Ketogenic diets: Part 1 – The Basics

Listen to the Influential Wellnesspreneur podcast interview with me on ketogenic diets:

• Part 1
• Part 2

Updated 17 October 2022

Unless you’ve been hiding under a rock for the past few years, you’ll have noticed that, although their star has waned somewhat, ketogenic diets remain wildly popular. I’m still regularly bombarded by clients and EmpowerEd members with questions about the ‘keto diet’ and the various forms of fasting that are promoted by its proponents.

Over the next couple of weeks, I’m going to answer all of these questions in a series of blog posts. In this week’s post, I’m starting with the basics:

• What is the ketogenic diet?
• Why was it developed?
• What are ketone bodies, and what role do they play in our metabolism during fasting?

What is the ketogenic diet?

The ketogenic diet is an eating pattern in which the intake of carbohydrates (the body’s preferred source of energy) is severely restricted, protein intake is moderately restricted, and fat provides the vast majority of daily energy (calories/kilojoules).

Why was it developed?

It was developed in 1924 by Dr Russell Wilder at the Mayo Clinic, a major US teaching hospital, as a treatment for refractory epilepsy (seizures that can’t be controlled by medication) in children. Drawing on earlier research (dating back to 1910) which showed that fasting was an effective treatment for seizure disorders, Wilder proposed that ketone bodies induced by the fasting state had an anticonvulsant effect.

The problem, of course, is that fasting can’t be carried out indefinitely or starvation and death will result, and children have a very limited ability to fast due to their rapid growth rate and high energy needs.

Wilder discovered that severely restricting carbohydrate intake and limiting protein intake, so that fat contributed the majority of calories consumed, also leads to a rise in ketone bodies and corresponding drop in blood glucose level – the state known as ketosis.

The diet devised by Wilder – now known as the ‘classic ketogenic diet’ due to the proliferation of variants of it – drew 90% of calories from fat, 6% from protein and 4% from carbohydrate. While the diet is extremely effective for some children, a 2020 Cochrane review (the gold standard in assessment of the effectiveness of medical interventions) was able to locate only 13 randomised controlled trials (RCTs) or quasi‐RCTs conducted on ketogenic diets. In the nearly 100 years since Wilder developed the diet, its effects have been rigorously studied on just 932 individuals (711 children aged 4 months to 18 years, and 221 adults aged 16 years and over).

The Cochrane reviewers were not exactly enthusiastic about the quality of those trials, either:

“We assessed all 13 studies to be at high risk of performance and detection bias, due to lack of blinding. Assessments varied from low to high risk of bias for all other domains. We rated the evidence for all outcomes as low to very low certainty.”

Ketogenic diets for drug‐resistant epilepsy

So, while their review of the RCTs on ketogenic diets for epilepsy found that children randomised to some form of the diet were more than three times as likely to be seizure-free after several months, and almost six times as likely to have fewer seizures, than if they were assigned to “usual care” (i.e. medication), due to the high risk of bias, the Cochrane team warned that “we are not confident that these estimated effects are accurate.” No adults experienced seizure freedom on any version of ketogenic diet.

Gastrointestinal side-effects including vomiting, constipation and diarrhoea were commonly reported in both children and adults assigned to a ketogenic diet, but these were also reported by participants assigned to usual care (most likely because epilepsy drugs cause them). Two of the studies (one conducted in children, one in adults) reported raised cholesterol in participants assigned to a ketogenic diet.

Drop-out rates were high in both children and adults, mainly because of adverse effects and the difficulty of adhering to ketogenic diets for an extended period.

Interestingly, the one study that assessed quality of life in children found that, despite being more than four times more likely to have reduced their seizure frequency by more than 50 per cent after 4 months on a ketogenic diet, there was no significant difference in quality of life compared with children on usual care. This is intriguing, to say the least. One would expect that children who were having significantly fewer seizures on a ketogenic diet would be enjoying a higher quality of life, so why weren’t they? Again, either adverse effects of the diet, or the difficulty in adhering to it, may be to blame. No studies conducted in adults measured quality of life.

The Cochrane reviewers concluded:

“The evidence suggests that KDs [ketogenic diets] could demonstrate effectiveness in children with drug‐resistant epilepsy, however, the evidence for the use of KDs in adults remains uncertain. We identified a limited number of studies which all had small sample sizes. Due to the associated risk of bias and imprecision caused by small study populations, the evidence for the use of KDs was of low to very low certainty.

More palatable but related diets, such as the MAD [simplified modified Atkins diet], may have a similar effect on seizure control as the classical KD, but could be associated with fewer adverse effects. This assumption requires more investigation. For people who have drug‐resistant epilepsy or who are unsuitable for surgical intervention, KDs remain a valid option. Further research is required, particularly for adults with drug‐resistant epilepsy.”

