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A Review of the Ketogenic Diet

Scientific evidence supporting the Keto Diet

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First published: 11.Oct.2018

Backed by Science: the Keto diet works

The Ketogenic Diet is based on a very low carbohydrate, moderate protein, and high fat intake. This nutrient combination shifts the body from using glucose as its fuel to burning fats.

This creates ketones that provide the body with energy. Fat is metabolized to provide energy, and this causes weight loss. As a bonus, ketones inhibit appetite.

The diet improves Body Mass Index (BMI) and reduces total cholesterol, triglycerides, and blood sugars; it improves HDL cholesterol.

It may have neurological protective effects for conditions such as Alzheimer's, Parkinson's disease, some tumors, ALS, and even acne.

This article will review the Keto Diet based on the evidence of scientific studies.

Ketogenic diets appear to be more effective than low-fat diets for the treatment of obesity and diabetes.
... chronic ketosis might confer unique metabolic benefits of relevance to cancer, neurodegenerative conditions, and other diseases associated with insulin resistance.
Based on available evidence, a well-formulated ketogenic diet does not appear to have major safety concerns for the general public and can be considered a first-line approach for obesity and diabetes.  Ludwig, 2020, (1)

Avoid low-quality carbohydrates: sugars, starches, and flour.

Sugar, fat, and our body's energy

Glucose is the "normal" energy

The body generates the energy it needs inside its cells in a process called "Cellular Respiration." The basic fuel is a carbohydrate, glucose, a six-carbon form of sugar.

Respiration is quite a complex process that we describe in a simplified manner below.

1. Glycolysis

The name combines the Greek words "glykys" = "sweet" and "lysis" = "splitting", meaning: "sugar splitting". That is precisely what takes place inside each cell.

Sugar in the form of glucose (a six-carbon chain) is broken down into two shorter sugar molecules containing three carbon atoms each, called pyruvate or pyruvic acid.

This splitting process requires an initial energy input that is provided by a molecule known as adenosine triphosphate or ATP.

Glycolysis generates energy in the form of more ATP molecules, and the pyruvic acid it produces enters the second step of respiration.

2. Production of Acetyl CoA

Pyruvic acid enters small organelles located inside the cell, called mitochondria. They are the "cell's powerhouse" and generate its energy.

Once inside a mitochondrion, pyruvic acid is converted into a shorter 2-carbon sugar called acetyl coenzyme A (or Acetyl CoA) and one molecule of CO2 (Carbon dioxide).

3. Krebs Cycle

Acetyl CoA takes part in a process known as the citric acid cycle, TCA cycle, or Krebs cycle. It is oxidized (that is why we need to breathe: to provide oxygen for the Krebs Cycle).

This cycle produces more CO2, some ATP, and hydrogen atoms.

In the final stage of respiration, known as "Electron Transport System" the hydrogen atoms react with even more oxygen to produce water and a large amount of energy that is stored as ATP.

The overall reaction can be summarized as follows:

Glucose + 6 O2 → 6 CO2 + 6 H2O + 36 ATPs

The ATP cycle and the Keto Diet

During a ketogenic diet, the body will tap its glucose stores, and when these run dry, it resorts to its stores of glycogen.

Glycogen and weight loss

Glycogen is a variety of sugar made up of glucose residues that is stored in the muscles and the liver (10% of the liver weight is glycogen, as is 2% of skeletal muscle weight).

Glycogen is metabolized following the same route as glucose, and in the process, 1 g of glycogen produces 3 g of water, which is eliminated in the urine (MacKay, 1932)(2).

An average man weighing 200 lb, with a normal muscle mass of 35% and a 3.5 lb liver, would therefore store 4 lb of glycogen in muscle tissue and 0.35 lb in the liver. This would result in 13.05 lbs of water bound to it.

Burning these glycogen stores would provoke a weight loss of 17.4 lbs of water and burned sugars.

The use of glycogen before the onset of ketosis explains the sudden loss of weight experienced during the first stages of a keto diet.

After using up the glycogen, the body needs more fuel to keep up with the cells' energy requirements, so it turns to its fat stores. And ketosis begins.

Burning Fat during a Keto Diet

Fat molecules known as triglycerides are the fuel that the body burns during ketosis.


Their name indicates that they have three fatty acid chains linked to a glycerol molecule. These triglycerides enter the mitochondrion and are broken down to produce acetyl-CoA, which then takes part in the Krebs Cycle to generate energy.

This process is known as β-oxidation.

