The ketogenic diet (or keto diet) has been touted for its many health benefits such as weight loss, cognitive function, 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 derives its benefits
- Genetic factors that may affect the safety and effectiveness of ketosis
- 17 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 .
The first ketogenic diets in the medical literature are noted in publications in the 1920s, although wider popularity and increased research was not seen in medical literature until the 1960s .
Variations of the diets have remained popular for the past 20-30 years, with proponents claiming that the diets boost weight loss and energy while offering protection from certain metabolic diseases .
The Physiology of Ketosis
How to Get Into Ketosis
In non-diabetics, ketosis can be achieved in 3 ways, i.e.
- Fasting or severe caloric restriction 
- Prolonged physical exercise in a fasted state, depending on intensity and duration [5, 6]
- Nutritional ketosis, i.e. by consuming a very low carbohydrate diet
- Supplementation, such as by supplementing with medium chain triglycerides, or exogenous ketones (ketone esters or ketone ester salts) 
There are 3 different types of ketone bodies, including :
- 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, 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; the concentration of acetoacetate 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 is highest in starved rats .
The concentration of beta-hydroxybutyrate in the blood and brain was 5-10 times greater than that of acetoacetate .
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 in the gut and absorbed in the gut, then either enter circulation or undergo first-pass metabolism in the liver .
Keto-adaptation refers to the process where cells transition from relying on glucose to relying on fat for fuel.
During this time, the cells shift from burning glucose to burning free fatty acids in the blood .
After prolonged fasting (over 2 weeks) or diet-induced ketosis, cells adapt to use fatty acids and ketone bodies (keto-adaptation), resulting in a significant reduction in glucose requirement .
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 .
Keto-adaptation is complete when after weeks of carbohydrate depletion, cells in the body cut down their uptake of ketone bodies, resulting in an increase of ketone body concentration in the blood to ~8 mM .
Keto-adaptation allows the brain to effectively uptake and use the ketone bodies because the protein that transports ketone bodies through the blood-brain barrier is more effective at higher concentrations (Km = 7 mM) .
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, so blood glucose levels remain stable at a normal level .
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 .
Ketone bodies can inhibit their own production , so ketone bodies in the blood typically do not reach ketoacidosis level in healthy people.
Type 1 diabetics have very high blood sugar and blood ketone levels can increase to over 20 mmol/L, which can lead to death because it can acidify the blood .
Genetic Factors that Determine Whether You Should Adopt a Ketogenic Diet
People with ApoE3 (CT for RS429358) and ApoE4 genotypes (CC for rs4712) may have very high cholesterol when they consume a high saturated fat diet . Therefore, the keto diet may be contraindicated for these people, especially for managing cardiovascular disease risks.
The Good: Health Benefits of the Ketogenic Diet
How the Ketogenic Diet Derives Its Health Benefits
At the cellular level, the ketogenic diet derives its health benefits by
- Increasing uncoupling protein, which reduces the number of oxidative species that are produced in the mitochondria .
- Increasing the mitochondria number (mitochondria biogenesis) and normalize ATP levels in active tissues such as the brain, heart, and muscles [21, 22].
- By stabilizing blood sugar and reducing cellular dependency on glucose, thus preventing problems that may arise from too high or too low blood sugar [23, 24].
- Decreasing reactive oxygen species upon exposure to stress, such as glutamate exposure in neuronal cells 
- Increasing mitochondrial glutathione levels by activating the Nrf2 pathway, thus reducing oxidative stress [26, 27].
- Stimulating autophagy (cellular cleanup) .
- By being a fuel source that is more efficient to burn into energy: ketone bodies requires only one molecule of NAD+ per molecule of CoA, whereas glucose needs 4 molecules of NAD+ 
- Anti-inflammatory effects, by activating PPAR-gamma, while inhibiting NF-kB, TNF-alpha, and COX-2 [30, 31, 32, 30].
Cognitive Function and Brain Health
1) Ketogenic Diets are an Effective Treatment for Epilepsy
A gradual initiation of the ketogenic diet is safer and better tolerated than fasting .
The ketogenic diet may be able to reduce epileptic seizures by :
- Increasing mitochondrial biogenesis
- Increasing mitochondrial glutathione
- Reducing oxidative stress
- Decreasing IGF-1, mTOR, Sirtuins, and AMPK
- Reducing glucose consumption in the brain by increasing levels of GABA, which can help reduce seizures .
- Increasing adenosine levels, although this effect is dependent on the production of the adenosine receptor called A1 receptor .
