Obviously people who are affected by PP want to know what to do about it but also want to know what causes it.
In the following article where a dermatologist describes some background, the link with ketosis is very strong. Various cases that all lead to higher ketone production are affected by PP. There is some thought that there is inflammation triggered.
Although what I’ll show in this article is in no way proven, the links are quite strong to suspect that I’m close to the reality. Just through observation we can find the following associations
One of the things noted is that the affected areas often the areas where people produce more sweat.
Asians seem to be more easily affected
Case reports reveal that anti-biotics resolve/ammeliorate PP
Ketosis is a necessary factor
The anti-biotics is already a strong indicator that it could be bacteria related. What is unique about ketosis are the metabolites that are produced which are acetoacetate, acetone and beta-hydroxybutyrate.
Acetoacetate is furder metabolised into acetone and beta-hydroxybutyrate. beta-hydroxybutyrate is confined in our blood and requires endothelial transfer via specific transporters. This doesn’t coincide well with the affected areas in the skin.
So acetone seems to be a good candidate to look into. It is the product that is known for the ‘keto-breath’ and evaporates easily. The affected areas are also on the upper skin, from the liver upwards.
OK, let’s see if there is a connection between bacteria and acetone. The article above described an inflammatory response to bacterial folliculitis.
The histologic presence of follicular bacterial colonies supports the theory that prurigo pigmentosa may be a reactive inflammatory response to bacterial folliculitis.
Looking into bacterial folliculitis we find the bacteria Staphylococcus aureus (Sa) popping up as a resident on our skin.
Bacterial folliculitis. This common type is marked by itchy, white, pus-filled bumps. It occurs when hair follicles become infected with bacteria, usually Staphylococcus aureus (staph). Staph bacteria live on the skin all the time. But they generally cause problems only when they enter your body through a cut or other wound.
What are the effects of acetone on Sa?
With Staphylococcus aureus and Streptococcus pyogenes, acetone washed forearms had 2- to 510-fold more organisms than the control arm (P = 0.0008 and 0.08, respectively). Similar results were noted with ether (average 1:62, P = 0.005). Candida albicans increased 2- to 200-fold (average 1:37, P = 0.002). This effect did not occur with Escherichia coli and Pseudomonas aeruginosa (P = 0.8). To determine the time required for natural replenishment of the antimicrobial substances, bacteria were applied 2, 3, and 5 hours after washing with acetone.
Wow, in this experiment they used acetone to wash away the anti-microbial substances! Acetone makes these bacteria on the skin thrive.
“SURVIVAL OF PATHOGENIC MICROORGANISMS ON HUMAN SKIN” (short link)
I found a second experiment from 1965 where acetone increased bacterial count in a similar way.
This establishes a clear link between acetone and bacterial growth, specifically Sa as the one that is very comfy on our skin.
Acetone and the skin
Those 2 papers applied acetone on the skin. Is the acetone really excreted through sweat when in ketosis? In the next paper they looked at skin acetone evaporation and found it in correlation with ketosis with emissions in the range of 0.00 to 2.70 ng/cm2/h in the studied patients.
With certainty we see that anti-biotic treatment works due to the case reports. Probably not any kind of anti-biotic works, depending on the type of bacteria that is triggering the PP. Although everything seems to point to Sa, it would be a good guess to start with but until there is clear proof by sampling and analysis, we can’t say this for sure.
You could also try to treat it first through sun exposure. Sun exposure makes your skin produce vitamin D3. This results in the endogenously produced anti-biotic cathelicidin.
If you are afraid of the sun or have no ability to expose your affected areas to the sun then vitamin D supplementation is also effective at increasing cathelicidin. I would recommend the sun though because this provides a much higher production of vitamin D.
After supplementation with 4000 IU/d oral vitamin D for 21 days, AD lesional skin showed a statistically significant increase in cathelicidin expression from a median of 3.53 relative copy units (RCU) before supplementation to a median of 23.91 RCU postsupplementation
It counteracts the biofilm that the bacteria produce to protect themselves. This biofilm has also been linked with impeded wound healing.
The helical human cathelicidin LL-37 was tested against S. aureus, and was found to exhibit effective anti-microbial, anti-attachment as well as anti-biofilm activity at concentrations in the low μg/ml range.
I’ve also scanned a few fora to see what people have tried and found helpful. They are listed here if I could find a reasonable link with either acetone or the bacteria since those 2 components are for sure involved.
As blood ketones go higher, the correlation with acetone seems to change in such a way that there is a higher increment in acetone. This study but also others I’ve seen indicate this. But the correlation doesn’t matter so much. Important to know is that as BHB goes up, so does acetone. So if you are affected, you could reduce your BHB levels while treating the bacterial issue or temporarily get off the ketogenic diet completely. You can still go low carb but just not in the ketogenic state.
With this piece of information I hope whoever is effected now has a good idea what to do. If all turns out to be correct then first of all you are dealing with a bacterial infection in the skin. That is priority one to resolve.
Secondly, you are probably short in vitamin D. So get sun exposure or at least supplement.
You could combine vitamin D with anti-biotic treatment to get the best result.
If all else fails then there is always the possibility to reduce the ketone production but that doesn’t help you get rid of the bacterial infection.
After writing about the liver buffers I wanted to understand a bit more on the regulation of gluconeogenesis and buildup of the resulting glucose as glycogen in the liver. I have also written about protein being a supply-driven process with the mechanism intended to increase liver glycogen storage.
In order for that supply-driven mechanism to be true we have to have a closer look and see how gluconeogenesis (GNG), glycogenesis and glycogenolysis are controlled.
The reason why I want to have a closer look at it is because one of the fundamental conclusions, if my interpretation within the above linked articles is right, is that glucagon-driven GNG continues while insulin-driven build-up of glycogen takes place. These 2 processes have to be running side-by-side.
We will look at 3 specific elements in these pathways: phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GCK) and glucose-6-phosphatase (G6Pase).
PEPCK – There is a cytosolic version and a mitochondrial version. PEPCK diverts energy substrates away from being metabolised towards forming glucose. It is an important factor in creating new glucose from different substrates such as glycerol, amino acids and lactate.
GCK – Glucokinase is the enzyme that converts available glucose into glucose-6-phosphate (G6P). G6P is an intermediate step between glucose and glycogen so it can go either way, depending on which process has the upper hand.
G6Pase – This enzyme causes the release of glucose out of the liver. When glycogen gets broken down into glucose-6-phosphate (G6P), G6Pase will further convert it to glucose, allowing it to be released.
Although some papers link G6Pase regulation to AMPK, it could still be that it is concentration dependent such that when G6P levels rise, so will G6Pase to clear out G6P as glucose from the liver.
I do not agree with the paper that a reduction in G6Pase leads to GNG. What I often see as a mistake is that GNG is equaled to hepatic glucose output. This can be true under multiple days of fasting but this is not applicable all the time showing that hepatic glucose output depends on other factors as well.
But those are details that will not make much difference for us…
What I do want to point out is that G6Pase is responsible for G6P conversion to glucose. You could say this is GNG but I want to make a distinction because there are to my view 2 different processes. 1) glycogen breakdown 2) conversion of substrates (amino acids, lactate, glycerol) into glucose. Otherwise we have to consider the breakup of starch into single glucose molecules also as GNG. The neo in gluconeogenesis means new and genesis refers to creating. Are we creating new glucose from glycogen? No
Why is this important? Because both processes are separately controlled as I intend to show with this article. But it is good to keep in mind that both GNG and glycogen breakdown can result in glucose output from the liver. Glucose output however does not say anything about which of the processes is producing the glucose. For that we need to have a broader look.
If I’m right about the mechanisms on the liver buffer and supply-driven protein GNG then these enzymes are individually and differently controlled via insulin and glucagon.
As a starter I would recommend you to watch this presentation to understand how diet affects the secretion of insulin and glucagon. Skip the first 30 minutes or so, it was a live recording with static image at the beginning.
I’ll summarize with a screenshot from the video below.
When eating protein, GIP is released from the intestines. When the amino acids reach the alpha cell, together with GIP they stimulate glucagon release.
When eating glucose, GIP is released from the intestines. When the glucose reaches the beta cell, together with GIP they stimulate insulin release.
When eating protein and glucose, GIP is released from the intestines. When the amino acids reach the alpha cell, together with GIP they stimulate glucagon release. When the glucose andglucagon together with GIP reaches the beta cell, it will be stimulated to release more insulin than when only stimulated by GIP and glucose.
When GIP is not secreted for example due to IV feeding then glucagon and insulin will be stimulated only a little bit.
So in a simplistic way: dietary protein ups glucagon secretion, dietary glucose ups insulin secretion, dietary protein and glucose ups glucagon secretion and double up insulin secretion.
OK, with the above in mind let’s now have a look at how these hormones influence PEPCK, GCK and G6Pase.
Both PEPCK and G6Pase are stated to be downregulated under strong insulin secretion (which also negatively regulates glucagon secretion) but what I specifically want to know is what happens under high glucagon and moderately elevated insulin which is more close to the low carb diet situation. My theory is that PEPCK at most will be weakly inhibited so that GNG still continues and G6Pase strongly inhibited so that glycogen buildup remains very active. So active GNG with active glycogenesis leading to liver glycogen increase.
the spike of postprandial insulin secretion will rapidly inhibit glucagon secretion and expression of PEPCK and G6Pase to reduce hepatic glucose output, as well as stimulate expression of glucokinase to promote storage of ingested food as glycogen.
PEPCK (creating new glucose) – The first paper referenced tells us that PEPCK is stimulated by glucagon but is dominantly inhibited by insulin.
So G6Pase cannot even be produced under influence of insulin which means that turning the G6P into glucose is inhibited. This is maximizing the buildup of G6P for conversion to glycogen because GCK is enhanced.
So the question really comes down to PEPCK. By how much does insulin affect PEPCK? This is hard to establish because PEPCK is not just inhibited by insulin, it is also increasingly expressed by glucagon.
This makes in vitro studies difficult to interpret but I managed to find one where they got pretty close to what I’m looking for. Here’s one where they measured the effect of insulin and cAMP. Glucagon stimulates PEPCK through cAMP so it is our proxy for glucagon. Also note that the study was done on rat hepatocytes so human mileage may vary.
