Tag Archives: exogenous ketones

are ketones insulinogenic and does it matter?

There has been a lot of hype around the interwebs lately about exogenous ketones and whether they are health promoting, particularly for people with conditions that relate to excess insulin such as diabetes, traumatic brain injury, Alzheimer’s, cancer, epilepsy, obesity etc.

exogenous ketone are trendy
exogenous ketones, Pruvit and Keto//OS are becoming trendy.

Exogenous ketones are becoming trendy, particularly in the low carb scene!

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A couple of people recently asked me whether I thought exogenous ketones are insulinogenic.

Roger Unger’s 1964 paper the Hypoglycemic Action of Ketones.  Evidence for a Stimulatory Feedback of Ketones on the Pancreatic Beta Cells[1] indicates that ketone levels are controlled by insulin and that ketones suppress lipolysis:

Ketone bodies have effects on insulin and glucagon secretions that potentially contribute to the control of the rate of their own formation because of antilipolytic and lipolytic hormones, respectively.  Ketones also have a direct inhibitory effect on lipolysis in adipose tissue.[2]

It seems that exogenous ketones are indeed insulinogenic to some degree.

But how do we test this hypothesis to find out whether they are just slightly insulinogenic like fats or more insulinogenic like carbohydrates?

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how to test the insulin response to exogenous ketones in someone with Type 1 Diabetes

If someone with Type 1 Diabetes stops taking their insulin both their blood glucose levels and blood ketones spiral out of control as they slip into ketoacidosis[3] which can be dangerous and fatal before very long without exogenous insulin injection.[4]   In metabolically healthy people,  high levels of ketones suppress mobilisation of body fat (lipolysis).[5]

In someone with Type 1 Diabetes, taking exogenous insulin brings both ketones and blood glucose under control.  So, based on what we see in people with Type 1 Diabetes, it seems logical that exogenous ketones would provoke an insulin response to keep ketones and glucose under control.

One way to test whether exogenous ketones are insulinogenic would be to have a Type 1 Diabetic to take a significant amount of exogenous ketones and monitor how much additional insulin they need to keep the continuous blood glucose monitor stable with the same amount of calories in glucose.

I initially became interested in exogenous ketones after hearing a number of podcasts with Patrick Arnold and Dominic D’Agostino thinking that it may be a useful alternative source of energy that does not rely on insulin for my wife, who has Type 1 Diabetes.  However, the one time she tried it resulted in such bad gut distress she never touched it again.  So scratch that n = 1.

food insulin index testing with exogenous ketones

Another way to test whether exogenous ketones are insulinogenic would be to run a food insulin index test[6] [7] using ketones rather than food.  This would involve giving 1000kJ of exogenous BHB (e.g. 48g of KetoCaNa) and measuring the insulin response over two or three hours.

The chart below compares the results of previous food insulin index tests undertaken for different foods.[8]   Comparing the area under the curve insulin response for the exogenous ketones to the insulin area under the curve for glucose would give you the insulin index for exogenous beta hydroxybutyrate.

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I am surprised that the companies marketing exogenous ketones to people with metabolic issues, as part of their due diligence, haven’t already done this testing to understand to what degree exogenous ketones are insulinogenic.

but wait, the food insulin index testing with exogenous ketones has already been done!

Then I came across this figure in a paper, Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes (Cox et al, 2016)[9],  where they have effectively done the food insulin index testing with exogenous ketones.

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Thirty-nine athletes took an isocaloric dose of ketone esters, carbs and fat in three different sessions. In the chart on the right (G) we can see that the ketones provoked about half the insulin response compared to the carbohydrate drink.  This test is different to normal food insulin index testing in that the participants started to exercise ten minutes after taking the drinks (i.e. at T = 0) at which point insulin and glucose start to decline.

updated insulin load formula, including exogenous ketones

The chart below shows the relationship between the food we eat and our insulin response based on the previous food insulin index testing.

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In lieu of more thorough food insulin index testing, I think we can update the insulin load calculation formula to:

insulin load = carbohydrate – fibre + 0.56 * protein – 0.725 * fructose + 0.5 * exogenous ketones

It appears that exogenous ketones provide about half the insulinogenic impact of carbohydrates (i.e. about the same as protein).


So, if you’re avoiding protein because of its impact on insulin, should you also consider exogenous ketones for the same reason?

Exogenous ketones stimulate insulin, but BHB also inhibits lipolysis directly via the nicotinic acid receptor PUMA-G in adipose.[10]

While exogenous ketones may be equally as insulinogenic as protein, they’ll also be a counterproductive use of insulin.

Whereas the insulin response to protein is a positive use of insulin to build and repair muscle, with exogenous ketones, insulin simply reduces oxidation of other fuels to allow ketones to be burned.

Exogenous ketones displace the burning of other substrates.  You know what else displaces the burning of other substrates?  Glucose. Carbs reduce the amount of fat you burn. Similarly, exogenous ketones displace both fat and carbs/glucose.

That’s a double whammy in the wrong direction! Substrate competition is key.

Mike Julian

total energy = glucose + ketones

In a healthy metabolism, endogenous ketones are generated as fat stores are mobilised to compensate for a decreased energy availability from glucose.  When glucose is not available, ketones come to the rescue to ensure survival.

