Medical establishment considers a causal role for cholesterol. There has been a great deal of effort put into lowering cholesterol without significant effect on curing and preventing the disease. How come the failure is so big? Is it really THE cause? I’m especially concerned because my LDL level is >300mg/dL
It turns out that the exact cause is unknown.
The exact cause of atherosclerosis isn’t known. However, studies show that atherosclerosis is a slow, complex disease that may start in childhood. It develops faster as you age.
Atherosclerosis may start when certain factors damage the inner layers of the arteries. These factors include:
Despite being unknown, a number of factors are listed that damage the arteries. As you can see it mentions high amounts of certain fats and cholesterol.
What is really at the basis? Is cholesterol a necessary component? Throughout the years I have seen a lot of material to compose a fairly descent picture today. I’ll present it as the step-by-step discovery, the way I did…
Atherosclerosis is recognized by a number of properties so we can start by looking into some of them and deviate as we pick up the breadcrumbs:
Where does the plaque come from? Foam cells that make up the plaque are macrophages that are stuffed with lipids, primarily oxidized LDL. Here we see why LDL cholesterol is claimed to be bad. It is in fact not the LDL cholesterol but the entire LDL particle so why single out only one of the elements that it is carrying?
One of the contributing elements for macrophage uptake of oxidized LDL is hypoxia (low oxygen levels).
But if I were to believe the information on wikipedia, one of the first things in atherosclerosis is macrophage infiltration in conjunction with foam cells. Could hypoxia already be present from the start? And what causes these macrophages to infiltrate in the first place? What attracts them?
Hypoxia before or after, it seems to have a major impact. In a mouse model of atherosclerosis, disabling HIF-1a they were able to reduce atherosclerosis by 72% ! HIF-1a is stabilized under low oxygen levels and sets a whole host of changes in motion to help the cell survive and signal distress through inflammatory markers.
And one more effect of low oxygen levels is the stimulation for growth. Again also here we see this happening in cancer. A lack of oxygen leads to glycolysis, the production of ATP from glucose without oxygen, which increases ROS production and this sets a transcription in motion of different genes that are specific for growth. The growth happens in the tunica intima layer mainly although it is also observed in the areas close to it.
The intima is a layer that grows thicker with age.
What we have seen so far are effects that have their origin in hypoxia. But does that mean hypoxia is the cause? Even if hypoxia can be established as a causal factor, what would cause the hypoxia? In order for any of the contributing factors to result in hypoxia we must find a link somehow. Below are 2 factors that we can look into as mentioned at the beginning.
This paper shows how nicotine causes senescence in vascular smooth muscle cells (VSMC), the cells that make up the tunica intima (but not only the tunica intima).
What is important is then to look at what senescent cells trigger. They send out scenecent-cell-specific signals that will attract macrophages. This will lead to the destruction of the cells by the macrophages. Interesting, because now we see at least that there are causal factors for attracting macrophages before they infiltrate and accumulate LDL particles.
Depending on whether MOs are in the classically-activated M1 or alternatively-activated M2 states, MOs can promote cell death through either cytotoxicity or phagocytosis, respectively. MOs in the M1 state secrete TNFα, IL-1β, and IL-6, potentially amplifying effects of the SASP [140,141].
But does this cause hypoxia? And VSMCs are responsible for the contraction and relaxation of the artery but then again they are lining up throughout all the arteries so do we have atheriosclerosis all over the place?
Atherosclerosis is not found all over the place. It is primarily seen at specific areas in the arteries. Namely at the bifurcations.
This has been investigated and the reason why it occurs there has to do with the shear stress. Measured in subjects with CVD in the carotid intima we see a lower level of shear stress compared to healthy individuals.
The bifurcation areas are specifically prone to low endothelial shear stress. That is to say – under certain conditions –
These areas of low shear stress at the bifurcations causes lower oxygen delivery to the arterial wall so we get to understand why hypoxia could be involved.
