Ketone dynamics

I have been in ketosis for 3 years now. I know, because I measure blood ketone and glucose levels with a finger-prick device (this one). However, ketosis is not a static state to be in, ketone levels are highly dynamic and change according to a wide range of internal and external conditions. Over the years I have made some intriguing observations. I will share some of these anecdotes in this post.

Background

First, a quick background to ketosis. This is a metabolic state that arises with prolonged dietary carbohydrate restriction.  In ketosis, we switch from a carbo-metabolism (burning glucose from carbohydrates for energy) to a fat-metabolism (burning fat and ketones for energy). Our bodies do not readily switch between the two, they need time to adapt.

Once fat-adapted, fats in the diet or in our adipose tissue are broken down into free fatty-acids (FFAs) which become the primary fuel source for muscle and other cells. In the liver, FFAs are further broken down to form ketones and released into the blood circulation. Ketones easily cross the blood-brain barrier (BBB) and are utilised by the brain. The result is that we make use of the most calorie-dense macronutrient (fat) to fuel brain and muscle (two energy-demanding organs, as well as others), stabilise blood-glucose levels (by avoiding carbohydrate overload), often lose weight (by effortlessly mining our own fat stores for energy), and reap a host of other benefits from the properties of ketones (neuroprotective, antioxidant, anti-inflammatory, epigenetic etc.).

The elegance of this, together with our evolutionary biology as carnivorous omnivores, leads me to conclude that ketosis is a natural and preferred metabolic state, even in healthy individuals. In contrast, most of the modern non-communicable disorders (type 2 diabetes, obesity, metabolic syndrome etc.) associate with excessive dietary carbohydrate and insulin resistance.

A Day in the Life…

Ideally, fasting glucose in a healthy individual should be in the range 4 to 5.5 mmol/L. After ingestion of dietary carbohydrate, this level will rise over a few hours (perhaps to 8-10 mmol/L or more depending on the meal and insulin sensitivity) and then fall back below baseline, which triggers hunger signals and repeated eating. The cycle continues regularly with meals during the day.

In ketosis, blood glucose remains stable during the day because little carbohydrate is ingested. This is a good thing. It is the ketone level that rises and falls during the day. This is not associated with meals, but rather with energy demands. In my experience, ketones start out low, increase to peak around the middle of the day, then decline as night approaches and activity decreases. The following observations come from a day in which I measured glucose and ketones every hour.

Glucose: Average glucose was 4.3 + 0.3 mmol/L over the day (blue line). There was no fluctuation in glucose associated with meals or energy demand. Glucose was essentially in a steady-state condition, with random variation (in a carbo-metabolic state, glucose would have gone off the vertical scale after meals for many people). This is both desirable and expected. I have made numerous random glucose measurements over the years, and blood glucose is usually around 4 to 5 mmol/L at any time of day in the healthy state (more about the unhealthy state later). HbA1c (a longer-term estimate of average blood glucose) is ~4.8%, which is low by a comfortable margin.

Ketones: Dietary ketosis is defined as a blood ketone level of 0.5 mmol/L or higher. In carbo-metabolism, there could be trace levels of ketones, around 0.0 – 0.2 mmol/L, perhaps as high as 0.4 mmol/L in rare situations. These ketones probably don’t come from fat, but rather from gut microbes that produce butyrate, which the liver converts to the ketone beta-hydroxybutyrate – the ketone detected by fingerprick devices.

On the day, the first (fasted) reading was 0.7 mmol/L and therefore within ketosis and normal for me (a 10-day fasting average was 0.9 mmol/L). As the day progressed, ketones increased steadily to peak around the middle of the day, then fell back to their starting values at the end of the day (red line). There were no meal-related interruptions to this bell-shaped pattern. This is because ketone synthesis is not dependent on dietary sources for fat – body fat is always available to meet energy need, even in normo-weight individuals.

Ketones peaked a little higher than usual on this measurement day (3.9 mmol/L) however, this is still below mean glucose (see later). On most days, I would expect peak ketones to be around 2-3 mmol/L.

The overall message is that metabolism in ketosis is not being stressed by repeated swings. Glucose is held steady, and ketones are synthesised and utilised during the course of the day according to need.

So, this provides a backdrop for some more interesting observations. I will start with thinking.