If you’re insulin resistant, you might have trouble releasing free fatty acids due to the high levels of insulin circulating in your bloodstream.  This inability to access your own fat stores will reduce your ability to create ketones and likely lead you to be more hungry and eat more than you otherwise would if you were insulin sensitive.  If you are insulin sensitive you can more easily access your own body fat stores.

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This chart demonstrates the concept of total energy (i.e. glucose + ketones) using more than a three thousand combined ketone and glucose readings from people following a low carb/keto lifestyle.  Other than in the extremes of extended fasts or major feasting, the body seems to use insulin to maintain a homoeostasis of around 5 to 6 mmol/L of total energy in the blood.

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On the left-hand side of the chart, when our blood glucose levels drop, we get a rise in ketones, but an increase in autophagy and all the good stuff that comes with fasting and ketosis.

On the right-hand side of the chart, when we drive our total energy high with excess energy (be it from processed carbs, Bulletproof Coffee, or exogenous ketones) the body releases insulin to stop stored body fat and glucose being released into our bloodstream.

People with the highest levels of metabolic health tend to walk around with a lower total energy in their bloodstream.  It seems you don’t need to buffer lots of energy in the blood if you can easily mobilise body fat and glycogen stores quickly when required.

Having high levels of energy sitting around in the blood stream is far from ideal and leads to glycation in the case of high blood glucose levels and oxidation in the case of free fatty acids.

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The total energy concept also seems to hold up with laboratory testing in rat pancreas islet cells, where exogenous ketone bodies promoted insulin secretion when there was greater than 5.0 mmol/L of glucose.[11]

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It appears that if your blood glucose levels are greater than 5.0 mmol/L (or 90 mg/dL), then exogenous ketones will be insulinogenic (at least if you’re a rat, but we have no reason to believe this wouldn’t occur in humans as well).

So if your blood glucose levels are greater than 5.0mmol/L (or 90 mg/dL),  then those expensive exogenous ketones will be working just like a quick burning insulinogenic fuel, just like a dose of carbs.

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do exogenous ketones “help” with fasting?

If exogenous ketones raise insulin and reduce blood glucose, then where does the glucose go?  It gets stuffed back into the liver. 

Think about all of these people who fast with the intent of depleting liver glycogen but drinking Keto/OS. They’re literally preserving glycogen stores! No wonder we were seeing whacky glucose and ketone response to fasting with exogenous ketones.

Instead of the normal trajectory of a fast that would result in depleted liver glycogen we see exogenous ketones keeps this from happening, so you would get purges of glucose out of the liver throughout the fast when people were fasting using exogenous ketones.”

Mike Julian

Let’s take a quick look at what Mike means by “the normal trajectory of glucose”.    In the chart below, we can see that blood glucose levels drop and ketone increase in four people.

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Where things get interesting is when you step look at the longer-term glucose and ketone trajectory of the fourth person who was taking exogenous ketones during the fast.

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What’s causing this anomaly in glucose and ketone response?   Is it a unique level of insulin resistance, or could this simply be explained by the use of exogenous ketones which are down regulating release of free fatty acids and endogenous ketone production?

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One theory is that exogenous ketones are switching off lipolysis, which drives the liver to release more glucose and ramp up gluconeogenesis to fuel the system during fasting?

The glucose : ketone index is the measure that Dr  Thomas Seyfried encouragescancer patients to use during a fast to measure its therapeutic effect.  The lower the better.  For most people the GKI continues to drop during extended fasting, but in this case the GKI dropped and then starts to rise over time when taking exogenous ketones.

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I would like to see some more thorough studies to understand if this is typical in people taking exogenous ketones during extended fasting.  It’s not conclusive, but n = 1s are useful to build a hypothesis that can be tested in a more controlled environment.

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oxidative priority

Ray Cronise and David Sinclair recently published an intriguing article, Oxidative Priority, Meal Frequency, and the Energy Economy of Food and Activity: Implications for Longevity, Obesity, and Cardiometabolic Disease (2016)[12] where they detailed the basis for the oxidative priority of different fuel substrates.

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  1. Alcohol will be burned first because the body has limited storage capacity for it. It sees it as a toxin that needs to be cleared.
  2. Protein will be burned second because you can only store a few hundred calories worth of amino acids in the bloodstream (though I think most people struggle to overeat protein when from whole food sources).
  3. Carbohydrate will then be burned before we can access our virtually unlimited stores of body fat.

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So, I think it would be logical that exogenous ketones would be first in line (before or just after alcohol) to be burned off because the body has no way of storing the exogenous ketones other than circulating in the blood stream.

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So, it seems that exogenous ketones neither lower insulin nor promote fat burning.  They’re just another fuel that will be burned before the fat on your bum and your belly.

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do exogenous ketones boost exercise performance?

Exogenous ketones in sports performance is an interesting area of research.  Rumour has it the Tour de France cyclists and British Olympic rowers are using ketone ester drinks (though it’s worth noting that the people spreading these rumours are selling the ketone esters).[13]

Some people use exogenous ketones as a preworkout, like caffeine, to give them a cognitive boost.  Research by Richard Veech and Kieren Clarke suggests that there may be a small athletic boost if you provide both exogenous ketones and exogenous glucose at the same time to provide a “dual fuel”.[14] [15]  This situation provides a fuel oversupply that would force the body to burn off the excess fuel quickly.