2) Ketogenic Diets Help with Alzheimer’s Disease
Consumption of medium chain triglycerides improved cognitive function in Alzheimer’s patients .
In a mouse model of Alzheimer’s, the ketogenic diet reduced the amount of amyloid beta in the brain, although cognitive performance did not improve .
Brain glucose uptake is impaired in Alzheimer disease. A ketogenic diet or supplementation with medium chain triglycerides can, therefore, provide another source of energy for the brain, which reduces symptoms in mild to moderate cases .
3) Ketogenic Diets Help with Parkinson’s Disease
In a small study of Parkinson’s patients, the severity of the disease as assessed by the Unified Parkinson’s Disease Rating Scale improved by 43% after 1 month on the ketogenic diet .
In a mouse model of Parkinson’s, beta-hydroxybutyrate can protect against dopaminergic neuron degeneration and mitochondrial damage .
4) Ketogenic Diets Help with Amyotrophic Lateral Sclerosis ALS
In inherited ALS cases, a genetic mutation in the gene superoxide dismutase 1 (SOD1) may cause ALS by reducing mitochondrial activity . In addition, ALS patients generally have decreased mitochondrial activity , which could be restored by ketone bodies .
In a mouse model of amyotrophic lateral sclerosis, the ketogenic diet slows the progression of movement symptoms and loss of neurons that control the movement in the spinal cord .
5) Ketogenic Diets Reduce Brain Damage from Traumatic Brain Injury and Stroke
Ketone bodies limit neuron dysfunction that is a result of traumatic brain injuries and strokes .
The ketogenic diet can help with traumatic brain juries by:
- Helping with impaired glucose metabolism that is present in traumatic brain injury 
- Reducing oxidative stress 
- Reducing inflammation 
- Increasing omega-3 fatty acid intake 
- Increasing BDNF 
6) Ketogenic Diets May Help with Autism Symptoms
In a study of thirty children, the sixty percent that could tolerate the ketogenic diet had improved autistic behavior. Therefore, the ketogenic diet may be used as an additional or alternative therapy to help autistic children .
7) Ketogenic Diets Help with Rett Syndrome Symptoms
Rett syndrome is a rare X-linked autistic-spectrum disorder that occurs primarily in young girls. The mutation found in Rett syndrome impairs energy metabolism and motor movement as well as increases seizure susceptibility and regresses social behavior. In a mice model of Rett syndrome, the ketogenic diet improves motor movements and reduced anxiety .
8) Ketogenic Diets May Help with Bipolar and Schizophrenia
The ketogenic diet may be an option to help stabilize the mental health of people suffering from psychiatric disorders. The diet helped stabilize the mood of two women with type II bipolar disorder and reduced the symptoms of a schizophrenic patient. However, more studies need to be done before any conclusive results are reached [54, 55].
9) Reduces Heart Disease Risk
A long-term ketogenic diet can help lower cholesterol and triglycerides in obese patients. By reducing these risk factors, the diet can protect against heart disease risk .
Ketosis increases the size and volume of the low-density lipoprotein molecules, such as triglycerides and LDL (“bad”) cholesterol .
This decreases the risk of heart disease, possibly by decreasing the amount of thickness of arterial plaque caused by lipoprotein accumulation .
In animal studies, a ketogenic diet was also able to protect the heart and increase recovery after a heart attack .
10) Help with Diabetes
A ketogenic diet can help lower blood sugar and improves glycemic control in type 2 diabetic patients .
The low carbohydrate diet has a more favorable outcome on metabolic syndrome than a low-fat diet .
However, since a ketogenic diet can significantly lower blood glucose levels, diabetic patients should be especially careful in monitoring their blood sugar levels .
11) Help with Weight loss
A 24-week ketogenic diet significantly decreased the weight and body mass of obese patients in one study .
A non-ketosis, low-calorie ketogenic diet, was also able to reduce weight in studies, but with a greater loss of both muscle and fat mass .
Compared to other low-calorie diets, participants who underwent the ketogenic diet also reported better mood , which might make long-term weight management easier.
In the long term, a rebound weight gain, or “yo-yo” dieting, did not occur in the maintenance period after a short-term ketogenic diet . Staying on a ketogenic diet will keep ghrelin (the hunger hormone) and appetite levels low if the subjects stay ketotic .
This shows promise for the use of ketogenic diets to promote successful long-term weight loss .
12) Can Help Manage Polycystic Ovary Syndrome
A ketogenic diet may help manage PCOS by reducing weight and improving insulin sensitivity, but more studies are necessary before any conclusions are reached .