Disrupting the Cycle

However, during special circumstances such as fasting, starvation, keto diet, after vigorous exercise, and in cases of non-controlled type 1 diabetes, the mitochondria in the liver alter their Krebs cycle.

They do so because they lack a critical molecule known as oxaloacetate. Which is used for another purpose, the production of glucose.

Insulin and sugars during ketosis

A Ketogenic diet reduces carbohydrate intake to very low levels (between 20 and 50 g daily), and insulin secretion decreases.

This drop also dampens the signal that tells the cells to store fat and glucose. Instead of being stored, they are consumed.

But the body needs sugar, so it produces it in the liver in a process known as "Gluconeogenesis."

Glucogenic amino acids from proteins or glycerol from fat are reassembled into glucose inside the liver.

The amino acid source gradually decreases as the days go by and is replaced by triglycerides. This effect is more noticeable in obese people, who generate up to 80% of their glucose by burning fat (Bortz, 1972) (3), while lean subjects burn more "protein" than fats (only 38% of their glucose comes from fats).

The liver releases this glucose into the bloodstream.

Ketone bodies

As oxaloacetate levels drop, not enough acetyl-CoA enters the Krebs cycle. Instead, it is diverted into the formation of "ketone bodies," which aren't bodies at all; they are water-soluble molecules known as ketones.

They come in three varieties.

  1. Acetoacetate.
  2. Beta-hydroxybutyrate (β-hydroxybutyrate) or BHB.
  3. Acetone.

The liver releases these ketone bodies into the bloodstream so that they are distributed to the body's cells. Their mitochondria can convert the ketone bodies back into acetyl-CoA, and feed it into their Krebs cycle to generate energy.

Ketone bodies can also enter the cells of the central nervous system (fat cannot cross the blood-brain-barrier, but ketones can) and provide them with a source of fuel when glucose is short.


Ketones in the blood cause a condition that is known as ketosis. Vargas (2018) (4) showed that β-hydroxybutyrate, which in non-fasting or non-keto-dieting individuals is less than 3 mmol per liter, increases to around 7-8 mmol ⁄ L during a keto diet, yet this does not alter the blood pH (ketones are acidic).

Ketosis is not the same as ketoacidosis

The keto diet induces a state of physiological ketosis which is not the same as diabetic ketoacidosis. In the latter ketones in the blood can reach concentrations of 20 mmol ⁄ L and acidify the blood of diabetic subjects.

Ketoacidosis is dangerous in diabetic subjects as it can cause coma and even death.

Acetoacetate, like most ketones, has a typical characteristic sweet and fruity smell. Its odor can be detected in the urine during ketosis. Acetone generated spontaneously from acetoacetate is a toxic byproduct that evaporates easily and is eliminated during respiration, giving a fruity odor to the breath (which, by the way, is a sign that the subject is in ketosis).

About 10 or 20% of ketone bodies are lost in the urine.

Ketosis can be defined as a metabolic state characterized by increased quantities of ketone bodies in the body tissues.

What is a Ketogenic Diet?

Ketogenic Diet, a definition

Ketogenic means "generator of Ketones," and that is the basis of the diet. Its aim is to generate ketone bodies through a restriction through a lower intake of carbs and an adequate input of protein and fats.

Masood and Uppaluri (2018) (5) provided a detailed scientific review of the ketogenic diet (KD for short). They defined it as a high-fats, moderate-proteins, and very-low carbohydrates diet.

The average breakdown of calories and quantities of these macronutrients are shown below. These values are known as Macros.

  • Carbohydrates: 20 - 50 g per day (5 - 10% of daily calorie needs).
  • Fats: 55 - 60% of total daily calories.
  • Protein: 30 - 35% of the daily caloric intake.

The moderate protein intake is to prevent the body from making glucose using protein from its muscles as a raw material (the process known as gluconeogenesis which we described further up). The idea is to supply the necessary amino acids but not more than that.

Based on this, and knowing your daily energy requirements you can calculate your "macros" for a Keto Diet tailored to your body and needs:

salmon and healthy fiber filled carbs: a ketogenic dish

Keto Macros Calculator

Work out the basic macros for your Ketogenic Diet, how much carbs, protein, and fat to eat, plus your caloric deficit if your goal is to lose weight.


How do the ketogenic diet macros compare with a typical American diet?

The Typical American Diet

The average American diet is based mainly on carbohydrates (55% of the daily caloric intake): 200 to 350 g ⁄ day.

A large proportion of refined carbs (sugars and starches) promote obesity and increase the risks of diabetes and metabolic syndrome.