Dr Mike T Nelson suggest that driving a chronic energy surplus from high ketones and high glucose might be problematic in the long term as there is no precedent in nature for this condition.[16]

I have dabbled with exogenous ketones (i.e. KetoCaNa, Pruvit and the Ketone Aid ketone ester).  The chart below shows  how my blood ketones rose to 3.5mmol/L and then back down to normal levels after about 3 hours.  Note how my body tries to remove the excess energy from the blood stream and bring the total energy back down to around 5.0mmol/L.

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I didn’t find a massive boost in performance in my workouts with any of the ketone products.  My best performance is when I was fasted without supplementation and it seems I could easily access my fat stores and breath more effortlessly.

I’m far from a high level athlete, but when I perform at my best cycling or in my kettlebell workouts, my breathing seems effortless and my time to exhaustion increases.   When we are insulin sensitive and / or don’t have excess glucose in our system and burn more fat for fuel we use less oxygen than when we burn glucose for energy.[17]  That reduction in oxygen usage is critical to make sure you don’t get out of breath and fatigue.  It seems that too much exogenous ketones or glucose in the system will mean that we’re less reliant on burning our own body fat.

I think the future of exogenous ketones in athletic performance will revolve around finding the right dose to boost ketones enough to get a performance benefit, without switching off lipolysis, which is where the real performance powerhouse lies.   If you put in so much fuel in line in front of your virtually unlimited fat stores, then you may risk gassing out because you can’t access your fat stores as easily.

Perhaps someone who is a normal carb burner might benefit from having ketones raised to the 3 or 4 mmol/L range, while someone who is more fat adapted might benefit more with ketones in the 1 to 2 mmol/L range so as to get a dual fuel boost without switching off fat burning?

It’s still early days.  Time and more experimentation will tell.

does it matter?

If you’re metabolically healthy and you enjoy the brain buzz of exogenous ketones more than alcohol or caffeine and want to use exogenous ketones as a pre-workout, then I say go your hardest if you can afford it.

However, if you are looking for improvements in your metabolic health or magical weight, I think you should be cautious.

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Companies like Ketopia are marketing exogenous ketones as a “bridge” through the keto flu, which I think is a more ethical approach (although many people say you can eliminate the ‘keto flu’ with good mineral supplementation).

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But you probably haven’t heard of Ketopia, because selling seven days’ worth of exogenous ketones isn’t a great business model in comparison to getting people to sign up for an ongoing subscription as a distributor buying thousands of dollars of ‘inventory’ up front so they can take it… Every.  Single.  Day.

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Perhaps when exogenous ketones are no longer the realm of overhyped multi level marketing campaigns people will be able to experiment with exogenous ketones and find whether they live up to any of the claims and are indeed worth the money?  This is starting to happen now with Julian Baker’s InstaKetones coming in at about one sixth of the price of Pruvit’s products.

If you’re using exogenous ketones with the hope of reducing insulin levels or reversing metabolic disease (e.g. Type 2, cancer, Alzheimer’s, obesity), then maybe think again.  Exogenous ketones may alleviate your symptoms while they’re in your system (about 2 hours), but I fear they might worsen the conditions that people are using them for in the hope of improved metabolic health.

Mike Sheridan’s article in T-Nation makes a number of excellent points:

Ketones may be depressing dieters’ hunger and giving them a hit of energy and cognitive enhancement, but it’s INHIBITING their ability to burn fat, providing zero nourishment, and doing nothing for their metabolic health. There’s an assortment of evidence suggesting that it’s probably making things worse.

Think of exogenous ketones kind of like alcohol. When they’re consumed, everything is stored and nothing else is burned. So any lipolysis (fat burning) that would be taking place is halted; any glucose and fatty acids in your blood that were circulating are stored; and the ingested ketones are burned until there aren’t any left.

But suggesting individuals already fasting, restricting calories, or cutting carbs will get anything other than a brain buzz is misleading. And to serve up exogenous ketones to an obese, insulin-resistant general population with promises of fat-burning and disease prevention is potentially damaging.

Sure, it might suppress hunger and give a damaged brain a useable fuel source, but what happens when pre-diabetic Pete starts adding ketones to his glucose-rich blood? Or anaerobic Andy continues reloading with the same amount of carbs post-workout even though the liver glycogen he normally burns during his sessions is now suppressed?[18]

Sure, exogenous ketones might provide energy to the muscles or brain cells of someone with Type 2 or Alzheimer’s who can’t use glucose well because of decades of hyperinsulinemia.  But, if someone already has super high glucose and insulin levels, will they worsen the condition by chasing high ketone levels with large doses of insulinogenic exogenous ketones?

If someone is trying to shrink their brain tumour by reducing growth stimulating insulin, will ingesting large amounts of exogenous insulinogenic ketones accelerate growth in the brain tumors?  Recent studies suggest that this may in fact be the case.[19]

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At the current rate, it looks like we will be able to confirm the long term effects of exogenous ketones sooner rather than later.