Ketogenic Diet as a Cancer Treatment
The Warburg effect is a phenomenon where most cancer cells rely on glucose to generate the energy needed for cellular processes .
Tumor cells cannot use fatty acids or ketone bodies as an energy resource and can even be harmed by them. A ketogenic diet can decrease glucose while increasing ketones to supply energy. In a cell study, ketosis reduces tumor growth [68, 69].
Patients adhering to a ketogenic diet can support fatty acid metabolism and inhibit glucose metabolism. So while the body can still get energy from ketone bodies, the tumors do not have a viable energy source .
There are several animal studies demonstrating that the ketogenic diet may help with brain, colon, stomach, and prostate cancers .
In humans, the ketogenic diet may be more effective as an adjunctive treatment to medication and chemotherapy, and additional clinical studies are necessary to confirm their effectiveness .
13) Brain Cancers
Astrocytoma, a type of brain cancer, may be treated by a ketogenic diet. In mice, ketone bodies, in combination with drugs that inhibit glycolysis, provides neuroprotective effects and reduces tumor growth .
Glioblastoma multiforme (GBM) is a highly aggressive tumor of the central nervous system. There has been little progress in treating this disorder.
However, a ketogenic diet can help reduce the viability of glioblastoma multiforme tumors. The diet can be used as an additional therapy for patients with GBM because it has little side effects and it effectively reduces glucose and glutamate levels .
14) Stomach Cancer
In animal studies of gastric cancer cells, a ketogenic diet can help delay the growth of tumors .
15) Lung Cancer
In combination with radiation therapy, a ketogenic diet resulted in slower tumor growth in mice with lung cancer compared to radiation alone. It also increased oxidative stress in the tumors .
16) Prostate Cancer
In comparison to a Western diet, a ketogenic diet prolonged survival and reduced tumor growth in mice with prostate cancer. However, that does not mean that the diet can be used to treat prostate cancer as an alternative to medicine or chemotherapy .
The ketogenic diet may help slow the growth of prostate cancer by lowering serum insulin and IGF-1 levels, as well as decreasing caloric intakes .
17) Breast Cancer
A ketogenic diet does not slow or prevent tumor growth in breast cancer patients, but it can improve some aspects of the quality of life by reducing insomnia and lowering BMI .
The Bad: Risks and Side Effects of the Ketogenic Diet
Side effects normally include nausea, vomiting, and lethargy due to reduced energy. The diet also impairs energy homeostasis and impairs the ability to perform high-intensity exercise .
The keto diet can significantly lower blood glucose levels, so diabetic patients should be carefully monitored in case their blood sugar levels become too low .
Children participating in a study of ketogenic weight-loss diets were susceptible to hypoglycemia (low blood glucose) and nausea due to low glucose intake .
The high-fat content of the diet can also cause stomach and gut problems. After one year of the diet, there is a progressive increase in cholesterol levels .
Ketosis can also cause disturbances in the gut microbiota .
Some animal studies show evidence of kidney failure .
This is thought to be related to the increased load on the kidneys to clear ketone bodies from the blood, but more research is needed to determine the severity and significance of this risk .
Patients are susceptible to deficiencies in minerals like selenium, copper, and zinc in the diet, possibly due to restricting carbohydrate-rich foods which would otherwise provide these nutrients .
Researchers have suggested that mineral supplementation should be included in the ketogenic diet to reduce this risk .
Who Should Not Follow the Ketogenic Diet
In mice, a ketogenic diet negatively altered embryonic organ growth and caused organ dysfunction, suggesting that the diet is likely not suitable during pregnancy or gestational diabetes .
How to Mitigate Potential Negative Effects of the Ketogenic Diet
Eating resistant starches while starting a ketogenic diet can help reduce some of the stomach problems that the diet can cause .
Carbohydrate cycling, or alternating between a low carbohydrate diet and high carbohydrate diet, can help lower negative effects of a pure ketogenic diet. This may help a dieter maintain the energy and ability to perform the high-intensity exercise, which can otherwise suffer when sufficient glucose is not available .
Taking Ketone Supplements
There are a variety of supplements that contain ketones that you can ingest, which will have many of the benefits discussed here.
Beta-hydroxybutyrate is a signaling molecule that can activate HDACs and thereby increase or decrease important genes during ketosis .
|Biochemical Pathway, Hormones, or Benefits||Ketogenic Diet||Calorie Restriction or Fasting||References|
|Nrf2||⬆||⬆||[26, 27, 89]|
|NF-kB||⬇||⬇||[32, 91, 30]|
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