Arterial Wall stiffness
OK so far we understand why it happens where it happens but we haven’t differentiated on why it happens in some people and not in others. But first, the shear stress is something that is negatively correlated with the elasticity of the arterial wall.
There are other effects at play with VSMC than senescence as we saw under smoking. They can change their phenotype from contractile towards proliferation depending on signaling that takes place. A loss of function sort of.
What do we have so far? Most of the noted effects such as plaque buildup, hyperplasia, angiogenesis are all factors due to hypoxia. The hypoxia result from regions in the artery that are prone to result in low shear stress regions. But before we get such regions there must be factors that cause the reduction in elasticity, which means factors that affect the functioning of VSMCs.
We’ve seen smoking causes scenescence of VSCM so that they reduce their elasticity. But are there other damaging effects that can cause VSCM to become inflammatory and start to function badly?
I mentioned smoking and sugar earlier on but haven’t touched on sugar yet so here we go…
Knowing what we know so far, we could ask the question why insulin resistance (caused by sugar) is a contributing factor. Does it affect the VSCM? Does it lead to wall stiffness? Does it lower oxygen in the blood?
What is specific about the effect of insulin is that it lowers the ability to survive for the VSMC so any negative effect on VSMC and insulin may reduce their recovery.
I’ve already referred to the following article but wanted to quote on the factors that lead to VSMC dysfunction (loss of contractile function):
Key pathological factors associated with diabetes mellitus including high glucose (HG), advanced glycation end products, growth factors, and oxidized lipids promote VSMCs dysfunction by enhancing inflammatory gene expression, migration, and proliferation via activation of multiple signal transduction pathways and downstream transcription factors.
Although not related to the stiffness there is more in the way fructose contributes to atherosclerosis. I also mentioned the oxidized LDL at the beginning which macrophages take up with higher affinity. Fructose causes an increase in oxidized LDL and in small dense LDL which oxidizes more easily.
In addition to increases of postprandial TG and fasting and postprandial apoB, we show for what we believe is the first time that fructose consumption increases plasma concentrations of fasting sdLDL, oxidized LDL, and postprandial RLP-C and RLP-TG in older, overweight/obese men and women, whereas glucose consumption does not.
LDL particles are more prone to oxidize depending on the type of fat it is carrying and lack of anti-oxidants it is carrying. The more unsaturated content the more oxidized it gets. That is in stark contradiction with the recommendation to reduce our intake of saturated fat.
The LDL oxidative state is elevated by increased ratio of poly/mono unsaturated fatty acids, and it is reduced by elevation of LDL-associated antioxidants such as vitamin E, beta-carotene, lycopene, and polyphenolic flavonoids.
Since about a year I focus on animal-based food and eat a high amount of butter. My vitamin E level pre-high fat diet was 11.3mg/L. The first 2 years into the diet it was 19.9 and 17.8mg/L and now since the more focused approach it is 25.3mg/L (reference values of 5 and 20).
A severe increase in saturated fat and a doubling of my vitamin E intake. I can only wonder how that has affected the level of oxidation of my LDL particles.
As you can see the overall picture is complex. As for the question “Do we know what causes atherosclerosis?”.
I think the answer is yes but science is in trouble. From what I could find, cholesterol is not the cause and that is also in line with how bad the results are in prevention. Not until research comes out that shows high levels of circulating LDL causes malfunction in VSMCs.
How can science keep up its multi-billion industry of cholesterol-lowering drugs while at the same time admitting that they were wrong about cholesterol?
We were able to ban cigarettes. We are unable to ban sugar. As long as we are not able to reduce the impact of sugar and high glucose, we’ll not be able to prevent atherosclerosis.
There are other causes than smoking and sugar but in order to be a cause, it seems first there must be a deleterious effect on the functioning of the VSMCs.
Update: In the comments there was a reference to Subottin’s work. After watching it again I realized why the thickening of the intima is taking place.
