can include nausea, vomiting, headache, fatigue, dizziness, insomnia, reduced exercise tolerance, and constipation. These symptoms resolve in a few days to weeks. Ensuring adequate fluid and electrolyte intake can help counter some of these symptoms. Patients with diabetes taking insulin or oral hypoglycemic agents may experience severe hypoglycemia if their medications are not appropriately adjusted before initiating a ketogenic diet.
More common side effects aren’t usually serious: You might have constipation, mild low blood sugar, or indigestion. Much less often, low-carb diets can lead to kidney stones or high levels of acid in your body (acidosis). Other side effects can include the "keto flu," which may include headache, weakness, and irritability; bad breath; and fatigue.
The ketogenic diet is contraindicated in individuals with pancreatitis, liver failure, disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase deficiency, porphyrias, or pyruvate kinase deficiency. Additionally, individuals following a ketogenic diet may rarely experience a false positive breath alcohol test due to the conversion of acetone to isopropanol by hepatic alcohol dehydrogenase, resulting in an inaccurate reading.
Following a very high-fat diet may be challenging to maintain. Some negative side effects of a long-term ketogenic diet have been suggested, including increased risk of kidney stones and osteoporosis, and increased blood levels of uric acid (a risk factor for gout). Possible nutrient deficiencies may arise if a variety of recommended foods on the ketogenic diet are not included. It is important to not solely focus on eating high-fat foods, but to include a daily variety of the allowed meats, fish, vegetables, fruits, nuts, and seeds to ensure adequate intakes of fiber, B vitamins, and minerals (iron, magnesium, zinc)-nutrients typically found in foods like whole grains that are restricted from the diet. Do the diet’s health benefits extend to higher risk individuals with multiple health conditions and the elderly? As fat is the primary energy source, is there a long-term impact on health from consuming different types of fats (saturated vs.
When your body burns its stores of fat, it can be hard on your kidneys. And starting a ketogenic diet -- or going back to a normal diet afterward -- can be tricky if you’re obese because of other health issues you’re likely to have, like diabetes, a heart condition, or high blood pressure.
Clinical Significance and Considerations
Recent epidemiological studies have challenged the popular belief that high-fat diets directly cause obesity and diseases like coronary heart disease, diabetes, and cancer. These studies have not observed a conclusive causal relationship between dietary fat intake and these conditions. Additionally, research on animals fed high-fat diets has not demonstrated a direct link to obesity. Regarding overall caloric intake, carbohydrates comprise around 55% of the typical American diet, ranging from 200 to 350 grams daily. Until recently, the significant potential of refined carbohydrates to cause detrimental effects was largely overlooked. However, emerging research has highlighted the negative impact of consuming excessive amounts of sugar-laden foods. Studies have shown that a higher intake of sugar-laden foods is associated with a 44% increased prevalence of metabolic syndrome and obesity and a 26% higher risk of developing diabetes.
A comprehensive study conducted in 2012 examining cardiometabolic deaths in the United States revealed that approximately 45.4% of these deaths, including those attributed to heart disease, stroke, and type 2 diabetes, were associated with suboptimal intakes of 10 specific dietary factors. Among the nutritional factors examined, the study found that the highest estimated mortality was associated with high sodium intake, accounting for 9.5% of cardiometabolic deaths. This was followed by nuts and seeds (8.5%), high intake of processed meats (8.2%), low intake of omega-3 fats (7.8%), low intake of vegetables 7.6%), low intake of fruits (7.5%), and high intake of artificially sweetened beverages (7.4%). The lowest estimated mortality was associated with consuming low polyunsaturated fats (2.3%) and unprocessed red meats (0.4%). In addition to the direct harm caused by excessive consumption of low-quality carbohydrates, another concern is that such consumption can crowd out healthier food options from the diet. When individuals consume an excess of low-quality carbohydrates, there may be limited space in their diet for more nutritious foods like nuts, unprocessed grains, fruits, and vegetables.
Available research on the ketogenic diet for weight loss is still limited. Most of the studies so far have had a small number of participants, were short-term (12 weeks or less), and did not include control groups. A ketogenic diet has been shown to provide short-term benefits in some people including weight loss and improvements in total cholesterol, blood sugar, and blood pressure. However, these effects after one year when compared with the effects of conventional weight loss diets are not significantly different. Eliminating several food groups and the potential for unpleasant symptoms may make compliance difficult. An emphasis on foods high in saturated fat also counters recommendations from the Dietary Guidelines for Americans and the American Heart Association and may have adverse effects on blood LDL cholesterol.
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