Ketogenic diets for drug‐resistant epilepsy

What are ketone bodies, and what role do they play in our metabolism during fasting?

Most people go on ketogenic diets in order to lose weight, and more specifically, body fat. To explain how ketone bodies relate to fat loss, let’s start with a quick overview of human metabolism, and the adaptations to our metabolism during fasting:

Glucose, produced from the digestion of carbohydrates, is utilised by most of our bodies’ cells as a primary or preferred fuel. Our brains are especially dependent on it. In fact, an adult’s brain consumes about 120 g of glucose daily, accounting for around 60 per cent of glucose utilisation by the entire body when in a resting state.

When we eat a carbohydrate-containing meal, glucose is absorbed into the bloodstream, stimulating the release of the hormone insulin. Insulin allows our cells to take in glucose in order to burn it as a fuel. (Insulin is also required for the absorption of amino acids into cells so that they can produce proteins, including muscle proteins, digestive and metabolic enzymes, neurotransmitters and certain hormones – insulin is the primary anabolic [body-building] hormone in the body, not the ‘demon hormone’ that low-carbers make it out to be!)

Our liver and muscles are able to turn any surplus carbohydrate into glycogen – ‘animal starch’ – for short-term storage. In between meals, the liver breaks down glycogen into glucose again (‘glycogenolysis’), and releases it into the bloodstream to ensure that all our cells have a constant supply of fuel.

But if we go for 18-24 hours without eating, the liver’s glycogen stores become depleted. In order to maintain a steady blood sugar level to sustain our glucose-hungry brain, as well as other tissues which are unable to use any fuel except glucose – including red blood cells, skin cells, and parts of our kidneys – the liver directs other tissues to switch to alternative fuels and to provide it with raw materials – amino acids (the building blocks of protein) and glycerol (the residue left when stored fat is released into the bloodstream and its free fatty acids split off) – to produce glucose from non-carbohydrate sources (gluconeogenesis).

Our muscles switch to burning free fatty acids released from our fat stores, and also begin to break down their protein in order to release amino acids into the bloodstream, most of which can be converted into glucose. Gluconeogenesis (and therefore body protein breakdown) reaches its maximum level at 4 days into the fast.

The liver itself utilises α-ketoacids derived from protein as a fuel source, sparing glucose for the tissues that need it.

Protein is a valuable and limited commodity in our bodies, however: losing one third to one half of our proteins results in death. On the other hand, even lean adults have enough fat reserves to provide for their resting energy requirements for 2-3 months. So after 2-3 days without food, fat cells begin releasing large amounts of fatty acids, and the liver begins to turn these into ketone bodies. These are used as a fuel source by the brain, skeletal muscles and heart muscle, although not by the liver itself.

The brain can’t run on ketone bodies alone; it still requires a small amount of glucose – 30 g per day – which comes from ongoing gluconeogenesis from protein breakdown (predominantly from muscles) and glycerol. However, after approximately 5-7 days of complete abstinence from food (sooner in women, later in men), ketone body production reaches a point at which it is able to meet most of the brain’s need for energy, and by 10 days into the fast, gluconeogenesis declines and protein breakdown drops to 50-100 g per day. Hence, switching to ketosis allows the body to maintain the brain while sparing vital proteins.

The take-home points if you’re considering various popular fasting protocols in order to lose weight, are that:

• Short fasts (under 3-5 days) don’t induce significant ketosis, and therefore most of the weight that you lose during these fasts comes not from fat, but from glycogen depletion and accompanying fluid loss. Adults store 500-1000 g of glycogen, and each gram of glycogen holds 3-4 g of water, so if you deplete your glycogen stores through fasting, you can drop several kilograms in a couple of days. Unfortunately, this weight will be regained as soon as you resume eating carbohydrate.
• Since muscle protein breakdown is highest in the early days of a fast, repeated short fasts (e.g. fasting one day per week) result in far greater loss of muscle than a single extended fast. The goal of weight loss should be body composition change – more muscle, less fat – and repeated short fasts are completely counterproductive to this goal.

In subsequent posts in this series, we’ll look at some of the most popular myths about the role that ketosis has played in human evolution, whether ketosis is our ‘natural state’, and the evidence for ketogenic diets as aids to weight loss, diabetes management, cancer treatment and more.

Curious to know more about fasting? The Deep Dive webinar “Fasting for Health” – part of the EmpowerEd health and nutrition education program – covers the science of fasting, from time-restricted to eating, to intermittent fasting, to prolonged water-only fasting. Learn about the benefits of fasting, and how to fast safely. Your first month of EmpowerEd membership is free – register here.

Read Part 2, Part 3, Part 4, Part 5 and Part 6 of this series.