But by then, the people running the MLMs will have driven off into the sunset and be on to another scheme.

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good news… endogenous ketones for free!

The good news is that all the benefits of endogenous ketosis is freely available risk free!  It’s not easy, but you can get the benefits of ketosis (e.g. autophagy, apoptosis, increased NAD+, mitogenesis etc) by keeping the insulin load of your normal diet down to the point that you can maintain normal blood glucose and insulin levels, then occasionally you can push the time between meals than usual in order to derive some extra benefits (i.e. intermittent fasting).

 

references

[1] https://www.dropbox.com/s/287bftreipfpf29/jcinvest00459-0078.pdf?dl=0

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC441933/

[3] http://www.webmd.com/diabetes/type-1-diabetes-guide/ketoacidosis

[4] http://www.webmd.com/diabetes/tc/diabetic-ketoacidosis-dka-topic-overview#1

[5] https://www.dropbox.com/s/hnycwc6b5pw37hr/Inhibition%20of%20Ketogenesis%20by%20Ketone%20Bodies%20in%20Fasting%20Humans.pdf?dl=0

[6] http://ajcn.nutrition.org/content/66/5/1264.abstract

[7] http://ses.library.usyd.edu.au/handle/2123/11945

[8] http://ajcn.nutrition.org/content/90/4/986.short

[9] https://www.ncbi.nlm.nih.gov/pubmed/27475046

[10] https://www.dropbox.com/s/j66y3osyasvq3b3/KETONES%20and%20NICOTINIC%20ACID%20receptor.pdf?dl=0

[11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1152056/

[12] https://www.ncbi.nlm.nih.gov/pubmed/27869525

[13] http://www.nutraingredients.com/Markets-and-Trends/Ketones-get-rough-ride-at-Tour-de-France

[14] http://journals.lww.com/acsm-msse/Abstract/publishahead/A_Ketone_Ester_Drink_Increases_Postexercise_Muscle.97232.aspx

[15] http://www.nourishbalancethrive.com/blog/2016/10/10/instant-ketosis-04-62mm-30-minutes/

[16] http://www.nourishbalancethrive.com/podcasts/nourish-balance-thrive/high-ketones-and-carbs-same-time-great-performance/

[17] http://www.freemocean.com/2017/02/22/oxygen-and-your-dna/

[18] https://www.t-nation.com/diet-fat-loss/avoid-this-ketogenic-rip-off

[19] https://link.springer.com/article/10.1186/s40170-017-0166-z

 

post updated July 2017

are exogenous ketones right for you?

I’ve spent a lot of time lately analysing three thousand ketone vs glucose data points trying to determine the optimal ketone and blood sugar levels for weight loss, diabetes management, athletic performance and longevity.

In this article I share my insights and learnings on the benefits, side effects and risks of endogenous and endogenous ketosis.

exogenous vs endogenous ketosis

But first, I think it’s important to understand the difference between exogenous and endogenous ketosis:

  • Endogenous ketosis occurs when we go without food for a significant period of time. Our insulin levels drop and we transition to burning body fat.  The ketones in our blood rise.
  • Exogenous ketosis occurs when we drink exogenous ketones or consume a ketogenic diet.

ketones vs glucose

Ketones are important.  As blood glucose decreases, the ketones in your blood increase to keep our energy levels stable.

The chart below shows three thousand blood glucose vs ketone values taken at the same time from a range of people following a low carbohydrate or ketogenic diet.

BHB ketones vs blood glucose

While there is generally a linear relationship between glucose and ketones, each person has a unique relationship between their blood glucose and ketone values that provide a unique insight into a particular person’s metabolic health.

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Some people produce more ketones.  Some people have higher blood glucose levels than others.

what our ketone and glucose values tell us about our metabolic health

Hyperinsulinemia has been termed as the “unifying theory of chronic disease” [1] [2] [3] [4] [5].  It’s very useful to understand where you stand on the spectrum of metabolic health and insulin sensitivity.

The chart below shows the typical relationship between blood glucose and blood ketone for a range of different degrees of insulin resistance/sensitivity.

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If your blood glucose levels are consistently high it’s likely you are not metabolising carbohydrate well.   When you go without food, endogenous ketones are slow to kick in because your insulin levels are also high.  You feel tired and hungry and you are likely to eat again sooner and not stop until you feel good.

By contrast, if you are insulin sensitive you may be able to naturally go longer between meals and you will not feel as compelled to eat as much or as often.  If someone is insulin resistant a lower insulin load dietary approach will help with satiety and carb cravings while keeping blood glucose levels and insulin under control.

hyperinsulinemia and metabolic disorders

Exciting research is coming out underway looking at the use of EXOGENOUS ketones as an adjunct treatment for cancer or to provide energy directly to the mitochondria for people with epilepsy, dementia, Alzheimer’s and the like.[6]  [7]  

EXOGENOUS ketones may help to relieve the debilitating symptoms and side effects of acute hyperinsulinemia, Alzheimer’s, dementia, epilepsy or other conditions where glucose is not used well.

exogenous ketones and the low carb flu

Patrick Arnold, who worked with Dr Dominic D’Agostino to develop the first ketone esters and ketone salts, has noted that exogenous ketones may help alleviate the symptoms of the ‘keto flu’ during the transition from a high carb to a low carb dietary approach.