Without stimulation of PEPCK by cAMP we see a strong effect of insulin on the suppression. 1nM is 1000pM.
Next we see that under cAMP activation, the level of synthesis is still up while under suppression of insulin. This time the insulin was 5nM. A 5-fold increase versus the strong inhibition already seen under 1nM but without cAMP stimulation.
Note also the additive effect of dexamethasone, a glucocorticosteroid.
The insulin side represents 5nM which is equivalent to a serum level of 720 mIU/L. To give you an idea, on my blood panel the upper range for fasted insulin is around 25 mIU/L. 0.2nM would be 29mIU/L which is close to the upper range for fasting and 1nM would equal around 144mIU/L.
In a study of obese people we get to see their insulin response to a diet with 15% protein, 65% carbohydrate. In the worst case it gets to around 90mIU/L. An other reason I wanted to reference this paper is because they also tested a high frequency-high protein diet (45% protein, 35% carbohydrate). It is not the same as our really low carb high protein but it gives an idea about the trend. It is hard to see from the graph but the insulin response is around 55mIU/L.
What this means is that even though insulin has an inhibiting effect on PEPCK, the level of insulin that needs to be reached to have a dramatic effect is quite high.
The level of insulin rise that we can expect on a high protein low carb diet is not sufficient to have a severe oppressive effect. According to our in vitro study,
PEPCK is also further controlled by glucose but for this glucose levels have to rise. I will ignore this part because glucose is generally well controlled under low carb. Even when protein is converted to glucose thanks to diverting the glucose to glycogen.
In this chinese study they tested a high fat, high carb and high protein meal and response. You can ignore the red line as these were obese. The idea is to have a look at the insulin sensitive people (blue line) and see what happens to their glucose and insulin.
As you can see in this study, the high protein meal has the best glycemic control. People would think that it is because the resulting amino acids are only converted to glucose on a demand basis. But if that would be true, there would be no reason to react with the highest insulin response compared to the other meals. The 2500% increase would mean that a fasting insulin level of 9mIU/L would go up to 225mIU/L. Such high increase is to be expected because the meals were liquid drinks which cause rapid absorption.
Did you watch the video on incretin a bit further up? Then you understand that as the amino acids start to stimulate glucagon, glucose levels are ramping up. GIP in the circulation together with glucagon and a rise in glucose will start to stimulate insulin production. So even protein, in isolation from glucose (carbohydrates) will also trigger insulin together with the insulin-stimulating amino acids.
If you read my article on insulin resistance then you will also understand that under a low carb high protein, the type of insulin resistance is the one that is still responsive to insulin. This is a good thing as you’ll see below.
With this deeper dive into the regulating mechanisms I’m now firmly convinced that dietary protein are partially converted to glucose and stored in the liver under a supply-driven mechanism.
The dietary glucagon-stimulating amino acids raise PEPCK so glucose production goes up. Normally that would also result in a higher glycolysis but in order to control blood glucose, insulin goes up (also in part stimulated by some of the amino acids from the dietary protein). Insulin has a much stronger counter-regulatory effect on glycolysis and a strong up-regulating effect on GCK effectively stopping the breakdown of glycogen and increasing the buildup of glycogen.
The modest rise in insulin (on a very low carb and certainly on zero carb diet) is not sufficient to counter the effect of glucagon on PEPCK so that any substrate, including glucogenic amino acids, are converted to glucose at a higher rate.
Some of the amino acids will end up in the cells, stimulating protein synthesis via mTOR so obviously not all of them get converted to glucose. It is simply a matter of substrate availability aka supply.
There is nothing wrong with this supply-driven conversion of amino acids to glucose. It likely helped our ancestors to survive as it protected them from muscle catabolism.
This is even more so important for lean individuals if they are unable to obtain sufficient fat to generate ketones. The ketones (BHB) would compensate for shortage of glucose.
Not enough fat? That means lower ketones thus more protein (muscle) catabolism to obtain glucose. The brain must have its energy. Being able to convert and store dietary amino acids helps to secure a supply of glucose for the brain without having to break down protein in the body.
As a short recap of my article on the liver buffer, insulin causes the build-up of glycogen in the liver. When I looked into protein and fructose, I touched the topic of protein protection for the first time.
With this article I wanted to go a bit deeper into this aspect and do this by looking at various diseases showing the link between your glycogen level in the liver and the protein protection that it provides.
We can have a look at a number of conditions but lets first look at an opposite condition to illustrate the interplay between hepatic glucose production and insulin.
NOTE: when the mechanisms are explained below, activity going up or down is not like an on/off switch. It means statistically different enough to note an effect but it doesn’t always mean that for example going down means reducing with 70% or 80% although that can be the case sometimes.
Glycogen Storage Disease (GSD)
Glycogen Storage Disease type 1 is a failure to break down glycogen into glucose resulting in a high glycogen buffer. Insulin still does its job and pushes the conversion of glucose to glycogen when feeding. When fasted, insulin goes down to let glucose come out of the liver but there isn’t much coming out in case of GSD1.
Type 1 of GSD is where G6P (G6P is the step to or from glycogen) cannot be converted to glucose by the enzyme GSPase. As a result we get hypoglycemia. Without a need for insulin to reduce hepatic glucose output, this disease presents itself in all forms possible that result from low insulin levels, including muscle weakness due to catabolism. I’m pointing out muscle weakness because one of the roles that will come back over and over again is that if blood glucose levels cannot be maintained then muscle protein is broken down unless the lack of glucose is compensated somehow with another protective factor.
Affected individuals usually present in the first year of life with severe fasting hypoglycemia, hepatomegaly, failure to thrive, growth retardation, and developmental delay. Other common findings related to hypoglycemia include sweating, irritability, muscle weakness, drowsiness, and seizures.
There are 2 ways in which IR can establish itself although both lead to lowered glucose absorption. This is explained in my article on insulin resistance in more detail but to recap… Either 1) fat builds up in the cell and it takes down the insulin receptor so insulin has no signaling effect in the cell or 2) low levels of insulin cause low stimulation through the insulin receptor. Both lower GLUT4 expression, causing lowered glucose uptake.
The first case is a problem that cannot be resolved until the fat is cleared. The second one resolves itself simply by releasing insulin. In this section I’ll be referring to the first case when talking about IR, the problematic case.
How can you get fat build up in the liver to cause IR? There are 2 possible ways.
A first one is high fructose containing drink. This causes a fast accumulation of fructose in the liver which gets mostly converted to fat.
A second one is to combine glucose with fat and some protein in a meal. The protein and glucose together will drive up insulin to very high levels. Insulin breaks down the ApoB protein in the liver so the circulating lipids from the meal that reach the liver get stored in the liver and are unable to go out until insulin goes down again and ApoB can start exporting the fat.
Both cases will lead to IR due to accumulating fat. What sets them apart is that the second one is usually happening only at dinner. The first one is happening every time a liquid is taken in which combines glucose with fructose, in other words sugary drinks. Sugary cereals with milk, orange juice, sugar sweetened beverages are all examples of liquids that will feed glucose and fructose into the body with fast supply of fructose to the liver. For most people this will happen during breakfast, lunch and any time in between and towards dinner and even after dinner.
The frequency by which the process of liver fat accumulation is repeated and the volume of fat that is generated is important to establish IR.
Now that we know a bit more on what causes IR, we can get back to the question. Does it also lead to the depletion of glycogen over time and thus muscle atrophy?
A key enzyme in the breakdown of glycogen and output of glucose from the liver is G6Pase which converts G6P to glucose. G6Pase is depending on absence of insulin.
Although not heavily activated, it is more active than expected given the level of insulin that is present in the circulation under IR conditions.
However, the normal activity is inappropriate for the prevailing hyperinsulinemia, indicating predominant hepatic insulin resistance. Thus, sustained G6Pase activity opposes GK (glucokinase) and limits the capacity of the liver to take up glucose
So we see that the glycogen breakdown is not interrupted by insulin while insulin normally does have that effect.
The quote mentioned glucokinase (GK). This enzyme is responsible for converting glucose into G6P. GK activity is driven by insulin. Also here, without insulin signaling, GK goes down. Putting the 2 together, the newly created glucose will be converted to glycogen at a lower rate and the glycogen breakdown will not fully stop under hyperinsulinemia.
What I get from the article is that the flux of the glycogen buffer normally would get depleted. But.. depending on the severity (level and length of time) of the hyperinsulinemia and hyperglycemia, it may still result in a net increase although not as much as would be expected under these severe conditions.
With the above info we don’t necessarily expect a loss of protein protection but… Just to briefly touch on this point because it is not about the liver… with the hyperinsulinemia that is associated with liver IR you would expect that this is actually very protective for skeletal muscle. High and prolonged insulin levels right? This may be true in an original phase but IR also establishes itself in the muscle. IR in the muscle further exaggerates the hyperinsulinemia and by not responding to the insulin signaling, the protective effect on skeletal muscle atrophy is uplifted. So as IR worsens in both the liver and skeletal muscle, the hyperinsulinemia and hyperglycemia worsen.
Another scenario we can look at is T1D where insulin production is impaired. When T1D goes untreated, it leads to protein/muscle catabolism. In part this is caused by the lack of insulin which would normally stimulate/protect the skeletal muscle but the role of insulin is 2-fold. When liver glycogen is high, low insulin would lead to a higher glucose output. In order to control this, insulin will raise to maintain homeostatic blood glucose levels.
If the liver glycogen goes down, so will the insulin level. This will gradually uplift the protective effect on skeletal muscle (unless compensated by sufficient BHB). So liver glycogen level and skeletal muscle breakdown are connected through insulin.
High or low liver glycogen, in our T1D case we have insufficient insulin without exogenous insulin supply.
Although I’ve already written about GNG being a supply driven process, afterwards I found another study showing that a mixed amino acid intake increased glucagon as expected. The resulting hyperglucagonemia caused a reduction of more than 50% in glucogenic amino acids. Glucagon stimulates GNG and GNG is not selective on substrates. Whatever can be converted to glucose will be converted to glucose. This is to highlight again the importance of refilling the liver glycogen buffer.