The reason why thickening of the intima takes place is to maintain blood pressure! Although people with high blood pressure are at higher risk, the problem is with localized low pressure.
The mechanism works in such a way that by increasing the thickness of the intima, pressure can be restored. So it is by design that the intima is supposed to increase in thickness but… The problem of low pressure isn’t fixed due to how we affect the flexibility of the arteries with our lifestyle so that a low pressure area persists and the thickening has to persist as well.
Previously I collected different studies to see how the mice perform on ketogenesis. Despite having a diet that often consists of >90% fat they produce disappointingly low BHB levels. Without thinking much about it I just assumed they are bad at fat metabolism biased by thinking they are typical high carb eating animals so they are less well adapted at burning fat.
But I may have been wrong about that idea.
A recent discussion and consequent article on exercise performance and the ketogenic diet brought up the hindrance of sufficient carnitine to import long chain fatty acids (LCFA) into the mitochondria at high intensity levels (>=80% VO2max). I looked for studies and found one that tested medium chain fatty acids (MCFA) versus LCFA at low and high intensities. And indeed MCFA metabolism at high intensity is not impaired. On the other hand, carnitine becomes less available at high intensity and we see a paralleled reduction in LCFA.
Back to our favorite lab animal… But we’re not talking about exercising mice!?! Indeed we are not but when I looked back at my overview page of the different studies with keto mice, I also mentioned a study that, instead of providing the usual fat, provided hydrogenated coconut oil and the mice were able to achieve BHB levels of >5mmol/L!
So this got me thinking, if they are able to produce high levels of BHB with the right type of fat then the issue must be in the import of LCFA and a reduced capacity to import them into the mitochondria. Does this mean they have an issue with carnitine availability?
We get carnitine from animal food and more so from red meat. If you had a look at the overview then you also see that the mice get a very low amount of protein, typically around 5% and occasionally only up to 10%. Could this have a limiting effect on their carnitine availability? The protein content may not be enough and then we have to see what the source of protein is because that may already be a poor source carnitine by itself.
Most of the ketogenic diet (KD) chow provides casein as a protein source so there is no naturally occurring carnitine in the diet which means the animal has to obtain it from its own production.
We may have forgotten that mice are scavengers and don’t pass on the deadly remains of other animals. They need their carnitine just as much as we do. They are not 100% herbivores.
Rodents scavenged both fresh and skeletonized remains with gray squirrels only scavenging skeletal remains. Wood mice were most active in winter and scavenged both soft tissue and bone.
Here I want to have a look at just a few studies of the many for available evidence that carnitine plays an important role in the fat metabolism of mice.
In a first study we see a 40% reduction in carnitine for mice on KD versus a regular diet.
Serum concentrations of β-oxidation intermediates carnitine and acylcarnitine were paradoxically decreased in STKD mice, indicating a possible dissociation between hepatic gene expression and serum content of oxidative markers (Fig. 6A).
In the next study in humans they supplemented healthy adults with carnitine and various conditions. These were not individuals on a KD diet. They fasted overnight and then did exercise with carnitine right before exercise. The carnitine supplementation had the strongest correlation with ketogenesis.
In conclusion, LC enhanced liver fat utilization and ketogenesis in an acute manner without stimulating EE under fat-mobilizing conditions.
In the figure (a) shows a very high correlation right after exercise. (b) shows the correlation 4 hours after exercise and (c) shows the combination of a and b together with the baseline sample 1 hour before exercise.
One more study shows a much better functioning of fat metabolism in patients who are carnitine deficient after carnitine supplementation. Their side effects remind us about the KD mice. Fatty liver, higher inflammation markers etc.. When supplementing with carnitine this all improves, including insulin sensitivity.
Inflammation, glucose intolerance, hepatic steatosis and other side effects
What happens when you must eat a higher volume to get to those fewer MCFA in your diet while you can’t process the LCFA? Fat builds up. It arrives in the liver but can’t get into the mitochondria that easily so it buffers up.