However, once you have successfully transitioned to a lower carb eating style it may be wise to reduce or eliminate the exogenous ketones to enable your body to fully up-regulate lipolysis (fat burning), maximise ENDOGENOUS ketone production and access your body fat stores.

As discussed in the article Are ketones insulinogenic and does it matter? it exogenous ketones require about half as much insulin as carbohydrate to metabolise (or about the same amount as protein).  Hence the continual use of exogenous ketones will limit how much our insulin levels are able to decrease.

Someone with diabetes who follows with a nutrient dense low insulin load dietary approach may be able to successfully normalise their blood glucose and insulin levels. When this happens, your liver will be able to more easily produce ENDOGENOUS ketones which will help improve satiety between meals and decrease appetite which will, in turn, lead to weight loss.

Exercising to train your body to do more with less is also helpful.

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my experience with exogenous ketones

The light blue “mild insulin resistance” line is based on my ketone and glucose tests when I started trying to wrap my head around low carb/keto.

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I enthusiastically started adding generous amounts of fat from all the yummy stuff (cheese, butter, cream, peanut butter, BPC etc) in the hope of achieving higher ketone levels and therefore weight loss, but I just got fatter and more inflamed as you can see in the photo on the left.

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My blood tests suggested I was developing fatty liver in my mid-30s!  And I thought I was doing it right with lots of bacon and BPC?!?!?

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The photo on the right is after I worked out how to decrease the insulin load of my diet and learning about intermittent fasting.  I realised that ENDOGENOUS ketosis and weight loss is caused by a lower dietary insulin load, not more EXOGENOUS fat on your plate or in your coffee cup.

I recently had my HbA1c tested at 4.9%.  It’s getting there.  But knowing what I know now about the importance of glucose control,  I would love to lose a bit more weight and see my HbA1c even lower.

I initially purchased a couple of bottles of KetoCaNa after hearing a number of podcast interviews with Dominic D’Agostino and Patrick Arnold.[8] [9]

Part of the reasons shelling out the money for the exogenous ketones was to see if it would provide a fuel source that didn’t need insulin for my wife Monica who has Type 1 Diabetes.

This metabolic jet fuel is definitely fascinating stuff!  My experience is that it gave me a buzz like a BPC but also has an acute diuretic effect.

I had hoped it would have a weight loss effect like some people seemed to be saying it would.

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I did find it had an amazing impact on my appetite.  While it was in my system I didn’t care as much about food.  However, once the ketones were used up my appetite came flooding back.

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Unfortunately, my hunger and subsequent binge eating seemed to more than offset the short term appetite suppression that had occurred while the exogenous ketones were in my system.  And it was not going to be financially viable for me to maintain a constant level of artificially elevated ketone levels which return to normal levels after a couple of hours.

do exogenous ketones help with weight loss?

I asked around to see if anyone had come across studies demonstrating long term weight loss effects of exogenous ketones.[11]   It was a VERY enlightening discussion if you want to check it out here.

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The Pruvit FAQ says that one of the benefits of Keto//OS is weight loss.  However, no reference to the research studies was provided to prove his claim.

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Also, the studies that were referenced in the Pruvit FAQ all appeared to relate to the benefits of ENDOGENOUS or nutritional ketosis rather than EXOGENOUS ketone supplementation.

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According to Dominic D’Agostino in a Pruvit teleseminar, the EXOGENOUS ketone salts were not designed to be a weight loss product and hence have not been studied for weight loss after all!

The only studies that we could find that mentioned EXOGENOUS ketone supplementation and weight loss were on rats and they found that there was no long term effect on weight loss.[12]   

So in spite of my hopeful $250 outlay, it seems that exogenous ketones ARE just a fuel source after all.

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Even the experts don’t seem to think exogenous ketones help with fat loss.

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Confused?

I don’t blame you.

Metabolically healthy

The “metabolically healthy” line in the chart above is based on RD Dikeman’s ketone and glucose data when he fasted for 21 days.

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Due to his hard-earned metabolic health and improved insulin resistance RD has developed the ability to fairly easily release ketones when he doesn’t eat for a while.  RD still doesn’t find going without food effortless, but it is easier than when his insulin levels were much higher which prevented his body from accessing his body fat stores.

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Through a disciplined diet and exercise habits RD has achieved a spectacular HbA1c of 4.4%.

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Perhaps a two or three day water only fast testing blood glucose and ketones with no exercise would be a useful test of your insulin status?  You could use RD’s glucose : ketone gradient as the gold standard.

RD also told me that when he is not fasting and is eating his regular nutrient dense higher protein meals his ketone levels are not particularly high. While RD fairly easily produces ketones when fasting, it seems they are also quickly metabolised so they do not build up in his bloodstream.

I know Luis Villasenor from Ketogains finds the same thing.

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total energy = ketones + glucose

Where this gets even more interesting is when we look at the glucose and ketone data in terms of TOTAL ENERGY.  That is, the energy coming from both glucose and ketones.