Low-quality carbohydrates don't leave room for healthy carb options with fiber such as nuts, unprocessed grains, vegetables, or fruits.

Origin and History of the Keto Diet

It was created by Russel Wilder in 1921, who used it to treat seizures in epileptic children in a time when antiepileptic drugs were unknown. Most studies on the long-term effects of ketosis were conducted on children.

Its use for dieting and weight loss is a relatively modern concept.

Should you eat a High-Fat diet to lose weight?

The consensus for many years has been that consuming less fat and replacing it with carbohydrates leads to weight loss.

However, the Ketogenic diet proposes the opposite: drastically cutting back on carbs and increasing consumption of fats.

Paoli (2014) (6) pointed out that the low-fat approach, which is the most commonly accepted dietary strategy, "yield only modest weight losses and suffer from low long-term compliance issues"; this is due to two factors.

  1. Obese people prefer foods that is rich in fat, that are usually restricted in conventional diets, and
  2. When they select carbohydrates, they choose highly processed foods made up of refined sugars rather than complex or raw carbs, worsening weight issues
Natural olive oil, a healthy fat.
Oregon State University

A low-carb and high-fat diet such as the ketogenic diet avoids both problems.

Bear in mind that fats do not necessarily mean unhealthy options like lard or saturated fats. Many healthy options allow you to include healthy fats into your diet, like olive oil or canola oil.

Conventional wisdom states that high-fat diets can cause heart disease, diabetes, and obesity, but this has not been observed in scientific studies. "Studies carried out in animals that were fed high-fat diets did not show a specific causal relationship between dietary fat and obesity. On the contrary, very-low-carbohydrate and high-fat diets such as the ketogenic diet have shown to beneficial to weight loss" (5).

How long should a Keto Diet Last?

Masood & Uppaluri (2018) (5) recommended following it for a period not shorter than 2 or 3 weeks and not longer than 6 to 12 months. They emphasized that kidney functions must be monitored while on a KD and that the transition out of a ketogenic diet to a normal one should be gradual and well-controlled.

Take-home point

If you have renal issues, don't follow a ketogenic diet.

In the next section, we will look into the health benefits of the Keto Diet.

The Ketogenic Diet helps to lose weight

Masood and Uppaluri (2018) (5) cited several studies that compared the long-term effects of diets (such as maintaining weight loss vs. recovering the lost fat after finishing the diet).

They found that "low-carbohydrate diets led to significantly greater weight loss compared to low-fat interventions."

They also reported that the quality of calories consumed influenced the number of calories burned. It is good for the body to maintain its Basal Metabolic Rate or BMR. That is what happens during a keto diet.

Low-fat diets, on the other hand, cause BMR to drop considerably. This makes the body burn less energy in response to its lower caloric intake, and weight loss slows down.

Learn more about Basal Metabolic Rate and how to calculate it.

Weight Loss

The initial weight loss during a ketogenic diet is up to 10 lbs in 2 weeks.

This loss is due to the diuretic effect of the diet. Water is lost due to the breakdown of glycogen to obtain glucose.

The intake of protein ensures that muscle mass is not lost.

Paoli (2014) (6) summarized the different ways that a ketogenic diet helps lose weight.

  • Less production of fats (reduced insulin causes a lower cellular uptake of fats).
  • Increased lipolysis. Breaking down ("burning") fats for use as fuel in the cells.
  • More energy is needed to generate glucose by gluconeogenesis. Making sugar from protein or fats requires around 400 to 600 Calories per day. It is an "expensive" way to obtain sugar. This additional energy requirement contributes to weight loss.

Take-home point

A ketogenic diet is effective in producing weight loss.

Another weight loss mechanism of the KD is its ability to decrease hunger.

The Keto diet suppresses hunger

A meta-analysis by Gibson et al. (2015) (7) found that individuals following a Ketogenic low-carbohydrate diet "were less hungry and had a reduced desire to eat. Although these absolute changes in appetite were small, they occurred within the context of energy restriction, which is known to increase appetite in obese people."

Take-home point

A ketogenic diet prevents an increase in appetite, making you feel slightly less hungry (or more full or satisfied).

Paoli (2014) (6) added that lesd appetite may be due to the effect of proteins that provoke a greater feeling of satiety or its effect on the hormones that control hunger (such as ghrelin).

Masood and Uppaluri (2018) (5) confirmed that ketosis diminishes hunger pangs.