Once you get fat accumulating in the liver you’ll experience insulin resistance so an OGTT will show glucose intolerance.
What doesn’t get picked up remains in circulation and goes again into fat storage. We know that increased storage of fat in the adipose causes a chronic low grade inflammation so it should not be a wonder that a KD diet in mice leads to these side effects.
So these mice are eating energy that they can’t use, naturally that also leads to weight gain which we observe in ad lib feeding.
There is of course a reason why mice need to have a low protein intake in the lab. They have a roughly 7-fold higher metabolism than humans. It results in too much gluconeogenesis from the digested amino acids and this would hinder ketogenesis.
So on one hand we need to keep the protein low to induce sufficient BHB but on the other hand we hinder their BHB production by limiting their carnitine availability.
So do mice have an impaired fat metabolism? I guess not. It looks like their diet causes them to be deficient in carnitine.
I only see a few options to correct the model and that is to increase carnitine supplementation and/or feed MCT oil. Any other type of feeding will not represent a human ketogenic diet sufficiently. Also carnitine may reduce their BHB production due go gluconeogenesis so probably the best is to put MCT oil in the diet.
What can we learn from this and apply in our human life? If you are on a ketogenic diet and want to compete in sports, it may be worthwhile to experiment with supplementation of carnitine before the race to maximize transport of the LCFA and somehow find a way to ingest MCT during the race for maximum availability of fat into the muscle mitochondria.
It is pretty obvious by now in sports is that if the body requires something then you need to give that in order to enhance performance. Be it vitamines, minerals, energy… whatever it needs to produce that wattage, make sure it doesn’t fall short to sustain the performance. Except for one element. Even though it is right there in front of our face and of all the researchers, it is overlooked…
A presentation I recently looked at summarized it all yet somehow seems to miss it.
A first thing to note is that endurance exercise such as running and cycling elicit AMPK activation. More so under a low glycogen state than under high but nonetheless the activation is there.
The reason I’m highlighting AMPK is just to give some background on what we are looking at. AMPK is responsible for setting in motion the growth of mitochondrial mass. During exercise, mitochondria get (partially) damaged. They need to be split up so that the damaged parts can get recycled and the other parts that are in good health become the seeds to multiply and grow a bigger mitochondrial mass overall.
What does this enhancement in mitochondrial mass result in? Indeed, increased exercise performance, higher ATP production.
In sports physiology they know very well that this results in a higher fat oxidation rate as the presentation further highlights.
The results below, in the presentation, are from a study looking at endurance training in a group of moderately overweight men. We see that there is no adaptation in the amount of carbohydrate oxidation but there is adaptation in the amount of fat oxidized. This is in the Trained group and the Diet group which were fed a reduced amount of calories.
The study also looked at a group to keep calories identical in order to exclude if the adaptation is due to weight loss. Also here the Trained-identical calories group shows the same adaptation in fat oxidation. C is the control group.
What this tells us is that both weight loss and endurance training stimulates a greater fat oxidation capacity with no change in carbohydrate oxidation.
I’ll speculate later on about why this is happening but let’s first have a look at what determines our level of fat oxidation, our maximum fat oxidation rate. The presentation continues on this topic…
As fasting is prolonged, the fat oxidation goes up and we see a correlation with the circulating free fatty acids (FFA).
Actually, the data shows us a very high correlation between the free fatty acids (FFA) and maximum fat oxidation.
Further evidence is given in the presentation from a study that looked at ultra-endurance. Normal diet, at least nothing specific to a ketogenic diet or high fat diet in general, yet we see again how the body adapts to increase fat oxidation.
Pointing out the obvious
So it should be clear by now that the body, as an adaptation to endurance, increases its fat oxidation capacity. On one hand by increasing mitochondrial mass and on the other hand by making more fat available in the circulation via FFA. Without more mitochondrial mass you cannot process more FFA and more mitochondrial mass is useless without additional fuel.