T1 diabetics know they have to compensate for protein in the meal. Without sufficient insulin, the newly created glucose goes out the liver, rising blood glucose. A specific study has been highlighted in the demand or supply article I wrote earlier.
The liver glycogen buffer is very important to prevent protein breakdown. We see that in an overnight fast, T1D already have just 2/3rd of liver glycogen left compared to controls. Their lack of insulin to regulate blood glucose causes a faster depletion of liver glycogen.
This is a very difficult situation because without insulin you can’t drive up the glycogen in the liver. Unless handled through insulin administration, this situation can be partially resolved by providing sufficient gluconeogenic substrates and high fat to increase BHB. Overnight fasts will lead to catabolism for T1Ds.
If there is no action of insulin on the liver, the glycogen storage goes down. This is not a case of IR but it is a case where there is no signaling effect triggered by insulin.
It mimics low carb diets whereby the diet itself keeps insulin low in a natural way.
If you read my article on the liver buffers and also the article on protein and fructose then you understand that the glycogen buffer is there to protect protein catabolism as I’ve also showed in this article.
In order to stimulate mice to overeat, it is sufficient to reduce the carbs in their diet and replace it with fat. This way they have to increase their food intake. The carbs directly provide protection by safeguarding basal glucose while the fat doesn’t. In order for the fat to provide protection, it has to be converted to BHB first, which mice are not good at.
In a mouse model where more protein is diverted to liver glycogen, we see that the mice do not become obese on the usual high fat (high carb) chow. The model results in higher liver glycogen levels thus no reason to overeat.
Could we have a similar satiety effect with hepatic IR? It is unlikely as it should lead to low glucose levels and we’ve already seen above that IR is associated with high glucose levels.
IR is also characterized by its inability to regulate glucagon secretion in the pancreas leading to higher circulating glucose because there is no response to insulin to store it in the liver and glucagon is responsible for GNG + glycogenolysis, putting out glucose from the liver.
There are many mechanisms through which hunger can be stimulated. A lowered blood glucose could be a direct contributor. However, our mouse example is opposite to the situation in IR where we have elevated glucose.
Insulin = survival
Our evolution has been driven through survival of the best fit. As such, probably nobody will argue that insulin has helped us to survive by storing energy. But most people will only think about storing fat.
After looking into the glycogen buffer, I consider insulin equally as important for survival by regulating replenishment of the liver glycogen. This buffer is not just to supply energy for the brain but by building up the buffer, it also helps to delay the need for protein breakdown.
Some say that we adapted to tolerate carbohydrates. I view carbohydrates as a (not so good) alternative to protein. Normally our liver glycogen buffer would be replenished through meat intake as I’ve shown in the article on supply versus demand.
With meat intake we had both a source for glucose and fat from the animals. With a reduction in meat intake, it became crucial to find an alternative source for glucose because we could not get enough fat and meat so without an alternative, our body protein would be degraded to provide energy to the brain.
This is not to say that protein is only used for the liver glycogen, of course not. No, but what I am saying is that as important as dietary protein is for building/maintaining protein in the body, equally important is its conversion to glycogen to maintain a longer survival.
For those who don’t know, LMHR stands for Lean Mass Hyper Responder and refers to the lipid profile of people who achieve high LDL cholesterol, high HDL cholesterol and low triglycerides. Hyper responder refers to the high LDL that is achieved and lean mass because most of these people appear to have low body fat.
LDL of 200 mg/dL (5.17 mmol/L) or higher
HDL of 80 mg/dL (2.07 mmol/L) or higher
Triglycerides of 70 mg/dL (0.79 mmol/L) or lower
I have written about LDL cholesterol before (r/ketoscience LDL wiki ; cholesterol or BHB) and why it raises for these people. In a recent article on the liver buffers I touched upon the mechanisms but I want to take a more extensive dive with a specific focus for these LMHRs and why they are able to go that high on LDL.
I will not provide references to scientific publications unless I found something new. If you would like to check on the concepts explained for which there is no reference then please refer to the previous articles mentioned.
The main reason to do this dive is because the high LDL is the effect of how things change over time and under which conditions. This is usually the most difficult thing to grasp for people compared to a simple on/off result. As already shown in the article on the liver buffers, there are different situations leading to different results.
So what ticks the boxes for the LMHR?
I’ve come to conclude that the main aspects that drive the levels are:
The production of ApoB100 lipoprotein by the liver
The clearance of ApoB100 lipoprotein by the liver
It seems obvious but there are plenty of other factors that contribute to the exact level but these 2 are the major ones. The control of these 2 elements is done via the hormones glucagon and insulin.
Let’s first explain what insulin does for LDL cholesterol and also why tests in humans may derail people to the wrong conclusions.
ApoB100 is produced in the liver. It loads up fatty acids and cholesterol and leaves the liver in the range of VLDL to LDL. Under high insulin stimulation, ApoB100 is broken down and cholesterol production is up.
As insulin starts to lower, it allows the ApoB100 production to go up. This is what has led researchers to state that with dropping insulin you get a faster ApoB100 production and this is true for a while.
However, the ApoB100 production is not only depending on low insulin. It is also depending primarily on fatty acid access under this low insulin situation. The low insulin will cause a clearance of the stored fatty acids but as the level of this storage goes down, so will the ApoB100 production.
So although lean, healthy subjects on a high carb diet have a higher ApoB100 production.. LMHR’s are on a ketogenic diet. They don’t stimulate insulin nearly as high as on a high carb diet which causes less of the fat being backed up in the liver.
LMHR’s have low hepatic fatty acid availability and low ApoB100 production.
If there are not sufficient fatty acids, ApoB100 gets broken down again until sufficient fatty acids are collected. With a cleared fatty acid buffer, the main source of fatty acids will have to come from the circulation.
In that case there are 3 sources of lipids for the liver. 1) Dietary fatty acids ; 2) albumin-bound fatty acids ; 3) ApoB100 lipoprotein uptake containing fatty acids.
We’ll look at dietary fatty acids later on. Albumin will be ignored for now so let’s check out the uptake of ApoB100.
The way that LDL cholesterol gets cleared by the liver is through the LDL receptor. This receptor is expressed depending on PCSK9. PCSK9 binds to the receptor and degrades it, lowering the LDL cholesterol clearance. This is also how PCSK9 inhibitors work and they do that very efficiently.
Yet the role that insulin plays on PCSK9 expression needs to be clarified. We find increased expression by insulin and reduced up to 80% by fasting. With reduced PCSK9 under low insulin we get a higher clearance. But PCSK9 is not the dominant factor.
If anything, insulin is at its lowest under fasting conditions so what is causing the LDL receptor to go down and is that applicable to our LMHR profile who are not fasting?
Free T3 (fT3) entering to the scene… It is anecdotal but many of the LMHR’s report hypothyroid symptoms. Good indicators are easily feeling cold at hands and feet and a dry skin.
We find a very good study showing correlation between fat mass and circulating T3 in 941 non-obese healthy men, cleared from any known underlying confounders.
Leptin is a stimulator of the thyroid and leptin production depends on the available fat mass. With 15kg of fat mass in the lowest quartile, these individuals are not yet as lean as in our LMHR. For me personally, at 75kg and +/- 12% body fat I have about 9kg body fat, 40% less than that lowest group. Notice the increasing drop in fat mass as you go from the highest to lowest FT3 quartile with an equal but stronger drop in leptin.
Also note that lean mass is inversely correlated (see article). Our body is able to sense energy availability according to energy demand. Lean mass = energy demand ; fat mass = energy availability. The balance between the 2 determines energy conservation or wasting via fT3 regulation.
Taking this information together, the LDL receptor is expressed according to the following situation:
NOTEabout the graph: Insulin represents the effect of a meal intake. It is much more amplified due to meal ingestion. fT3 has a slower change and the line here represents fasting levels across a longer time frame in which you get leaner.
We can expect insulin to be the most dominant at all levels to ensure storage. Energy storage/conservation has the highest priority. Reducing the LDL receptor to avoid losing energy via hepatic clearance fits into this narative.
As insulin clears and does not dominate anymore, your T3 state becomes the dominant factor in LDL receptor expression.
LMHR’s have low insulin and low fT3 (resulting from the balance between fat mass & lean mass).
Not only does fT3 influence the LDL receptor expression, it also influences the binding affinity of LDL to the LDL receptor. High ft3 results in a stronger binding and uptake thus we see in the LMHR a reduction in binding affinity resulting in an additive lowered clearance.
We addressed point 3 (1. Dietary fatty acids ; 2. albumin-bound fatty acids ; 3. ApoB100 lipoprotein uptake containing fatty acids) with the LDL receptor. Now let’s have a look at point 2.
As mentioned, fT3 is the regulator for energy expenditure. With low fT3 the body wants to conserve energery. fT3 influences lipolysis. A reduction of fT3 will lead to lowered lipolysis and with lowered lipolysis we have a reduction in non-esterified fatty acids or free fatty acids.
A determining effect is the low fT3 but this has further reaching consequences. fT3 also influences the lipolysis in the fat cells.
Normally with dropping glucose and insulin, there will be a higher rate of lipolysis leading to the liberation of more fat, shifting energy metabolism from glucose to fat. Yet, also here we have a similar effect as with the LDL receptor. Insulin is the storage agent, as insulin goes down, lipolysis will go up. fT3 however determines the rate of lipolysis when insulin is down. As such, becoming more and more lean, fT3 will go down and so will lipolysis.
To further showcase fT3’s action on energy, the reduction in heat generation when having low fT3 status is in part because fT3 is involved in the UCP1 mediated heat generation. This is the uncoupled metabolism which essentially means wasting energy to generate heat. fT3 amplifies this effect around 4-fold in rats. With a reduction in ft3 there is less heat generated.
LMHR’s have lower circulating fatty acids due to lower lipolysis (versus non-lean mass subjects on a low-carb diet)
This already makes it difficult to generate cholesterol but also to generate ketones.
With point 2 and 3 covered we can now look at point 1 (1. Dietary fatty acids ; 2. albumin-bound fatty acids ; 3. ApoB100 lipoprotein uptake containing fatty acids)
So far we have looked at the state of our LMHR. We’ve identified low ApoB100 production and low clearance. So how do we get high LDL numbers out of it?