The Keto Diet is better than a "low-fat" diet

Brehm (2003) (8) conducted a trial with 53 healthy obese women that followed a low-calorie diet for six months. Half of them went on a very-low-carbohydrate diet, and the other half followed a low-fat diet.

The very-low-carb group lost more weight than the low-fat group (18.7 lb. vs. 8.6 lb.), and more body fat (10.6 lb. vs. 4.4 lb.)

The authors concluded that "a very low carbohydrate diet is more effective than a low fat diet for short-term weight loss and, over 6 months, is not associated with deleterious effects on important cardiovascular risk factors in healthy women."

The effects of Ketogenic Diets

Negative effects

We have separately reviewed the negative aspects of a keto diet in our Negative Aspects of a Keto Diet" webpage, so here we will go over its positive aspects.

Positive effects of the KD

A review of different scientific papers by Rubini, Paoli, Volek, and Grimaldi (2013) (9) mentioned the "emerging evidence" of the benefits of a ketogenic diet. They reported its success in treating not only obesity but also "pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors."

Let's look into some detailed benefits of a ketogenic diet.

Cardiovascular Disease and Blood lipids

Dasthi et al. (2004) (10) studied 83 very obese subjects who followed a keto diet for 24-weeks with the following macros:

  • 30 g carbohydrates.
  • Protein: 1 g/kg of bodyweight.
  • Fats were 20% saturated fat and 80% polyunsaturated and monounsaturated fat.

Learn more about Macros on our Keto Diet Calculator webpage.

All subjects lost weight and improved their Body Mass Index.

All key indicators improved. Total cholesterol dropped, HDL ("good" cholesterol) increased, LDL ("bad" cholesterol), triglycerides, and blood sugar dropped.

The authors concluded that their "study confirms that it is safe to use a ketogenic diet for a longer period of time than previously demonstrated."

Masood and Uppaluri (5) mentioned several health benefits that overweight subjects would notice after following a keto diet.

  • Better glucose control, and insulin sensitivity.
  • Improved blood pressure.
  • Lower blood lipids (triglycerides).
  • Higher "good" cholesterol (HDL).

However, "bad" LDL cholesterol may increase on a KD

Take-home point

A KD improves HDL, BMI, Total Cholesterol, Triglycerides, and fasting glucose levels. Watch out for LDL!

nurse holding a paper heart
Look after your heart.

Keto Diet Reduces Fat Mass and Abdominal Fat

Vargas (4) studied trained athletes during resistance training to observe the effects of a ketogenic diet. He concluded that:

  • To achieve a state of ketosis carbs intake should be reduced to not more than 50 g per day (approx. 10% of the total daily caloric intake).
  • Protein intake should range from 1.2 to 1.5 g per kg of body mass daily.
  • Fats should account for 60 to 80% of the daily calorie intake

Athletes lost fat but not muscle

Compared to a group following a non-keto diet, those on the ketogenic diet "experienced a greater reduction in Fat Mass and Visceral Adipose Tissue" and their Lean Body Mass or LBM (muscle) was maintained. "This research showed no significant changes nor effect size on LBM."

Both outcomes are good news for those who diet to lose fat and not muscle, but maybe not optimal for athletes seeking to build up more muscle.

No adverse heart effects

Kosinski and Jornayvaz, (2017) (11) found that subjects following a low-carb, high-protein diet were not affected "with higher mortality after 12 years of follow-up" and that they were "unanimous about general positive effects" on cardiovascular risk factors.

The brain, neuroprotective effects of ketones

Alzheimer's, ALS, and Parkinson's

The KD has also shown some "promising" effects in several health conditions such as epilepsy, dementia, ALS, and traumatic brain injury.

White and Venkatesh (2011) (12) reported that ketones may have a neuroprotective effect. "Studies of Parkinson's disease and Alzheimer's disease confirm the encouraging effects of ketones... Other conditions that may be responsive to ketones include amyotrophic lateral sclerosis and certain brain tumors."

The authors believe that ketones decrease free radical production. For instance, when glutamate, an amino acid that acts as a neurotransmitter, appears in high concentrations in the brain, it causes the death of neural cells. Ketones may protect against this effect by oxidizing coenzyme Q and decreasing the formation of free radicals in the mitochondria.

Ketones also increase cerebral blood flow.

Dashti, et al. (10) also reported that a KD can act as a mood stabilizer in bipolar illness and induce gene expression in the brain.

Regarding gene expression (Noh, 2004) (13), β-hydroxybutyric acid or BHB acts on the genes that encode certain mitochondrial enzymes in a part of the brain known as the hippocampus. The extra energy boost that ketones give those cells may prevent cellular death and mitigate the effects of age-related degenerative brain diseases.