But what are these researchers missing? The type of fuel!
If the body wants to increase fat oxidation in order to sustain that demand in performance, wouldn’t it be natural to provide the body with that fat, which it is demanding for, during exercise?
Why is there not a single trial that involves ingesting fat in one way or another during exercise?If we want to go for a higher peak fat oxidation, shouldn’t we simply eat fat to get our FFA up?
Is it fair research when putting athletes on a high-fat diet, thereby having a higher reliance on their maximum fat oxidation rate, to supplement them with carbohydrates pre/during exercise which releases more insulin so that the insulin can stunt fat release thus lowering their circulating FFA and showing no performance gain, or worse, performance loss?
In the pre‐treatment trial, all subjects received a standardised CHO‐rich breakfast providing 2 g kg−1 CHO;
That is comparing highly optimized high-carb athletes with high-carb fueling to highly optimized high-fat athletes with stunted fueling. You might as well just put a concrete block around their legs.
A study that compared normal versus ketogenic diet in exercise monitored the FFA during the exercise. It shows how important the availability of FFA are during exercise. Being the main source of fuel and being greatly dependent on, it is only natural to supplement with fat. The mixed diet group has a much lower reliance on fat and we also see that in a much lower fluctuation during this exercise exercise.
Specifically towards the most intense part of exercise during this test we see the lowest availability of FFA. What would happen if we’re able to maintain that level of FFA from the start towards the end by ingestion or, just for the sake of experiment, infusion?
This is an area where research could see a lot of surprises and progression in understanding.
A point I did not address is the type of fat used. This is actually very important because long chain fatty acids (LCFA) require carnitine for transport into the mitochondria.
Carnitine content reduces to less than 30% during high intensity (100% VO2max)
Medium chain fatty acids (MCFA) do not require carnitine and thus are able to sustain a higher rate of appearance in mitochondria. But for that they need to be made available in circulation at a higher rate as well.
It is of course just a hypothesis but the most obvious thing would be protein sparing. Engaging in long duration activity requires energy. If it would all have to come from glucose then our body would have to break down muscle as a source for gluconeogenesis. By relying more on fat, both the energy requirement can be met and at the same time protect our muscle from catabolism.
If you want to go more in depth on this protection mechanism then you can read a few of my previous post on the subject. You’ll see it has quite broad implications.
I have received a cancer diagnose last year. Thankfully my predating interest in metabolism already exposed me to lots of research material, including about cancer. I already collected material in the event I would ever get cancer. It may seem a bit ironic but we have a high chance being faced with it in our eventual life, either personally or someone close to us. I look at it from the positive side, it gave me a head start in figuring out what to do about it .
It allowed me to put together a number of things that would, at least in theory, help cure my cancer. Now it was time to put that theory into practice.
Along came my brother in law with glioblastoma half a year later who I have guided onto the protocol with great results so far.
I want to share with you my protocol because research is advancing in the field of standards of care (SOC) which means surgery, radiation and chemo, and the combination of it with dietary therapy. Specifically the ketogenic diet is promising but why should you have to wait another 10 or 20 years before they make it part of a suggestion in therapy.
Why combining it with the ketogenic diet? Research is stil frail but positive. What I’ve seen from papers is that a very low carb diet, which the ketogenic diet is, is creating a much more favorable environment to target cancer with SOC of which all the details still need to be unraveled.
It modulates the immune system, lowers growth factors, reduces usable energy metabolites etc. Underneath the description of the protocol I go a bit deeper into the effects of each so that you can understand why they are part of it.
In the unfortunate event that you are unable to stop the cancer, the protocol will provide you a much needed reduction in side effects. That alone makes it already worth doing.
So let’s first have a look at the protocol and then the rationale of it.
Below are the elements required and we’ll see how to put them into practice.