This comes down to the effect of a pulsatile production without an equal compensation in clearance. With each meal, the stimulation of production is greater than the stimulation in clearance.
On a low-carb diet, the stimulation in insulin is much lower than a high carb diet. Yet enough to load up the liver with fatty acids resulting from the left-over chylomicrons that are circulating from the fatty meal.
Keep in mind now that we are looking at a profile with low fT3 thus already lowered LDL receptors. Insulin, stimulated by the meal, will also clear the LDL receptors. Now as insulin weans off, the LDL receptors increase again in expression but not as much as for a person with higher ft3.
The production however is depending on that time frame in which fatty acid availability was increased post-absorption. Due to the high fat content of the meal, more fat is obtained in the liver for subsequent ApoB100 release into circulation.
This production is greater than the clearance.
Anecdotally we hear from LMHR’s that when they go on a carnivore diet, they see their LDL cholesterol go even higher. This is where you have to understand the role of incretins.
You can go through the following video to understand the effects (skip the first 30 minutes because it is static image):
The carnivore diet for most people will result in a higher intake of protein. This protein contains amino acids which both increase glucagon and insulin secretion. The increase in glucagon will stimulate more GNG. Normally this would lead to elevating glucose levels but that doesn’t happen because insulin increases as well to maintain homeostasis and storage.
When you watched the above video you’ll understand why that is. The effect won’t be as strong as when you combine carbohydrates with the meal but the level of protein intake does make a difference.
So a carnivore diet will result in a higher insulin stimulation. This results in more fat storage from the diet in the liver. As a consequence, post-absorption and with insulin going down, we’ll have more fat stored in the liver to generate and release more ApoB100 lipoprotein.
So the pulsation on a carnivore diet is stronger the more you take in protein with fat. There will be a maximum point because you can’t keep the fat intake high while continuing to increase protein intake and it’s the fat availability that will lead to higher LDL cholesterol.
Other clearance factors
If there were no other clearance factors then we would be facing an ever increasing level of LDL.
I won’t go into detail here as I mainly wanted to focus on the liver side but note that the skeletal muscle is also a great clearing site of LDL lipoprotein.
With that I hope you enjoyed reading this article and gained some more insights into why the LDL cholesterol goes up on a low carb diet for people who are lean.
In the introduction on vaccination there were a couple of questions raised to delve deeper into. In this post we’ll have a look at the following question:
Do vaccines get tested for safety in the same (rigorous) way as other drugs?
So we need to look at how drugs are tested in general and then see for evidence if vaccines undergo the same protocol. If they are not, we’ll have to address the question if they need to and if their different protocol is adequate.
When creating drugs, 2 things are important. 1) Are they effective? 2) If any, what are the side effects? The latter is equally important. You don’t want to cure a person of a disease and at the same time cause the person to die from something else due to the drug.
With vaccines this is even more important because we need to evaluate preventively administering a drug. How many people are we able to protect versus how many people are we harming and to what extend are we harming them?
Drug development goes through several phases with a pre-clinical phase where lots of tests are done in petri dishes and in animals. This approach is intended for addressing the efficacy and safety of the drug and takes many year. Up to +/- 15 years on average and a good 1 billion dollar according to the reference on wikipedia.
But there are differences between vaccine development and chemical drug development. I found the following list worth mentioning as it addresses the safety level and complexity.
The following differences from drug development mandates special precautions while conducting vaccine clinical trials in a pediatric population:[2,3]
Unlike drugs, which are given to patients, vaccines are received by healthy individuals, thus the safety margin should be very high.
As vaccines have to be stored under refrigeration, there are always logistical challenges during clinical trials considering that Phase II and Phase III are field studies.
As healthy children also receive immunization under the national program, the trial design gets complicated due to the possibility of interference during coimmunization.
The clinical development for vaccines for infants involves a step-down approach where safety is first tested in adults, followed by adolescents, children, and lastly infants.
Adjuvants are incorporated into vaccine formulations to modulate and improve the immune response. The compatibility of the adjuvant with the vaccine antigen and the quality and stability evaluation of antigen/adjuvant formulation are important aspects of clinical development.
The immune response primarily measured during early stages of vaccine development (Phase I/II) should evaluate: Amount, class, subclass, and function of each specific antibody.
Relationship between functional and nonfunctional antibody assays.
Kinetics of immune response such as lag time for onset, antibody persistence, seroconversion rate, and induction of immune memory.
Components of the immune response according to mode of delivery [whether immunoglobulin A (IgA) or immunoglobulin G (IgG)].
Quality of the antibody response: Specificity and/or epitope recognition and avidity.
Potential for formation of cross-reactive antibodies or immune complexes.
Immunological factors that might affect the humoral immune response as preexisting antibodies (including maternal antibodies).
Cell-mediated immune (CMI) response and the possibility of immune interference and/or cross-reacting immune responses when vaccines containing more than one antigen or two or more vaccines are coadministered, especially to children and young infants with immature immune systems.
With the above information it is clear that each vaccine needs to be individually assessed for safety. How did they go through this process of development?
We see that for the corona/COVID-19 virus they are able to fast-track and get it to market in 18 months. 18 months??? Because they have experience working with prototype viruses and other corona viruses like the flu.
How does that work out with the well known flu virus? It seems to be a hit or miss (1 ; 2 ; 3). Even when vaccinated, you can still get infected although they promise milder symptoms.
So how much of a hit or miss can we expect on a more different corona virus like COVID-19 where they still need to perform much more rigorous testing yet get it onto the market in 18 months? And what if the virus mutates like the flu?
The following report went through a whole list of potentially associated side effects but almost all of them were concluded with insufficient evidence to accept or reject a causal relation. Only 1 was sufficient to conclude rejection and a few were sufficient to accept causality.
If you are interested in other vaccines you can jump to all the other ones covered.
With a hit or miss and potential side effects on a virus where we have a lot of experience with, we have an insecure future with something like COVID-19. Because it is part of the corona family, it is open to recombination under mixed infection for up to 25%! Recombination means when 2 viruses get together, it can form a 3rd type. Kind of the child of the 2 original ones.
recombination frequencies within the coronavirus family have been calculated to be as high as 25% during mixed infection.
In an ideal world we are able to identify the people who are at risk.
People at risk of having side effects that are more severe than the benefit they would get from vaccination.
People at risk of having life threatening complications from the virus when not vaccinated.
The former group should not be vaccinated. The latter group should get vaccinated. Everybody else should contract the virus and build up immunity.
This has to be evaluated per vaccine. Without the ability to evaluate this, it will remain a hit or miss.
We do not need to be good at detecting safety for the general population, we need to become good at detecting people at risk. For most people the vaccine will be safe and unnecessary. We need to know those for who it is unsafe and necessary.
One of the things I noticed in studying metabolism and the overall functioning of the body, is how important the liver is. A lot of what we do and a lot of what we measure is influenced by the liver and its buffers. Understanding these buffers in conjunction with these measurements may help us a great deal in evaluating health and disease.
There is a lot of controversy on what we measure and if that is healthy or not. I think most of this controversy is created due to lack of context. As we all acknowledge, an obese Type 2 diabetic (T2D) person is vastly different from a lean athlete and numbers measured have to be interpreted accordingly. Someone on a ketogenic diet with high ketone levels (>1mmol/L) can walk around just fine with 50mg/dL glucose while someone else on a Standard American Diet (SAD) will experience hypoglycemia at 65mg/dL glucose.
It is the same with diet, a low fat high carb (LFHC) diet will stimulate hormones differently than a high fat low carb (HFLC) diet. And that difference is also there when comparing a diet high in processed foods versus whole foods etc.
My goal is to provide that context to provide you with a better understanding. Apart from sugar I will not get into processed food. Processed food is a big failure in our human history.
What are the elements that we will look at?
There are 2 main hormones (insulin and glucagon) which influence the buffers in the liver so we’ll look at what changes those hormones in various situations such as food, exercise, fasting etc.
I’ll explain what happens over time according to my current understanding. As I’m self-educated I appreciate any input and certainly to correct any misrepresentations.
We’ll have a look at how insulin and glucagon levels are modified but also the functions they stimulate or block in the liver. We’ll look at the following aspects:
gluconeogenesis (GNG): creating glucose from substrates such as lactate, glycerol, amino acids
glycolysis: breakdown of glycogen to form glucose
lipolysis: breakdown of fat (triglycerides or triacylglycerol or TAG) into free fatty acids so not bound to their glycerol backbone
ketogenesis: creating ketones, we’ll talk about beta-hydroxybutyrate (BHB) specifically
glycogenesis: converting glucose into glycogen
cholesterol: cholesterol production through ApoB100 lipoprotein (VLDL, IDL, LDL) efflux from the liver. I’ll be mentioning ApoB in the article but talking about ApoB100 specifically.
de novo lipogenesis (DNL): creating fat from glucose
de novo lipogenesis (DNL): creating fat from fructose
I listed DNL twice. That is because DNL from fructose is done without insulin playing a role. This makes an interesting combination in sugar. I will get more into it in the sugar situation below.
The buffers that we will look at are those of the glycogen (stored glucose) and lipids. A few words may be at place for why I think those buffers exist. This may help understanding the changes that we see taking place in the scenarios below.
This is our glucose reserve. The body strives to maintain a constant level of blood glucose at rest. Under different situation, it may deviate from this homeostatic level so a buffer is needed to respond to these changes. Below are a few examples on how blood glucose is regulated.
Elevate: Viral infections need to be countered with elevated glucose levels to stimulate our immune cells to proliferate. Exercise can rapidly consume glucose so more glucose must be released in order to maintain the right level.
Maintain: The brain is an energy hungry animal frequently quoted as being 2% of our body weight while consuming 20% of the energy. It requires a steady influx of energy all the time.
Suppress: During times of food deprivation we need to switch towards preferring fat so that we can spare glucose or otherwise the body will increasingly target protein sources for GNG. More on that under the fasting scenario.
The liver is also metabolically active. Depending on the situation it may be consuming more glucose or more fatty acids. Either way and no matter how it got a hold of the fat, when allowed to, it will release and clear itself of the temporarily stored fat to redistribute it across the body.