Ketones and the brain

For individuals operating a carbo-metabolism, there’s only one fuel source that’s available for the brain and that’s glucose. This results in a vulnerable brain. If anything happens to the supply of glucose (for example, with endurance exercise without adequate carb-loading) or, more important, to the ability of the brain to utilise glucose, then brain function is jeopardised.

However, for individuals with a fat-metabolism and in ketosis, ketones become the brain’s insurance policy – they are an alternative brain fuel that can be made on demand.

The importance of this mechanism is becoming steadily more apparent. For example, imaging studies of people at risk of Alzheimer’s disease show that glucose metabolism is reduced in critical areas of the brain decades before the appearance of even mild cognitive impairment. The common interpretation has been that cells are dying and so glucose uptake is reduced.

However, recently it has become possible to also image ketone uptake in the human brain. Glucose can be measured concurrently in the same individual and imaging session. Radio-labelled glucose and ketones are injected into an individual, and images formed with Positron Emission Tomography (PET) scanning. These are dual-tracer studies, made possible by the different half-lives of the two radio-isotopes.

These studies show that in areas of the brain where glucose metabolism is decreased, ketone metabolism is normal. This means that brain cells are still alive in these areas, but starving. They cannot metabolise the only fuel normally available – glucose. Supplying ketones as an alternative fuel may rescue them. The elegance of dietary ketosis is that the supply of ketones is uninterrupted throughout the day, and can be increased as needed without conscious intervention.

Which brings me to my next observation. After a few hours of significant cognitive effort (such as finalising one of these posts) my blood ketones go up while glucose remains the same. Whenever I have put this to the test, ketones have been in the 4 – 5 or more mmol/L range. This represents a substantial elevation.

As an example, I’ve been concentrating on this post, mostly uninterrupted, quite intensely for a few hours now. I have paused for a moment and taken a measurement: glucose is a normal 4.6 mmol/L, ketones are a surprising 5.4 mmol/L.

My interpretation is that the brain prefers to turn to ketone metabolism, if available, to satisfy an increase in energy demand. That the brain has done this supports an important role for ketones in brain function. It also supports one of the main reasons I choose to be in ketosis: neuro-insurance.

Ketones and infection

 One day, some time ago, I did a random measurement and to my surprise had readings of 6.2 mmol/L for ketones and 3.3 mmol/L for glucose. Both of these readings were well outside normal for me. I had done nothing unusual, and I felt fit and healthy. Repeat measurements during the day came up with the same pattern – high ketones and low glucose.

The next morning I woke up with symptoms of a common cold. The symptoms were mild, and only lasted 2 days. It is tempting to think that the ketone/glucose pattern was an early protective response to infection.

More recently, I had the opportunity to test this a bit more systematically, when a guest arrived for lunch at my house while suffering the symptoms of a cold. Over the next 5 days, I took repeat measurements of ketones and glucose at 3-hourly intervals, to see if the previous pattern repeated itself in the event that the infection had been transmitted.

The ketone/glucose pattern during Day 1 (the day after exposure) was normal. The first sign that metabolism was adjusting was Day 2 – ketones started out unusually high (2.7) and rose to peak of 4.8, while glucose was on the low side and dipped down to 3.5.

Day 3 was peak-effect. Ketones started out (fasted) at a whopping 3.1 (normally a peak), and went up (at 3 hourly intervals) to 4.9, 6.7, 6.8 and 7.8 mmol/L, before sliding back to be at 3.2 at the end of the day. Glucose remained low (average 3.9, minimum 3.5).

Day 4 was like Day 2, Day 5 like Day 1, and then it was all over. Interesting, but tedious.

To give a perspective to the peak value of 7.8, it’s the sort of value one might expect after a 2-month water-only starvation diet (yes, this experiment has been done – in obese individuals monitored in a hospital metabolic ward).

It seems a virus achieved that in 3 days! Ketones may have gone higher, as I was only sampling every 3 hours.

Throughout this experience, I was free of any symptoms. During the 5 days in total, there was no fatigue and I went about normal activities of daily living, including exercise.

I did avoid human contact though because, even in the absence of symptoms, I presume there was still a reasonable chance I could pass it on. Even in the general population, who are presumably not in ketosis, it is recognised that some individuals may carry a virus without symptoms, but they remain infectious.

It is the magnitude of the ketone effect, combined with a general suppression of glucose, that suggests this was an important phenomenon.

