Introduction
The idiom "Diseases enter by the mouth," highlights the profound association between dietary factors and various diseases. Dietary planning has gained popularity as a crucial intervention for maintaining health and as a non-pharmaceutical option for disease management. Among the numerous diets available, the ketogenic diet (KD) has garnered significant interest due to its potential therapeutic effects on a wide range of diseases.
What is a Ketogenic Diet?
The ketogenic diet (KD) is a high-fat, very low-carbohydrate diet with adequate protein. It 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 recent 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. The KD mimics the metabolic effects of fasting without significant calorie deprivation.
Types of Ketogenic Diets
Several variant KDs with similar efficacy to the original form have 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 LCT KD
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. 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. Calorie and fluid restriction is unnecessary as no beneficial effect was proved with these two factors.
MCT KD
Due to the severe carbohydrate restriction, the LCT KD is unpalatable, difficult to prepare, and, therefore, difficult to maintain. 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. 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.
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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.
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.
Impact of the Ketogenic Diet on Metabolism
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.
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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. 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.
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Potential Benefits of the Ketogenic Diet
The ketogenic diet offers a range of potential benefits, particularly for weight loss and metabolic health.
Effective Weight Loss
Research suggests that the keto diet can be highly effective for weight loss. 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.
Better Blood Sugar Control
For individuals with type 2 diabetes or insulin resistance, the keto diet may help lower blood sugar levels and improve insulin sensitivity. 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.
Neurological Benefits
The keto diet was initially developed as a treatment for epilepsy. Today, it is still used to help manage drug-resistant epilepsy, particularly in children. 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. 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.
Heart Health
While a high-fat diet may seem counterintuitive for heart health, some research suggests that the keto diet can improve cardiovascular risk factors such as HDL (good cholesterol) levels and triglycerides. 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.
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.
- 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.
- Neurodegenerative Disorders: The ketogenic diet regulates brain metabolism, mitochondrial homeostasis, and inflammation in Alzheimer disease by increasing mitochondrial function and reducing oxidative stress. In Parkinson's disease, a pilot RCT showed that the ketogenic diet led to more significant improvements in nonmotor symptoms compared to a low-fat diet.
- Cancer: The therapeutic impact of the ketogenic diet on tumors is attributed to its ability to downregulate GPR109A expression, activate mTORC1, and reduce glucose uptake at the tumor site.
Potential Risks and Considerations
While the keto diet may be beneficial for many, certain individuals should avoid it or consult a healthcare provider before starting.
Nutrient Deficiencies
Eliminating or severely restricting carbohydrate-rich foods can lead to deficiencies in essential nutrients like fiber, vitamins, and minerals. 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.
Keto Flu Symptoms
Many people experience flu-like symptoms, known as the "keto flu," when first starting the diet. 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.
Heart Disease
While some studies suggest cardiovascular benefits, others raise concerns about the long-term impact of high saturated fat intake. A meta-analysis of 13 randomized controlled trials found that participants following a very-low-carbohydrate ketogenic diet (VLCKD) had a significantly greater increase in low-density lipoprotein cholesterol (LDL-C) levels when compared to participants following a low-fat diet (95% CI: 0.04 to 0.2; p=0.002).
Other Potential Risks
- Increased risk of kidney stones and osteoporosis.
- Increased blood levels of uric acid (a risk factor for gout).
- 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.
- 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.