The average TOTAL ENERGY of the three thousand data points from these healthy people working hard to achieve nutritional ketosis is around 6.0mmol/L. It seems the body works to maintain homoeostasis around this level.

optimal fasting ketone and blood sugar levels in ketosis

When the TOTAL ENERGY in our bloodstream increases outside of the normal range it the body raises insulin to store the excess energy.  That is, unless you have untreated type 1 diabetes, in which case you end up in diabetic ketoacidosis with high blood glucose and high ketones due to the lack of insulin available to keep your energy in storage.

Regardless of whether your energy takes the form of glucose, ketones or free fatty acids, they all contribute to acetyl-coA which is oxidised to produce energy.  Forcing excess unused energy to build up in the bloodstream is typically desirable and can lead to long term issues (e.g. glycation, oxidised LDL etc).

I’m not sure if ketones can be converted to glucose or body fat, but it makes sense that excess glucose would be converted to body fat via de novo lipogenesis to decrease the TOTAL ENERGY in the blood stream to normal levels.

A number of studies seem to support this view including Roger Unger’s 1964 paper the Hypoglycemic Action of Ketones.  Evidence for a Stimulatory Feedback of Ketones on the Pancreatic Beta Cells.[14]

Ketone bodies have effects on insulin and glucagon secretions that potentially contribute to the control of the rate of their own formation because of antilipolytic and lipolytic hormones, respectively.  Ketones also have a direct inhibitory effect on lipolysis in adipose tissue.[15]

image26[16] [17] [18]

Looking at the glucose and ketones together in terms of TOTAL ENERGY was a bit of an ‘ah ha’ moment for me.  It helped me to understand why people like Thomas Seyfried and Dominic D’Agostino always talk about the therapeutic benefits and the insulin lowering effects of a calorie restricted ketogenic diet. [19] [20] [21] [22]

Dealing with high ketones and high glucose is typically not a concern because it doesn’t happen in nature or when eating whole foods.  But now we have refined grains, HFCS, processed fats and exogenous ketones to ‘bio hack’ our metabolism and send it into overdrive.

While fat doesn’t normally trigger an insulin response, it seems that excess unused energy, regardless of the source, will trigger an increase in insulin to reduce the TOTAL ENERGY in the blood stream.

I am concerned that if people continue to enthusiastically zealously focus on pursuing higher blood ketones “through whatever means you can[24] in an effort to amplify fat loss they will promote excess energy in the bloodstream which will lead to insulin resistance and hyperinsulinemia.

Using multi-level marketing tactics to distribute therapeutic supplements to the uneducated masses who are desperate to lose weight with a ‘more is better’ approach also troubles me deeply.

My heart sank when I saw this video.

MORE investigation required?

There are anecdotal reports that exogenous ketones provide mental clarity, enhanced focus and athletic performance benefits.  At the same time, there are also people who have been taking these products for a while that don’t appear to be doing so well.

A July 2016 study Ketone Bodies and Exercise Performance: The Next Magic Bullet or Merely Hype? didn’t find that EXOGENOUS ketones to be very exciting.

Recently, ketone body supplements (ketone salts and esters) have emerged and may be used to rapidly increase ketone body availability, without the need to first adapt to a ketogenic diet. However, the extent to which ketone bodies regulate skeletal muscle bioenergetics and substrate metabolism during prolonged endurance-type exercise of varying intensity and duration remains unknown. Therefore, at present there are no data available to suggest that ingestion of ketone bodies during exercise improves athletes’ performance under conditions where evidence-based nutritional strategies are applied appropriately.

However, another study by Veech et al (who is trying to bring his own ketone ester to market) from August 2016 Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes found in favour of ketones.

Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease.

I can understand how exogenous ketones could be beneficial for someone who is metabolically healthy and consuming a disciplined hypo-caloric nutrient dense diet. They would likely be able to auto regulate their appetite to easily offset the energy from the EXOGENOUS ketones with less food intake.

While it seems that EXOGENOUS ketones assist in relieving the symptoms of metabolic disorders I’m yet to be convinced that a someone who is obese and / or has Type 2 Diabetes would do as well in the long term, especially if they were hammering both more fat and exogenous ketones (along with maybe some sneaky processed carbs on the side) in an effort to get their blood ketones as higher in the hope of losing body fat.

Some questions that I couldn’t find addressed in the Pruvit FAQ that I think would be interesting to answer through a controlled study in the future are:

  1. What is the safe dose limit of EXOGENOUS ketones for a young child?  How would you adjust their maximum intake based on age and weight?
  2. IF EXOGENOUS ketones do have a long term weight loss effect what is the upper limit of intake of EXOGENOUS ketones to avoid stunting a child’s growth?
  3. Is there a difference in the way EXOGENOUS ketones are processed in someone is metabolically healthy versus someone who is very insulin resistant?
  4. Does the effect on appetite continue beyond the point that the ketones are out of your system?
  5. Do you need to take EXOGENOUS ketones continuously to maintain appetite suppression?  Does the effect of ENDOGENOUS wear off as your own ENDOGENOUS ketone production down regulates?  Do you need to keep taking more and more EXOGENOUS ketones to maintain healthy appetite control?
  6. How should someone with Type 2 Diabetes adjust their medication and insulin dose based on their dose of EXOGENOUS ketones?  Should they be under medical supervision during this period?
  7. Is there a difference in health outcome if you are taking EXOGENOUS ketones in the context of a hypocaloric ketogenic diet versus a hypercaloric ketogenic diet?  What about a diet high in processed carbs?
  8. Is there a minimum effective dose to achieve optimal long term benefits to your metabolic health or is MORE better?
  9. Are the long term health benefits of EXOGENOUS ketones equivalent to a calorie restricted ketogenic diet?