Clear Mind

Furthermore, a study by Murray (2016) (14) that used rats, found that "ketosis improve[d] cognitive performance during a maze test of working memory" and suggested that the brain prefers to use ketone bodies instead of glucose.

Perhaps this is the reason for the un-fogged brain reported by keto dieters on websites that promote this diet.

Take-home point

Positive effects on your brain and central nervous system

two overweight women view of rear and thick waist
Obesity, full hips, and wide waist

Closing Comments

A ketogenic diet or KD is an effective way of losing weight, abdominal fat, and improving several indicators such as BMI, total cholesterol, blood sugar, and HDL.

It should, as with any diet, be supervised by a nutritionist or a physician. Renal side effects may appear, LDL cholesterol may increase.

The transition out Keto diet should be gradual, and it has some negative side effects, but also many positive effects.

References and Further Reading

(1) Ludwig DS. (2020) The Ketogenic Diet: Evidence for Optimism but High-Quality Research Needed. J Nutr. 2020 Jun 1;150(6):1354-1359. doi: 10.1093/jn/nxz308.

(2) EM MacKay, (1932). The relation between glycogen and water storage in the liver

(3) WM. Bortz, Pavle Paul, AC. Haff, and WL. Holmes, (1972). Glycerol turnover and oxidation in man, J Clin Invest. 1972 Jun; 51(6): 1537-1546. doi: 10.1172/JCI106950

(4) Salvador Vargas, (2018). Efficacy of ketogenic diet on body composition during resistance training in trained men: a randomized controlled trial, J Int Soc Sports Nutr. 2018; 15: 31. 2018 Jul 9. doi: 10.1186/s12970-018-0236-9

(5) Wajeed Masood and Kalyan R. Uppaluri, (2018). Ketogenic Diet, 2018, StatPearls Publishing LLC. Bookshelf ID: NBK499830PMID: 29763005

(6) Antonio Paoli, (2014). Ketogenic Diet for Obesity: Friend or Foe?, Int J Environ Res Public Health. 2014 Feb; 11(2): 2092-2107, 2014 Feb 19. doi: 10.3390/ijerph110202092

(7) Gibson AA, et al., (2015). Do ketogenic diets really suppress appetite? A systematic review and meta-analysis, Obes Rev. 2015 Jan;16(1):64-76. doi: 10.1111/obr.12230. Epub 2014 Nov 17

(8) Brehm BJ, Seeley RJ, Daniels SR, D'Alessio DA., (2003). A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women, J Clin Endocrinol Metab. 2003 Apr;88(4):1617-23

(9) Paoli A, Rubini A, Volek JS, Grimaldi KA., (2013). Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets, Eur J Clin Nutr. 2013 Aug;67(8):789-96. doi: 10.1038/ejcn.2013.116. Epub 2013 Jun 26

(10) Hussein M Dashti, et al., (2004). Long-term effects of a ketogenic diet in obese patients, Exp Clin Cardiol. 2004 Fall; 9(3): 200-205

(11) C. Kosinski and F. R. Jornayvaz, (2017). Effects of Ketogenic Diets on Cardiovascular Risk Factors: Evidence from Animal and Human Studies, Nutrients. 2017 May; 9(5): 517. 2017 May 19. doi: 10.3390/nu9050517

(12) Hayden White and Balasubramanian Venkatesh (2011). Clinical review: Ketones and brain injury, Crit Care. 2011; 15(2): 219. 2011 Apr 6. doi: 10.1186/cc10020

(13) Noh HS, (2004). A cDNA microarray analysis of gene expression profiles in rat hippocampus following a ketogenic diet, rain Res Mol Brain Res. 2004 Oct 22;129(1-2):80-7

(14) Andrew J. Murray, (2016). Novel ketone diet enhances physical and cognitive performance, FASEB J. 2016 Dec; 30(12): 4021-4032, 2016 Aug 15. doi: 10.1096/fj.201600773R

About this Article

Ketogenic Diet: a Review, A. Whittall

©2018, 11.Oct.2018. Updated. 31.Dec.2020.

Tags: A review of the ketogenic diet, what is the keto diet, ketogenic diet, keto diet, Obesity, keto diet pros, benefits of the KDs.

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Subject: Review of the Ketogenic diet. The Keto diet is an effective diet for weight loss with many health benefits. This article explores the scientific evidence supporting the keto diet for weight loss, and how it positively affects your health.

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