Contrary to glycogen, the liver does not try to maintain a lipid buffer. It temporarily holds lipids to enhance absorption and redistributes the lipids afterwards. It is like our adipose tissue but more of a temporary buffer that will be consumed first before switching to adipose (in a simplified way).
So let’s start with the fasted state, probably the most well known state with the least controversy.
With fasting I mean prolonged fasting. Not the time between for example lunch and dinner and also not the time between meals such as in One Meal A Day (OMAD) so multiple days without food.
GNG – Under fasting, both buffers will go down. There is no stimulation of insulin so they will drop down to their lowest level. That allows glucagon to dominate. Because glycogen levels go down, the contribution of glycogen to the blood glucose goes down as well. This means that GNG will become the highest contributor to blood glucose. So much that after 40 hours we can see GNG delivering 96% of the circulating glucose.
Lactate – With a buffer going empty, what are the substrates for GNG? At first there may be some lactate still but lactate will go down. Glucose will go down over time and is the substrate in metabolism that will generate the lactate. Glucose goes down because there is not sufficient substrate available to keep up the homeostatic level through GNG.
BHB – Depending on our available fat mass, BHB will be produced in sufficient quantity to make up for the lack of glucose. The brain is equally happy with BHB as it is with glucose. And at the same time, the glycerol from the fatty acid breakdown provides a source for GNG. But at a certain point, our fat mass will reduce too much and become insufficient to support the right level of BHB production leading to a declining BHB level and that will also be paralleled with a decline in glycerol.
Protein – If neither glucose nor BHB levels can be maintained sufficiently for the brain, protein will start to be broken down more and more to be a source for GNG. The whole system works in such a way that it tries to spare protein until it is no longer possible. The brain must continue to function and continues to consume energy.
The liver glycogen level is an important buffer for glucose but as it runs out, BHB will provide protection from protein breakdown. Fasting cannot be maintained forever (although the record of 382 days is quite long). The fat will eventually be insufficient as you get lean so gradually protein breakdown will go up to continue sourcing energy for the brain.
Ignore the bumps in the lines below, I’m a lousy drawer 😉 Also ignore the proportions. The general concept is that at the beginning glucose goes down quickly and then over a longer period gradually goes down further. BHB goes up sharply over the first few days and then over a longer period gradually will go down. Protein breakdown will gradually go up over a long period as glucose and BHB become insufficient.
But the body is clever with protein, notice there is no excess skin in the face of our 382 days record holder (check the picture via the link). Also if you look at pictures from the unfortunate concentration camp prisoners during the world war, they have no excess skin.
Cholesterol – From the moment we start fasting the liver releases the stored triglyceride. This will create an abundance of acetyl-coa so that temporarily ApoB lipoprotein output can increase. ApoB efflux increases with dropping insulin but only when it has sufficient material to load such as cholesterol and lipids. Otherwise ApoB breaks down again. The increase in glucagon will also divert those acetyl-coa towards ketone production. This means that ApoB will quickly drop because the liver can’t maintain cholesterol production due to glucagon and with the lipid buffer being cleared up, we don’t have an abundance of acetyl-coa so the majority will go out the liver as a ketone.
Fat – With the liver being cleared from its lipid storage, the fatty acids it can obtain are now coming from the circulation. This is the reason why BHB will drop over time. Our fat stores will shrink with less and less fatty acids reaching the liver.
Sugar (glucose & fructose)
Let’s review now what happens if we take in sugar or high fructose corn sirup (HFCS), both will give us a roughly equal intake of glucose and fructose. Notice the 2 arrows for glucagon, explanation follows.
Glucose – A first thing we note is that both buffers are increased. High glucose flowing in the body provides a great stimulation for insulin secretion. This will suppress glucagon release and we don’t have any other elements that would stimulate glucagon secretion.
High glucose availability under high levels of insulin will convert glucose to fatty acids. Insulin stimulates glycogenesis so glucose causes both an increase in glycogen buffer and in fatty acids but limited to the period in which insulin is elevated.
Fructose – Now keep in mind we also have fructose as part of the sugar (half glucose, half fructose). The fructose that gets absorbed into the body will be fully converted to fatty acids in the liver, increasing the lipid buffer. How much gets absorbed depends on the volume, speed and frequency of how you take in the fructose. Sugar sweetened beverages are well associated with non-alcoholic fatty liver disease (NAFLD)
What is remarkable is that frequent, fast and large enough quantities of fructose will create hepatic insulin resistance. If this influx of fructose is repeated often enough over time then the signaling of insulin to the liver starts to fail leading to more and more fatty acids export.
At some point the adipose fat cells are full and those fatty acids start to accumulate as visceral fat in and around the organs.
The pancreas is an important organ in this case because the visceral fat will make it also less and less responsive to insulin with a reduction of control on the glucagon secretion. Due to the hepatic insulin resistance and increasing glucagon, glycogenesis will reduce, GNG will increase and glycogenolysis will increase leading to higher plasma glucose and certainly high glucose spikes with subsequent sugar intake.
This is why there are 2 arrows next to glucagon. At first the increasing insulin will lower glucagon when the pancreas is still responsive but as we progress over time, insulin fails to affect glucagon secretion due to the visceral fat in the pancreas so that glucagon goes up as insulin looses its grip on the production.
ApoB – Post-prandially the liver secretion of ApoB particles will become high as insulin subsides. Because we had high insulin, cholesterol production went up, we have increased the lipids and insulin also breaks down ApoB. With insulin going down we increase ApoB production again and now have abundant cholesterol and lipids for ApoB secretion from the liver.
Cholesterol – As we build up insulin resistance over time, the ApoB secretion will increase. Cholesterol production depends on insulin signaling and is a necessary component for secretion but lipid availability is far more important. So why do we see elevated cholesterol levels? As insulin resistance builds up, the LDL receptors (LDLr) will go down which normally take out ApoB lipoprotein from the circulation. The ApoB output will be higher than the clearance resulting in a buildup.
In addition, what does get secreted doesn’t find a place anymore. With adipose tissue full, not accepting any more lipids and visceral fat already building up, the triglycerides remain in circulation longer. The lipid catabolism of the ApoB particles run at a slower rate. The result is elevating cholesterol and triglycerides.
BHB – I’m missing some clear data but I suspect that over time, if this situation continues then BHB production will go up slightly due to glucagon secretion increasing and liver response to insulin decreasing. With glucose available in abundance, probably acetyl-coa will become available in abundance in the liver mitochondria allowing some to escape into the ketogenic pathway. This situation is also recognized in the literature by case reports of ketoacidosis in T2D patients. Below is a review referenced.
As the situation gets worse and worse, also the insulin secretion by the pancreas may become impaired. This leads to further increase of glucose release from the liver. You could think with all this glucose output and VLDL output that the liver becomes depleted but keep in mind we are talking about continuous repeated intake of sugar. This is a situation that builds up over several years and is now a problem that even our children are affected with.
The system works out in such a way that as the liver reaches the maximum or is at the maximum of its buffer and there is an overflow to the rest of the organs, glucagon is increasingly elevated and insulin, although increased at first due to the insulin resistance, will go down. This allows a maximum clearance of the liver but by continuing the sugar intake, it will continue to fail.
Notice how I covered the risk factors (obesity, insulin resistance, hypertriglyceridaemia) in the reference below. Yet the driving force sugar,as explained in this scenario, is not mentioned.
What happens during and post exercise? There is a lot going on but I’ll try and stick close to the liver as much as possible.
We see that exercise is somewhat similar to fasting but the difference in activity causes different reactions.
Glucose – First of all exercise will increase the consumption of glucose leading to an initial drop of plasma glucose. This will lead to a lowering of insulin and an increase in glucagon. Unlike fasting across multiple days, we exercise for only a few hours. For most people this means we start will a decently filled glycogen buffer so we start in a situation where glucose homeostasis can be maintained for a while. This allows to bring up the glucose level as the hepatic glucose output is increased in response to the exercise.
From the moment we stop exercising, glucose levels will shoot up for a while above homeostatic level. This will be corrected in the next minutes to a few hours by a slight increase in insulin so that glucagon goes down and hepatic release of glucose goes down.
BHB – During exercise fatty acids will be increasingly released from adipose tissue but this will be picked up directly by albumin and delivered to the muscles. Blood flow to the liver is reduced so we don’t see much fluctuation in BHB. It will depend on the duration and intensity. As we progress in our endurance activity, more fat will be released so there is a chance of small increase in BHB during the activity.
But certainly, from the moment we stop exercising, just like with glucose, the fatty acids release from adipose will go down only gradually so we are in a situation where blood flow to the liver has been restored, the blood is more saturated with fatty acids and glucose levels in the liver went down. We have insulin lowered and glucagon increased. An ideal situation to produce ketones so we see levels of BHB go up right after exercise.
Cholesterol – Here I’m in doubt because most research looks at the prolonged effect of exercise on lipids or the before and after effect but I want to know during exercise itself.
I would need to find tracer studies but lets go by the mechanisms that we know. Insulin lower and glucagon higher. This promotes higher ApoB production but ApoB export depends on the ability to assemble cholesterol and fatty acids onto it. I suspect that the cholesterol production is down during exercise thus VLDL and LDL output may go down.
It really depends on the state of the buffers. If the lipid level in the liver is sufficiently high then some cholesterol synthesis may be going on. On the other hand, if the lipid buffer is fairly low, the total volume of available lipids could be low. The main source of lipids will be from the circulation. An obese person is more likely to have higher liver fat and adipose fat while a lean person is more likely to have low liver fat and low adipose fat.
For the lean person it will rather follow the path of ketogenesis while for the obese person it will be shifted more to cholesterol synthesis but at a reduced rate depending on the state of insulin resistance and liver glycogen level. As I said, context matters 😉
We see that in the study from Jeff Volek, et al. where, over time during the exercise, BHB production goes up. Both groups are fat adapted but the LCD group has lower glycogen levels due to the diet and a higher lipolysis rate. Note that these athletes received a recovery drink at the end of their run so the graphs will be different from mine. Context again.
For the diet I want to present 2 relatively extreme sides. We have the currently general recommended a High Carb Low Fat diet (HCLF), and a High Fat Zero Carb diet (HFZC) such as the ketogenic diet. The ketogenic diet does allow for some carbs but for simplicity I’ll consider the situation of zero carbs.