Unfortunately, I think we will find the answers to these questions sooner rather than later with the large scale experiment that now seems to be well underway.

Perhaps the burden of proof is actually on Pruvit to prove it rather getting their Pruvers to demonstrate that within 59 minutes they are successfully peeing out the product they’ve just paid some serious money for!

The lower the better?

Alessandro Ferretti recently made the observation that metabolically healthy people tend to have lower TOTAL ENERGY levels at rest (and hence have a lower HbA1c), but are able to quickly mobilise glycogen and fat easily when required (e.g. when fasting or a sprint).

Metabolically healthy people are both metabolically flexible[25] and metabolically efficient.[26]   These people would have been able to both conserve energy during a famine and run away from a tiger and live to become our ancestors, while the ones who couldn’t didn’t.

image29

Similar to RD Dikeman, John Halloran is an interesting case.  He has been putting a lot of effort into eating nutrient dense foods, intermittent fasting and high-intensity exercise.

image13

He is also committed to improving his metabolic fitness to be more competitive in ice hockey.  His resting heart rate is now a spectacular 45 bpm!

image08

And he’s been able to lose 10kg (22lb) in one month!

image12

At 5.2mmol/L (i.e. glucose of 4.0mmol/L plus ketones of 1.2mmol/L) John’s TOTAL ENERGY is well below the average of the 26 people shown in the glucose + ketone chart above.  It seems excellent metabolic health is actually characterised by lower TOTAL ENERGY.

MORE is not necessarily BETTER when it comes to health.

fast well, feed well

To clean up the data a little I removed the ketones vs glucose data points for a couple of people who I thought might be suffering from pancreatic beta cell burnout and one person that was taking exogenous ketones during their fast that had a higher TOTAL ENERGY.  I also removed the top 30% of points that I thought were likely high due to measuring after high-fat meals or coffee.

So now the chart below represents the glucose and ketone values for a group of reasonably metabolically healthy people following a strict ketogenic dietary approach, excluding for the effect of high-fat meals, BPC, fat bombs and the like.

image22

The average ketone value for this group of healthy people trying to live a ketogenic lifestyle is 0.7mmol/L. Their average glucose is 4.8mmol/L (or 87mg/dL).  The average TOTAL ENERGY is 5.5mmol/L or 99mg/dL.

ketones (mmol/L)

blood glucose (mmol/L)

total energy (mmol/L)

average

0.7

4.8

5.5

30th percentile

0.4

4.6

5.2

70th percentile

0.9

5.1

5.8

The table below shows this in US units (mg/dL).

ketones
(mmol/L)

blood
glucose (mg/dL)

total
energy (mg/dL)

average

0.7

86

99

30th percentile

0.4

83

94

70th percentile

0.9

92

104

It seems we may not necessarily see really high ketone levels in our blood even if we follow a strict ketogenic diet, particularly if we are metabolically healthy and our body is using to ketones efficiently.

the real magic of ketones

When we deplete glucose we train our body to produce ketones.

This is where autophagy, increased NAD+ and SIRT1 kicks in to trigger mitochondrial biogenesis and ENDOGENOUS ketone production (i.e. the free ones).[27]   The REAL magic of ketosis happens when all these things happen and ketones are released as a byproduct.

I do not believe that simply adding EXOGENOUS ketones will have nearly as much benefit to your mitochondria, metabolism and insulin resistance as training your body to produce ENDOGENOUS ketones in a low energy state.

Everything improves when we train our bodies to do more with less (e.g. fasting, high-intensity exercise, or even better fasted HIIT).  Resistance to insulin will improve as your insulin receptors are no longer flooded with insulin caused by high TOTAL ENERGY building up in your bloodstream (i.e. from glucose, ketones and even free fatty acids).

image01

Driving up ketones artificially through EXOGENOUS inputs (treating the symptom) does NOT lead to increased metabolic health or mitochondrial biogenesis (cure) particularly if you are driving them higher than normal levels and not using them up with activity.

You may be able to artificially mimic the buzz that you would get when the body produces ketones ENDOGENOUSLY, however, it seems you may just be driving insulin resistance and hyperinsulinemia if you follow a “MORE is better” approach.

Simply managing symptoms with patented products for profit without addressing the underlying cause often doesn’t end well.

Perhaps as more exogenous products come to market without the marketing hype that that comes with multi level marketing (e.g. Julian Baker’s Insta Ketone which are a sixth of the price of the Pruvit products) people will get to see if they really do anything useful.