I want to stress though, if you want this to be successful then under no circumstances deviate from it. More curcumin and more omega-3 is OK but more protein is not OK, less ketogenic is not OK. They all have a specific purpose, including the timing! Read the explanation below to be better informed about the why.
Curcumin (Theracurmin double strength)
Omega-3 oil (EPA; DHA)
Ketogenic diet – High on fat, very very low carbohydrate (<20% but preferably as close to zero as possible)
This protocol contains a ketogenic diet. It requires some adjusting for your body to get into it which may lead to some discomfort at first. In the initial phase you may loose weight through fluid clearance. This also clears some electrolytes so make sure you take up a bit more salt.
Get acquainted with the diet and the side effects during initiation. Stick through it and check around how to resolve the issues. If issues occur, they are normally very minor and generally require a little bit of adjustment and they fade away after about the second week.
Get an estimation of your body weight and fat percentage so that you know how much protein you can eat. For example, an 80kg person with 20% body fat means 80 * 20% = 16 kg of fat. 80 – 16 = 64 kg of lean mass. We simply change the kg of lean mass to gram so we get 64 gr of protein per day. This looks very little but I’ll explain further down.
The intake of protein has to be spread across the day, we’ll do that in 3 meals. Roughly 25%, 30% and 45%. It doesn’t have to be super exact but make sure the morning contains less and the evening more but don’t change it too much. 20%, 30%, 50% is still OK or 20%, 35%, 45%. So according to the example above: 25% of 64gr or 16gr protein for breakfast, 30% of 64gr or 19.2gr at lunch and 45% of 64gr or 28.8gr.
As soon as you wake up, take 4 pills of the Theracurmin double strength and 1 pill of Omega-3 supplement containing DHA. Do the same right before going to bed but now also include the melatonin (+/- 3mg).
Vitamin D3 is not shown on the schedule but I recommend to take a daily dose in the morning and/or before exercise and to start taking it as soon as possible. It takes a while before your plasma level is up so just covering the SOC period is not enough. 10 000 IU every day will likely be needed. This may seem as a lot initially but you have to understand that vitamin D3 supports your immune system and your immune system will be consuming vitamin D3. It is important to keep the level up. Personally I want to reach around 80 mg/dL of 25(OH)D to make sure I hit the maximum out of the linear dose reponse that it brings.
As you can see from the graph, it takes 4 months to reach the plateau of +/- 80 mg/dL with a daily dosage of 10 000 IU (250 microgr).
MCT oil must be taken regularly throughout the day. I’ve mentioned 8 times on the schedule. You can vary to more times but I would not recommend less than 5 times. You can, for example, make a blend called bulletproof coffee which is the MCT mixed with coffee, butter (real butter!) and coconut oil. Be creative, take it however you want but take as much as possible and regularly throughout the day.
Breakfast, lunch and diner are high fat, ketogenic meals, preferably zero carb but at least very very low carb. How high in fat? As much as you can comfortably eat to feel full. If you are still hungry after a meal or if you are losing weight, increase fat intake. You will not get fat from the fat. More than likely you will be losing weight. Even if you would gain, you can sort that out after getting cured from cancer!
There is no snacking between the meals. You will not be hungry anyway but (bad) habits can be strong. No sugary drinks at all, no fruit, no nuts & seeds, no low-carb candy bar etc… We aim for zero carb during the whole day and limit dietary intake to those 3 meals.
Do your best to leave 4 hours between diner and going to bed. The more hours in between the better. But aim for at least 4 hours.
The protocol should be applied at least across the duration of SOC. The ketogenic diet however is recommended for the rest of your life. It is one thing to get cured from cancer but you need to prevent recurrence as well.
The good thing is that, perhaps apart from rare genetic issues, this protocol is safe to apply for long duration. So if the tumor is receding but not so fast, you can continue applying the protocol for a longer period. The diet itself is covered by a lot of research, showing improvements in health. For example it is used to treat epilepsy and reverse Type 2 Diabetes. In general it will make you a healthier person.