I won’t consider fructose intake here. Most of the fructose comes in the form of sugar and as stated at the beginning, I don’t consider processed food. Diet should at least be whole food and 1 or 2 pieces of fruit will not have the same impact as pure sugar.
Glucose – With fructose mostly excluded, a high carb diet will primarily bring in glucose as energy so we get an increase as the meal gets digested. As we’ve seen under the sugar scenario, this triggers insulin resulting in increase of glycogen and a smaller part ends up as saturated fatty acids (palmitic acid). How much will depend on the volume of glucose and level of insulin.
Insulin resistance will not establish itself unless perhaps if we start overfeeding on starch rich food on regular basis. This may be induced in part by the dip in glucose levels as insulin starts to push down glucose. After the food intake all other processes will proceed as normal.
Blood glucose levels will be maintained.
BHB – BHB remains suppressed because insulin brought down glucagon, lipolysis and upped the glycogen buffer. Post-absorptive, insulin goes down again restoring glucagon and lipolysis but the glycogen buffer now provides glucose into the liver mitochondria causing the TCA cycle to run at a high enough speed so that there is no excess acetyl-coa for ketone production.
Because the glycogen buffer is full enough, insulin will not go to its lowest level to keep glucagon under control so that there is not too much glucose released from the liver. As such, fasting insulin levels are in function of how well glucagon needs to be suppressed to prevent too much glucose release from the liver.
Cholesterol – Insulin breaks down ApoB so we get a build-up of fatty acids in the liver and an increase in cholesterol production. After a while, as insulin subsides, ApoB production goes up, which will start to clear the temporarily stored fatty acids.
Due to the increase in insulin there was also a stimulation in LDL receptors. Due to the high carb diet, the LDLr are already numerous so that the clearance rate is much higher. This allows for lower LDL values when measuring fasting in the morning.
We’ll assume a long term HFZC, not just one meal after a long period of HCLF. With carbs out of the meal we only have fat and protein.
In the fasted state before the meal, because we have a very low glycogen buffer, insulin will be very close to its lowest value possible in order to give glucagon all the power to release the glycogen that remains and stimulate GNG, trying to maintain glucose homeostasis.
Because the meal is missing carbohydrates, we’ll have only a small stimulation of insulin. Glucagon will remain high and maybe increases a bit thanks to the glucagon stimulating amino acids in the protein. There are also insulin stimulating amino acids. Due to the high fat content of the meal, the amino acids will come in at a slower rate. This will also cause a lower stimulation of both hormones so that there is a lower change in their levels.
The high amount of fat will be distributed, some in the adipose, some directly used as fuel throughout the body but also a part is taken up by the liver for later release.
Glucose – Glycogen phosphorylase (breaks down glycogen into glucose) is stimulated by glucagon and inactivated by insulin and separately glycogen synthase (creates glycogen from glucose) is stimulated by insulin. By preventing glycogen breakdown and instead stimulating glycogen creation, the only source for glucose output by the liver will be the GNG while already part of that glucose from GNG will be used for the glycogenesis. This means the glucose output from the liver goes down which would normally cause a drop in blood glucose.
Such an effect would result in hypoglycemia if it were not for the kidneys. They increase their GNG capacity under the same stimulation of glucagon aiding in the maintenance of homeostatic blood glucose levels.
BHB – The actions of insulin cause a mild buildup of glycogen and a reduction in lipolysis. This will create a temporary reduction in ketone production. As insulin reduces post-absorption, the high fat from the meal is still circulating and lipolysis picks up again creates sufficient supply to the liver to generate ketones.
Cholesterol – ApoB production is already at a very low level before the meal because the liver is as good as fully cleared from fatty acids. What comes in from the blood stream is either metabolized or used for ketone production. Very little will lead to cholesterol production. With the slight increase in insulin, ApoB production will be further prevented so more lipids are stored and cholesterol production is temporarily increased.
Insulin goes down faster after the meal compared to the high carb meal, so we get a quicker increase in ApoB production again. The fatty acids will be cleared and gradually output goes down again.
Regarding the LDLr, before the meal we are at a very low level thanks to the very low level of insulin. The meal will not provide sufficient stimulus to greatly increase the number of LDLr’s. As a result, the temporary increase in ApoB production will lead to higher levels of LDL-c while the clearance remains low.
Under normal circumstances it seems that a full liver glycogen may reduce appetite.
No matter how high or low the glycogen buffer is, insulin has a steady proportionate influence on hepatic glycogen breakdown and GNG. I’m sure there is a limit to this contribution though. As we’ve seen under fasting, glycogen breakdown can not continue forever and GNG will take the upper hand so the relative contribution shifts.
Diets come in many forms and some are keen on high protein amounts. While I agree that can be tasty, I’ve come across some material that may put a different light on what that intake means to longevity.
There are many aspects to protein and the different type of sources but I’m more interested in what protein does related to ageing and be conscious about it.
I’m not going to make recommendations on how much protein we should eat. It depends on what you want in life and I don’t know what is ideal for a specific person so this article will not tell you either. This is purely a focus on longevity.
Another aspect is health. Animal sources of protein are complete and are packed with other nutrients. This may be beneficial for health so I’m certainly not saying that protein intake in general is unhealthy. Again, the focus is on longevity.
A recently published article that triggered me to think about it is the following.
In it they checked for a lot of effects and one of the striking things is that the phosphorylated SIRT1 was reduced. What this means is that there was less active SIRT1. SIRT1 is a protein that does DNA repair. If you are not familiar with SIRT1 then I would recommend reading the book “Lifespan: Why We Age―and Why We Don’t Have To” from David Sinclair or check out his publications. You’ll find more information about it on a post I did in December last year.
To explain the concept briefly, cells either grow/proliferate or perform cell maintenance (autophagy, DNA repair). Amino acids (AA) stimulate growth through mTOR and we see that resulting in lowered DNA repair. Energy goes into one or the other, not both.
Ageing sets in due to insufficient DNA repair and reaching the limit of cell proliferation. This creates dedifferentiated cells. They don’t behave properly anymore as a specific liver cell or brain cell but becomes something of a mix, not fully functioning and responsive as it should. A senescent cell. Over time this builds up and leads to diseases of ageing/organ failure.
In this review paper they found the AAs serine, threonine and valine specifically to affect ageing and DNA damage. They also go over the mechanism of why high protein intake leads to a reduction in longevity.
Now we can’t live without eating protein, we absolutely require them. There are essential and conditionally essential AA. This means that growth will be stimulated every time we eat. Be it protein or something else like carbohydrates. The carbohydrates stimulate insulin the most and insulin is also an activator of mTOR.
The following publication found the AAs methionine, serine, threonine and phenylalanine specifically to be detrimental to life-span. Out of these, methionine, phenylalanine and threonine are essential. Serine is conditionally essential. This is not really a surprise. Non-essential AAs can be produced endogenously so essential AAs must signal mTOR activation in order to build those other AAs. mTOR is a protein that is made up of serine and threonine which explains their involvement. And I would call phenylalanine very essential, it gets incorporated into many different proteins and is also converted to an other AA called tyrosine.
One of the reasons people may survive longer into old age is suspected to be a reduced functioning of IGF-1. Many of the blue zone centenarians are shorter. Even the Okinawans are shorter than mainland Japan.
This raises an interesting question when you look at protein consumption in centenarians. Are they living long because of their protein intake or despite their protein intake? If they have reduced functioning in IGF-1 signaling then it could be despite.
If you had your genetics analyzed, you can use the following study to look up your predisposal to longevity.
“Polymorphic variants of insulin-like growth factor I (IGF-I) receptor and phosphoinositide 3-kinase genes affect IGF-I plasma levels and human longevity: cues for an evolutionarily conserved mechanism of life span control.” https://www.ncbi.nlm.nih.gov/pubmed/12843179/
If we know that AAs stimulate growth via IGF-1 then we can also expect growth to be reduced during low protein intake such as the ketogenic diet for treatment of epilepsy in children. In this case they provide protein below 80% of the recommended intake (!!!) and this is naturally affecting their normal growth.
A recent report in the Lancet also warns about high protein intake but they, rightfully, also warn about low protein intake. We just saw how that affects children. Both cases are not favorable. The warning goes to longevity but also towards health in both directions.
If you look at the conclusions in humans it is even more important to determine context. Notice how, depending on age, we get a different result with low protein.
The effect of low protein intake
Metabolic benefits of low protein intake
Aged 50 years or older: Diabetes-related mortality↓
Aged 50–65 years: All-cause mortality↓, cancer-related mortality↓, LP intake is more effective than MP or HP intake.
Aged 50–65 years: Serum IGF-1↓ in LP intake group compared to IGF-1 in the HP intake group
Aged 66 years or older: All-cause mortality↑, Cancer mortality↓ HP intake is more effective than LP intake.
Aged 66 years or older: No change in serum IGF-1 levels between LP and HP intake groups.
What it does not tell us is how we arrived in this situation. Disease, ageing builds up over time. How does that affect us at old age to determine what is good for us and what isn’t good for us? If we take a different dietary life path from the start, will we end up differently at old age so that dietary requirements are different? There is plenty of research left to do.
We all want to live a long and healthy life but I have my doubts if a high protein diet is one of the ways to get you there…
A ketogenic diet may be more favorable. Due to the high fat intake, protein can be spared and can be lowered in the diet, reducing IGF-1 stimulation and giving more time to promote DNA repair.
Research in the past and present has shown us that fat causes insulin resistance. With ketogenic diets becoming increasingly popular, many people fear for a potential negative effect by inducing this insulin resistance.
It is true that insulin resistance does appear on low carb high fat diets such as the ketogenic diet but the context is very different, the mechanism is different and as a consequence the outcome on health is different.
With this post I’ll explain those mechanisms and provide my viewpoints on the cases where it is healthy and where it is detrimental to health.
Pathological Insulin Resistance (unhealthy)
When absorbed, fructose is converted into fat in the liver. The type of fat that is created is palmitic acid (PA) and this is the same type of fat when glucose is converted to fat. What the effects are of this PA is explained under glucose but keep in mind that those effects are also applicable to fructose.