Some idle speculation

I can find no previous report, anecdotal or in the literature, that describes this ketone/glucose pattern when a person in ketosis is exposed to an opportunistic viral infection. However, people in ketosis do often remark that they don’t get colds or flu anymore.

It is unwise to generalise from an anecdote, but there are some interesting things to think about.

Perhaps the most obvious is that glucose metabolism may have been down-regulated to deprive the virus of glucose, while ketone metabolism was upregulated to provide additional energy for the host.

Viruses sit on the boundary of life. They are not included in the main taxonomic Domains of life (bacteria, archaea or eukaryota), mostly because they do not metabolise, they are inert objects for carrying DNA/RNA. But they are clearly important components of the planetary biosphere – viruses are estimated to be greater in number than all of the cells of all plants, animals and fungi combined, by a factor of 10-100.

However, while viruses do not need glucose to generate energy to maintain themselves, they do need glucose for their replication once inside a host cell. The virus redirects the main process a cell uses to generate energy (in organelles called the mitochondria) to use a less efficient but rapid source of energy (by a type of glucose fermentation). This process, called the Warburg Effect, also happens in cancer cells, and it is thought that some viruses may trigger a healthy cell to convert to cancerous. A number of viruses are known to be cancer-causing. As well as being detrimental to host cell metabolism, the viral DNA (or RNA) potentially alter the host cell’s own DNA, resulting in cellular mutations.

This was almost certainly going on in earliest evolution, where some viral-life exchanges were beneficial and probably accelerated evolution. Our own DNA (and cellular nucleus) may be largely of viral origin. It is thought that these processes continue even today. Add in that mitochondria were originally bacterial, and our cellular life takes on a broader perspective.

While glucose was abnormally and persistently low for me, it wasn’t all that low. The body may not be free to severely lower glucose, partly because red blood cells can only metabolise glucose (they don’t have mitochondria). Red blood cells use the same glucose-fermentation pathway that viruses and cancer cells use, but not so aggressively.

However, surely there was no need for ketones to go that high just for an energy shortfall. Perhaps cells went into hyper-metabolism to protect themselves, or perhaps ketones served a more fundamental role in fighting the virus. Or perhaps the high ketones were secondary to something else. We are only just beginning to understand the many facets of ketones.

It is not certain that individuals running a carbo-metabolism would have access to ketones in fighting infection, although there may be individuals in borderline ketosis that could. This might explain the prevalence and severity of cold and flu symptoms in the general population, and why people in ketosis don’t seem to get as sick. Furthermore, individuals in carbo-metabolism are more likely to eat carbs/glucose (comfort foods), and thereby undo any effort the host may have made to lower glucose. A loss of appetite may also be relevant to keeping glucose low.

There has been some recent suggestion that the metabolic response to bacterial infection may differ from that to viral infection, although this was in mice. Still, there are sure to be layers of complexity on complexity. I have, on one opportunity only, noted the same ketone/glucose pattern during a gastrointestinal infection, but I cannot say whether that was bacterial or viral.

Immunosuppression

While I am in good health, I have suffered, for most of my life, from a hypersensitivity disorder (from unknown allergens) that over time affected me all year round and required daily medication.

After 8 months of ketosis (but not until then), this disorder resolved and I was no longer symptomatic. I continue to be asymptomatic without medication.

We know that ketones are themselves anti-oxidants, and they up-regulate gene expression for the cellular production of anti-oxidants. As well, burning ketones for fuel generates fewer free radicals. All in all, ketones reduce chronic inflammation. It may be this resetting that has given me relief. For those that understand these things, my high-sensitivity CRP (a rough measure of inflammation) is 0.1 mg/L, which is ten-fold lower than what is considered ‘low’.

Comment

I’ve shared some personal anecdotes, rather than delve into peer-reviewed scientific literature as I usually do. However, anecdotes and case studies have their uses, and can be hypothesis-generating (e.g. the role of ketone metabolism in acute infection). Naturally, all of this only applies to me and I cannot predict how generalisable these observations are. Still, I think these changes have been fun to observe, and are an ongoing motivation to remain in this metabolic state.


Print This Post Print This Post

Related Posts or further information

The ketogenic diet page 

Brain ketone imaging in AD – read a review, or watch a video

Cancer 

The brain 

Inflammation