I was diagnosed with nodular lymphocyte-predominant Hodgkin lymphoma. I had the luxury to try out my protocol without SOC because it was a slow growing tumor. I wanted to know its strength, a first try-out of the theory. Note that I was about 2.5 years on very low carb at the moment of diagnosis, have applied the full protocol without SOC for about 1 month and after the protocol I remained very low carb.
Now 1 year later, there is no change in size. No regression but also no worsening. It is possible that my case proves itself rather difficult to cure with the protocol alone because it is located in lymph glands with cancerous b-cells. Cells that are themselves part of the immune system and designed to clear cancerous cells.
I have started radiation therapy and we’ll see how that works out in a couple of months.
My brother in law was diagnosed with glioblastoma with a high % chance of recurrence within 5 years. The standard protocol was applied. First surgical removal of the tumor followed by radiotherapy combined with chemotherapy. The periods of standard treatment, apart from the surgery, were every time fully covered by my protocol.
The first image is before surgery showing the tumor on the back side of the brain on the left.
The following picture is the result after surgery.
The protocol was started shortly before radiotherapy and chemotherapy, which lasted for 1.5 months. He was essentially symptom free from the treatment. It was so remarkable that he was interviewed because of it.
The MRI after 3 months, shown below, is encouraging. No relapse so far.
The treatment is not finished yet. There are 6 rounds of 1 full week of heavy chemo whereby he follows the protocol starting 1 week before and covering the week of the chemo. Throughout the rest of the period he remains close to very low carb but not fully.
We’ll have to wait for the next 5 years to see how successful we have been but in the mean time another scan was done, 6 months post surgery, with a doctor who was very enthusiastic about the result. Still nothing came back so far. Crossing fingers.
The beauty of this treatment is that it targets the energy source of cancer, it targets the uptake mechanism of the energy and actively works on the growth mechanism without negatively affecting healthy cells. Secondary, it also helps activate immune cells promoting the detection and clearance of cancer cells. In addition it can even work to augment the effectiveness of certain chemo drugs like temozolomide (1) (2) .
Sounds too good to be true? It isn’t but it is also no miracle cure by itself. Cancer is a though beast to handle. The cancer cells live in a tumor micro-environment which needs to be destroyed as well. The protocol is a potent adjuvant to SOC.
PS: The references below are just there as a first hint if you want to look into it more deeply. I didn’t provide a reference for every statement but in case you want to delve into it deeper, I’ve mentioned the molecules involved so it should be relatively easy to come up with the research.
Curcumin has been widely studies, also in combination with cancer treatment. It shows great potential and while its effects are via multiple mechanisms, perhaps the most important one is PI3K inhibition in cancer cells. However, raising insulin very potently increases PI3K activation and destroys the effect that curcumin has on PI3K, therefore it is vital to keep insulin low. That is why the first meal should be zero carb but also very low in protein, to let curcumin work while insulin is low. This is also the reason why I recommend 4 hours between dinner and bedtime with curcumin so that insulin is low enough for curcumin to do its work during the night without being hindered by insulin.
Plain curcumin powder will not work !!! The absorption is very bad and we need to get a high enough dosage into the cancer cells. The reason I recommend Theracurmin is because this has shown to be the highest bio-available form. I am not affiliated with them and will not hesitate to recommend a different brand if I find another one that has a higher bio-availability. However, my experience is with this brand and dosage.