A first thing to be aware of is that fructose increases the fat accumulation in the liver. Not only by triggering the fat production but also by reducing the liver’s capability to utilize that fat. This has repercussions when we look at diacylglycerol (DAG), a form of stored fat which increases due to this effect.
“Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism.” https://www.ncbi.nlm.nih.gov/pubmed/18924245
The proposed method of action is that the increase in DAG causes a higher activation of PKCe which reduces the expression of insulin receptors 1 and 2 (IR-1 and IR-2).
The accumulation of DAG may result from a disproportionate low level of diacylglycerol acyltransferase (DGAT1) versus the increase in DAG production and potentially further exaggerated by acetyl-coa abundance which also leads to DGAT1 consumption to form TAG.
Palmitic acid (PA) is a saturated fat that lowers GLUT2 expression in the pancreas and liver leading to increased glucose levels in circulation as the liver is less responsive in the uptake of glucose and the pancreas is less stimulated to secrete insulin due to a reduced uptake of glucose.
“Dexamethasone Induces Posttranslational Degradation of GLUT2 and Inhibition of Insulin Secretion in Isolated Pancreatic Beta Cells. Comparison With the Effects of Fatty Acids” https://pubmed.ncbi.nlm.nih.gov/9013557/
Glucose is not PA right? Indeed it isn’t but large amounts of glucose stimulate insulin to such levels that de novo lipogenesis takes place. Glucose will be converted to fatty acids. When this happens, the fatty acid that is produced is PA.
We also see that PA has greater potency to induce apoptosis in liver cells. I’m not sure if this contributes to insulin resistance. What is clear is that PA interferes in the signaling cascade of insulin resulting in a deregulated response.
GLUT2 and GLUT5 are the only transporters for absorbing fructose. With PA (originating both from glucose and fructose) reducing the GLUT2 in the liver and pancreas, what are the consequences of this circulating fructose?
Some amount of the fructose is converted to glucose. The kidneys secrete part of this glucose. The muscle cells also convert some to glucose but further synthesizes it to glycogen.
Fructose does in the muscle cell what it does in the liver. It gets converted into the fatty acid PA, builds up DAG, stimulates PKCe and finally reduces the insulin receptors. The insulin receptor is needed to move GLUT4 into the cell membrane to take up glucose. Unless you do regular exercise, your muscles are now less responsive to insulin. Without the receptor they will not take up insulin from the circulation.
DAG is normally further processed into TAG which does not cause the insulin resistance. This is done by DGAT1. There is no clear data available showing why DAG would accumulate but I suspect, like in the liver, it would be the shear volume of DAG production that overwhelms the capacity to convert the DAG to TAG. As seen under fructose, synthesis of fatty acids from acetyl-coa also involves DGAT1. This could be taking place in the muscle as well.
This study looked at TAG formation using oleic acid and used 2 different concentrations. Despite a double in concentration, it did not lead to a doubling in speed of TAG formation indicating that under high DAG formation there could be a delay in processing leading to the insulin resistance effect described earlier.
My original information led me to believe that a reduction in IRS1 would not take place under a low carb diet but it does seem to be the case. It would be interesting to find out if a reduction in IRS1 can be caused by low basal insulin or if the same mechanism is taking place, a reduction due to increased intracellular fat content (DAG or TAG). On a high fat diet, the lipid droplets in myocytes increases, similar to endurance exercise.
This makes me doubt the information that IRS1 reduction would only be due to DAG or we see an equal DAG production under low carb diets. Either production or absorption from the circulation. It is also possible that DAG is produced, not by de novo lipogenesis but by the breakdown of TAG into NEFA. I’ll need further research to understand this.
I speculate (with a high degree of certainty) we will not see the same IRS1 lowering in the liver as the liver exports its fat content under low insulin. This is also indicated in the paper showing that the hepatic insulin sensitivity index is (non-statistically) even higher for the low carb group. This would make sense given that the high carb group does stimulate insulin to a higher degree. The maintained insulin sensitivity would also indicate that IRS1 doesn’t lower due to lower insulin secretion.
Furthering speculation as I understand the mechanism… This effect does entail a level of glucose sparing that is beneficial in a resting state on a LCHF diet as general glucose availability is lowered. This implies that insulin resistance under low insulin can’t be seen as problematic and it is only localized to skeletal muscle tissue. There is not a problem disposing glucose since glucose levels are well maintained and the liver maintains its sensitivity. OGTT will be worse though since less can be absorbed by the skeletal muscle under resting conditions.
As you will see further down, exercise does move GLUT4 to the cell membrane which overcomes the insulin resistant effect in the skeletal muscle. It would be great to understand how long GLUT4 remains expressed after exercise stops. The reference above noted reduced GLUT4 in a fasted state.
END update 2020-05-16
Low Carb High Fat diet (LCHF)
Reading through the above sections it is understandable for people to be worried about a high fat diet and certainly if it contains saturated fat such as palmitic acid. It is clear that fat causes the insulin resistance.
Let’s have a look at which of the above effects are applicable to our high fat diet.
Fructose & glucose
Those are excluded from the diet apart from small amounts. Certainly sugar is, and fructose may come from fruit which includes fiber, slowing the absorption and the detrimental effects.
This causes the production of lipids to be close to non existing. This prevents the abundance of lipid generation that may overwhelm the TAG production from DAG through DGAT1. This mechanism of IR will thus not take place in the liver, pancreas and muscle.
Dietary Palmitic Acid
But the diet may contain palmitic acid. Certainly when animal fat is consumed. Although that is true, we see that people on a low carb high fat diet have lower circulating levels of PA than high carb low fat diets.
First of all we see this effect in the fat and milk of cows who are grass-fed versus grain-fed. So if you take in fat from animals and you are worried about PA, lower
Can we expect a similar effect in humans? If we eat grass.. no I mean if we keep carbohydrates out of our diet, do we get lower circulating PA fatty acids?
That study has been done looking at the composition of all the different sources of fatty acids in our body and looked at how much of them are made up of PA. They noted:
11% reduction of PA in the circulating triglycerides.
No change in the phospholipids
8% reduction of PA in cholesterol
The fatty acid palmitoleic acid is derived from PA. With less PA available, it is reasonable to assume that palmitoleic acid will be affected as well. They noted:
32% reduction of palmitoleic acid in the circulating triglycerides
35% reduction of palmitoleic acid in phospholipids
44% reduction of palmitoleic acid in cholesterol
What is even more impressive is that the intervention was with calorie restriction. Despite the restriction, the high carb group did not notice any change in PA circulation. The high fat group did continue to consume an equal amount of fat as before the intervention yet were affected by the reductions listed above.
So is there no insulin resistance at all under a high fat low carb diet? It was already mentioned that GLUT4 expression into the cell membrane requires activation via the insulin receptor. Under frequent insulin stimulation, more GLUT4 will be available to take up more glucose from the blood stream.
Under chronic low insulin conditions such as the LCHF diet less GLUT4 is available. This happens in the liver and in the muscle. If you now eat something that is fast and high in carbs then the body will have issues with clearing the glucose because it will take a bit of time before, under stimulation of the insulin, GLUT4 reaches the cell surface and starts taking in glucose.
There are other GLUT transporters active which do not depend on insulin so it is not that glucose absorption completely fails.
What you have to understand is that under a LCHF diet, the liver glycogen buffer is much more reduced so that glucose availability becomes low. In such a situation it makes sense for a mechanism that spares glucose. The brain is the most dependent on glucose while the liver and the muscles are fine with fatty acids to generate energy.
In the following paper we see that after a 58 hour fast, the c-peptide measurement is much higher versus the control (an overnight fast). C-peptide is an indicator of how much insulin is secreted. But when measuring insulin, the level is less increased. What this means is that there is a larger proportion of insulin taken up by the liver under the 58 hour fast. Yet when you look at the increase in glucose, it was higher in the longer fast. It’s a showcase of prolonged low insulin reducing the GLUT4 availability in the liver. When insulin is released, GLUT4 protein will be created and moved to the cell membrane but this doesn’t happen instantaneously.
One other way to avoid this lack of GLUT4 expression is by exercising. Contraction of the muscles also moves GLUT4 to the cell membrane. This may not increase expression of GLUT4 in the liver but it keeps the muscles more active in absorbing glucose when blood glucose rises and thus helps to keeps insulin levels lower than without exercise.
As you see there are very different reasons and situations that lead to insulin resistance. In the unhealthy state we have a full liver glycogen and reduction in insulin receptor signaling. In the healthy state we have an almost empty liver glycogen and maintain insulin receptor signaling.
In the healthy state, the insulin resistance is easily resolved with a few rounds of triggering insulin as the signaling is not broken and thus will consequently lead to higher GLUT4 expression. In the unhealthy state, you must leave out the carbs from your diet and/or abstain or reduce food intake for a while to resolve the situation where the fat storage in the liver prevents insulin signaling.
I would also like to propose a name change. Because the described insulin resistance under a LCHF diet is more like a function rather than an issue, it would be good to have a name that describes that function. Glucose Sparing Insulin Resistance (GSIR) seems appropriate. And perhaps the pathological insulin resistance can better refer to its cause: Fructose or Glucose Induced Insulin Resistance (FGIIR).
One of the pervasive thoughts in the keto community is that when they measure lower levels of ketones, the longer they are on the ketogenic diet, that this is caused by a better utilization of the ketones in the body. This is an effect noticed over several months or even years.
But is this true?
I have already highlighted this before here that there is a dependency on metabolism and fat mass but I wanted to highlight a few other things by looking at it from the angle of what it would take to have an increased utilization that would lead to lower measurable levels.
One of the things to start with is the blood circulation. An interesting article that was actually about something else, showed in a simplified way the blood circulation. Their main point was about glucagon levels where glucagon release from the pancreas flows directly into the liver which processes most of it. What you measure in the arteries is the left over. In a similar way, we need to check where BHB originates from and what it passes when we measure via our finger tip.
What you see on the simplified diagram is that the blood flowing out of the liver goes to the heart and lungs. From there it is spread into the arteries. Our upper extremities including the arms and head get the same supply. Although the head can be a big consumer of ketones, it does not ‘steal’ away ketones from the blood to then leave low ketone levels to the arm, where you measure your BHB level. Both the arms and head get the same fresh supply of blood.