Just like having low blood glucose is not necessarily good if it is primarily caused by high levels of EXOGENOUS insulin coupled with a poor diet or having lower cholesterol due to statins, having high blood ketone values is not necessarily a good thing if it is achieved it by driving up the TOTAL ENERGY in your blood stream with high levels of purified fatand/andd EXOGENOUS ketones.

nutrient density

When we feed our body with quality nutrients we maximise ATP production which will make us feel energised and satisfied.  Nutrient dense foods will nourish our mitochondria and reduce our drive to keep on seeking out nutrients from more food.

Greater metabolic efficiency will lead to higher satiety, which leads to less food intake, which leads to a lower TOTAL ENERGY, greater mitochondrial biogenesis, improved insulin sensitivity and lower blood glucose levels.

Prioritising nutrient dense real food is even more important in a ketogenic context.[28]  While we can always take supplements, separating nutrients from our energy source is never a great idea, whether it be soda, processed grains, sugar, glucose gels, HFCS, protein powders, processed oils or exogenous ketones.

the best exogenous ketone supplement

If your goal is metabolic health, weight loss and improving your ability to produce ENDOGENOUS ketones, then developing a practice of FEASTING and FASTING is important.

To start out, experiment by extending your fasting periods until your TOTAL ENERGY is decreasing over time.  This will cause your circulating insulin levels to decrease which will force your body to produce ENDOGENOUS ketones from your ENDOGENOUS fat stores.

best exogenous ketone supplement

Check out the how to use your glucose meter as a fuel gauge article or how to use your bathroom scale as a fuel gauge for some more ideas on how to get started with fasting.

If you really want to measure something, see how low you can get your glucose levels before your next meal.  Then when you do eat, make sure you choose the most nutrient dense foods you possibly can to build your metabolic machinery and give your mitochondria the best chance of supporting a vibrant, active and happy life.

As my wise friend Raymund Edwards keeps reminding me, FAST WELL, FEED WELL.

 

references

[1] http://www.thefatemperor.com/blog/2015/5/6/the-incredible-dr-joseph-kraft-his-work-on-type-2-diabetes-insulin-reigns-disease

[2] http://www.thefatemperor.com/blog/2015/5/10/lchf-the-genius-of-dr-joseph-r-kraft-exposing-the-true-extent-of-diabetes

[3] https://profgrant.com/2013/08/16/joseph-kraft-why-hyperinsulinemia-matters/

[4] https://www.amazon.com/Diabetes-Epidemic-You-Joseph-Kraft/dp/1425168094

[5] https://www.youtube.com/watch?v=193BP6aORwY

[6] http://fourhourworkweek.com/2016/07/06/dom-dagostino-part-2/

[7] http://www.thelivinlowcarbshow.com/shownotes/10568/848-dr-dominic-dagostino-keto-clarity-expert-interview/

[8] http://superhumanradio.com/579-shr-exclusive-patrick-arnold-back-in-the-supplement-business.html

[9] http://superhumanradio.com/shr-1330-best-practices-for-using-ketone-salts-for-dieting-performance-and-therapeutic-purposes.html

[10] http://docmuscles.shopketo.com/

[11] https://www.facebook.com/groups/optimisingnutrition/permalink/1574631349504574/

[12] https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-016-0069-y

[13] https://www.facebook.com/groups/optimisingnutrition/permalink/1574631349504574/

[14] https://www.dropbox.com/s/287bftreipfpf29/jcinvest00459-0078.pdf?dl=0

[15] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2129159/

[16] https://www.facebook.com/BurnFatNotSugar/

[17] http://www.dietdoctor.com/obesity-caused-much-insulin

[18] http://www.lowcarbcruiseinfo.com/2016/2016-presentations/Hyperinsulinemia.pptx

[19] http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0115147

[20] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1819381/

[21] http://healthimpactnews.com/2013/ketogenic-diet-in-combination-with-calorie-restriction-and-hyperbaric-treatment-offer-new-hope-in-quest-for-non-toxic-cancer-treatment/

[22] https://www.google.com.au/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=0ahUKEwjK8Jvku7DOAhUJspQKHS5-DkwQFggbMAA&url=http%3A%2F%2Fwww.rsg1foundation.com%2Fdocs%2Fpatient-resources%2FThe%2520Restricted%2520Ketogenic%2520Diet%2520An%2520Alternative.pdf&usg=AFQjCNFuTA7xmWX1pFr6wBTV_hsS7C5j_w&sig2=pcBN_f_kCLSgFKYUy–uug&bvm=bv.129391328,d.dGo

[23] https://www.facebook.com/DocMuscles/videos/10210426555960535/?comment_id=10210431467003308&comment_tracking=%7B%22tn%22%3A%22R9%22%7D&pnref=story&hc_location=ufi

[24] https://www.facebook.com/DocMuscles/videos/10210426555960535/?comment_id=10210431467003308&comment_tracking=%7B%22tn%22%3A%22R4%22%7D&hc_location=ufi

[25] http://guruperformance.com/episode-3-metabolic-flexibility-with-mike-t-nelson-phd/

[26] http://guruperformance.com/tag/metabolic-efficiency/

[27] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852209/

[28] http://ketotalk.com/2016/06/23-responding-to-the-paleo-mom-dr-sarah-ballantynes-claims-against-the-ketogenic-diet/

 

post last updated: July 2017