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. Our insulin levels drop, and we transition to burning body fat and 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 measured at the same time from a range of people following a low carbohydrate or ketogenic diet.

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.

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

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

Hyperinsulinemia has been called as the “unifying theory of chronic disease” [1] [2] [3] [4] [5].  It’s beneficial 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.

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 go longer between meals naturally 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.

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.

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.

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?!?!?

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.

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.

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.

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.

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.

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.

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

 ^[13]

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.

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.

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

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.

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.

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]

^{[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 mobilize 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.

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.

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!

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

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.

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).

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 fat and/or 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, increased 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.

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 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