So the only place where a higher consumption could build up over time, leading to a lower measurement, could take place in the heart and/or lungs.
One key element for that to investigate is the monocarboxylic transporter 1 (MCT1). This transporter is what brings BHB across and into the cell. In order for the cells to take up more BHB it has to upregulate its MCT1 expression. There are other MCT’s but we’ll focus on MCT1.
MCT1 is important enough for the usage of BHB that it would cause ketoacidosis if not sufficiently expressed. It also disregulates lactate efflux from the cells. Keep that in mind when going further down in this article.
“Monocarboxylate Transporter 1 Deficiency and Ketone Utilization”, Peter M. van Hasselt, M.D., Ph.D., Sacha Ferdinandusse, Ph.D., Glen R. Monroe, M.Sc., Jos P.N. Ruiter, B.Sc., Marjolein Turkenburg, B.Sc., Maartje J. Geerlings, M.Sc., Karen Duran, B.Sc., Magdalena Harakalova, M.D., Ph.D., Bert van der Zwaag, Ph.D., Ardeshir A. Monavari, M.D., Ilyas Okur, M.D., Ph.D., Mark J. Sharrard, F.R.C.P.C.H., Maureen Cleary, M.D., Nuala O’Connell, M.B., Ch.B., Valerie Walker, M.D., M. Estela RubioGozalbo, M.D., Ph.D., Maaike C. de Vries, M.D., Gepke Visser, M.D., Ph.D., Roderick H.J. Houwen, M.D., Ph.D., Jasper J. van der Smagt, M.D., Nanda M. VerhoevenDuif, Ph.D., Ronald J.A. Wanders, Ph.D., and Gijs van Haaften, Ph.D., 2014, https://www.nejm.org/doi/pdf/10.1056/NEJMoa1407778
To get BHB from the blood into the tissue, it first has to pass the endthelial cells. With the endothelial cells being a first barrier for transport from the arteries towards the organ tissue, this is already a limitation for organs to increase their uptake.
To my knowledge there is no organ specific endothelial adaptation to increase uptake. I don’t think this research has been done so we’ll keep this option open.
We do see a change in starvation whereby uptake through the blood-brain-barrier increases with 50%~60% in rat brains. This reached its maximum in about 2 days. So there is some adaptation in expression of MCT1 but still the question is if this is at specific locations or systemic. This is important to know for the heart and lungs.
The heart probably has already sufficient MCT1 expression. We can guess this from its ability to take up BHB in case of acute heart failure. But we can look at the mRNA at several organs in mice and we see that there is no change at the level of the heart. Luckily they also checked for protein expression and also here found no change.
If you check the reference, you’ll notice that expression is up in liver and kidneys. These are the 2 most important organs for gluconeogenesis. I suspect they primarily do this to take up lactate and convert it into glucose.
On the lungs we don’t find much data. One article shows MCT1 expression similar to the heart but this is not about fasting or low carb/ketogenic diet. It is in pigs and they were specifically bread to have higher AMPK which induces MCT expression.
“Chronic activation of AMP-activated protein kinase increases monocarboxylate transporter 2 and 4 expression in skeletal muscle”, E. M. England, H. Shi, S. K. Matarneh, E. M. Oliver, E. T. Helm, T. L. Scheffler, E. Puolanne, and D. E. Gerrard, 2017, https://www.ncbi.nlm.nih.gov/pubmed/28805903
When it comes to lactate production, they are close to zero unless there is a respiratory issue. More on lactate further down.
We have to be careful with this interpretation but what we see in cancer is that there is an increase in MCT1 expression upon glucose deprivation. So it is possible that, in order for MCT1 to be increased in expression, we must experience a reduction in blood glucose. Glucose deprivation seems to stabilize MCT1 and CD147.
Not only glucose deprivation but also hypoxia stabilizes and upregulates MCT1. Hypoxia will result in reduced oxidative phosphorylation and more lactate production. We’ll get back to this further below.
“Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration” C J De Saedeleer, P E Porporato, T Copetti, J Pérez-Escuredo, V L Payen, L Brisson, O Feron & P Sonveaux, 2013, https://www.nature.com/articles/onc2013454
I have highlighted CD147 specifically because this is required to increase MCT1 movement into the membrane. This is shown in a study on Saccharomyces. A long stretch from humans but MCT1 is maintained across all eukaryotes and we see this in the research on tumors as well.
“Co-expression of a mammalian accessory trafficking protein enables functional expression of the rat MCT1 monocarboxylate transporter in Saccharomyces cerevisiae”, Judita Makuc, Corinna Cappellaro, Eckhard Boles, 2004, https://academic.oup.com/femsyr/article/4/8/795/627683
MCT1 is not only used to bring in BHB, it is also used bi-directional to regulate pH intracellular affected by lactate concentrations. This was already highlighted in our MCT1 deficient cases above. It is also a hallmark of cancer cells which export all the lactate to maintain pH balance.
We also see that with exercise, MCT1 is rapidly adjusted in its expression in skeletal muscle and depends on the metabolism of the cell. It is interesting that it adjusts so quickly. Could it mean the skeletal muscle prevents, as much as possible, the uptake of ketones in a resting state to preserve it for the brain? The higher fat metabolism will certainly not create more lactate at rest.
When we check what is going on with the brain under fasting, we see that it increases lactate in the brain. This lactate could potentially increase MCT1 in the blood-brain-barrier, causing a local effect in the epithelial cells. This would be a novel way for the brain to increase its absorption of BHB. If other organs don’t do this then higher levels may mean its all to favor the brain.
Interestingly, in fasted rats they observed normal lactate levels. I suspect that upon increased fat metabolism our lactate production goes down because you need glycolysis for that. But the brain may be increasing its lactate production and export so that plasma levels of lactate appear unaffected.
We see basal lactate unaffected in the FASTER study of athletes who were at least 6 months on a low carb diet. But here we have highly trained athletes so their lactate disposal may be optimized.
The following study discusses the increase in lactate production by astrocytes when glucose levels are on the downward trend. This further supports the idea of an increase in brain lactate production under a low carb diet.
So first of all we have the endothelial cells to keep in mind which are lining the blood vessels. MCT1 expression is influenced by glucose availability but we are not witnessing an increasingly lower glucose over time when we see a lower BHB production. On the contrary, a reduction in glucose is giving us higher BHB measurement. After all, that is part of what BHB is supposed to do, serve as an alternative fuel to the brain. Only when BHB goes up significantly we’ll see a drop in glucose.
Lactate also stays at normal level, there is no hypoxia in endothelial cells so we have to conclude there is no systemic trigger to increase MCT1 in the endothelial cells.
Then there is the possible local effect of lactate on MCT1 expression so do the heart or lungs generate more lactate as the brain seems to do? Also here we have to say no. We don’t see any increase in protein levels in the heart which evidence no increased requirement for lactate export. There is also no reason to assume the lungs do.
We’ll have to conclude for now that if you are measuring low BHB, you are producing low BHB. There is no reason to believe that your body is better at utilizing BHB.
After all, the brain is the one most in need of BHB as glucose levels drop. Would it make sense for all other organs to consume increasingly higher levels? No.
The blood in our finger is of the same composition as what travels to the brain.
What follows is a list of research that shows how a ketogenic diet can have effect on the immune system. A lot of this research is done in non-human bodies or circumstances so none of it has been proven to be similar in humans.
This is very important to know because mice and rats have a somewhat more different and stronger immune system than humans.
1. A first, most recent article is where it helps gamma-delta T-cells respond better to Influenza. How exactly the ketogenic diet caused an increase in these gd T-cells is not clear yet.
2. The next one talks about improved functioning of CD8-T cells. However, this is caused by the enhanced PGC-1α expression. Beta-hydroxybutyrate (BHB) and butyrate itself increase PGC-1α expression through their HDAC inhibitory function. But butyrate may have the upper hand in this.
3. Further on the CD8-T cells we find epigenetic modulation. The result is that these cells are able to divert energy towards glycogen, which is the stored form of glucose. What I suspect from this is that it gives these T-cells the ability to respond more quickly, proliferate more quickly when a pathogen is detected. Just like cancer cells, fast growing cells need a lot of glycolysis, not only to support the metabolic demand but also to synthesise fatty acids to form membranes for the new cells. I see a potential link here with the first paper on gd T-cells where the same mechanism could help in the fast proliferative response.
4. We continue a bit more on CD8-T cells. When they are challenged in an environment of low glucose and low oxygen, they switch over to fatty acid catabolism. In a tumor environment where cancer cells take up glucose 10x to 100x more than normal cells, glucose becomes scarce. Being able to switch fuel can help preserve efficacy. Hypoxia itself changes their metabolism towards fatty acids. If they are shown to take up BHB then it could be a very effective way to continue that efficiency against cancer. And the previous article seems to indicate this is the case.
6. Not only CD8 T-cells but also CD4 T-cells seem to be affected positively. The next paper fed mice high fat and saturated fat, thinking it would result in a negative situation. However, what they found was a reduction of cholesterol in the membrane of these T-cells and an increase in proliferation response. Of note, mice with LDLr-/- have a higher metabolism (see second link).
7. A ketogenic diet contributes to a higher AMPK activity. AMPK helps the T-cells to survive longer and proliferate better. These memory T-cells are the ones that respond to a specific antigen which is valuable when a second infection arrives from the same virus.
Overall it looks like a high fat, ketogenic diet seems supportive to the immune response helping in the proliferation capability and survival/efficacy in challenging environments.
There are also lots of anecdotes in various channels where people on a ketogenic diet report improvements in resistance to flu. Either they no longer get sick or the duration is shortened with less severe symptoms.
I would say, give the diet a try and take good care of yourself as we go through this COVID-19 episode.
Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome and decreases pathogenic monocytes in lungs of infected aged mice.
So far these were all animal studies. The following is in vitro and in vivo human research.
We show that ketone bodies profoundly impact human T-cell responses. CD4+ , CD8+ , and regulatory T-cell capacity were markedly enhanced, and T memory cell formation was augmented. RNAseq and functional metabolic analyses revealed a fundamental immunometabolic reprogramming in response to ketones favoring mitochondrial oxidative metabolism. This confers superior respiratory reserve, cellular energy supply, and reactive oxygen species signaling.