“Curcumin Inhibits Joint Contracture through PTEN Demethylation and Targeting PI3K/Akt/mTOR Pathway in Myofibroblasts from Human Joint Capsule” – Ze Zhuang, Dongjie Yu, Zheng Chen, Dezhao Liu, Guohui Yuan, Ni Yirong, Linlin Sun, Yuangao Liu, Ronghan He, and Kun Wang – 2019 – https://www.hindawi.com/journals/ecam/2019/4301238/
“Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway.” – Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, Yang D, Yang A, Yu Y- 2018 – https://www.ncbi.nlm.nih.gov/pubmed/29328421
One specific feature of the fatty acid DHA is that it needs to have its place in the cell membrane. By taking it as a supplement we increase our intake and chances for it to end up in the cell membrane. This is very crucial because DHA has been shown to prevent the conversion from PIP2 to PIP3. PI3K triggers the conversion of PIP2 to PIP3 and from there AKT gets activated which in turn stimulates mTORC1 resulting in growth. Omega-6 oils displace DHA in the cell membrane so we want to avoid omega-6 (seed oils).
“Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells” – Zhennan Gu, Jiansheng Wu, Shihua Wang, Janel Suburu, Haiqin Chen, Michael J. Thomas, Lihong Shi, Iris J. Edwards, Isabelle M. Berquin, and Yong Q. Chen – 2013 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765042/
Melatonin has many synergistic effects with the keto diet and curcumin. They all enhance fat metabolism, forcing cells to adapt to it or die if they cannot. Furthermore it is able to destabilize HIF-1a and inhibit AKT expression and phosphorylation (activation). Both important factors in the growth of cells.
We have an opportunity to make the effect of curcumin stronger by combining it with melatonin. I have only found 1 example but I don’t see a reason, for now, to think that the effect would only be limited to this case. Of course further studies will have to validate against other forms of cancer.
AKT and mTORC1 and mTORC2 (driven by PI3K) all 3 target NF-kB which further drives growth transcription. So it is great to see that the combination of curcumin and melatonin together have a higher potency to stop NF-kB.
“Melatonin potentiates the antitumor effect of curcumin by inhibiting IKKβ/NF-κB/COX-2 signaling pathway” – Sandeep Shrestha, Jiabin Zhu, Qi Wang, Xiaohui Du, Fen Liu, Jianing Jiang, Jing Song, Jinshan Xing, Dongdong Sun, Qingjuan Hou, Yulin Peng, Jun Zhao, Xiuzhen Sun, and Xishuang Song – 2017 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592853/
Melatonin’s actions don’t stop there! It actually forces cancer cells to reduce glycolysis in the cytosol by increasing the uptake of pyruvate in the mitochondria. It lowers the lactate production and fast ATP production that are normally the result of glycolysis.
Melatonin also helps to scavenge electrons in the electron transport chain that didn’t flow through it correctly and would otherwise create reactive oxygen species (ROS). It is so important, melatonin even increases endogenous antioxidant production. SOD2 activity is increased via SIRT3 on which melatonin has an enhancing effect.
Melatonin uptake into cells is thought to be through GLUT1. It likely competes with glucose for uptake into cells of which the result is a lower uptake of glucose.
“Melatonin uptake through glucose transporters: a new target for melatonin inhibition of cancer.” – Hevia D, González-Menéndez P, Quiros-González I, Miar A, Rodríguez-García A, Tan DX, Reiter RJ, Mayo JC, Sainz RM – 2015 – https://www.ncbi.nlm.nih.gov/pubmed/25612238
Furthermore, there is interaction between glucose, insulin and melatonin. Taking melatonin supplement has the ability to lower insulin and glucose secretion providing additional power to curcumin in its fight against PI3K.
It inhibits gluconeogenesis in the liver and increases glucose uptake in skeletal muscle and adipose tissue helping to reduce glucose availability to cancer cells.
“Melatonin Uptake by Cells: An Answer to Its Relationship with Glucose?” – Mayo JC, Aguado A, Cernuda-Cernuda R, Álvarez-Artime A, Cepas V, Quirós-González I, Hevia D, Sáinz RM – 2018 – https://www.ncbi.nlm.nih.gov/pubmed/30103453
The effects of vitamin D on the immune system are very important. When the immune cells need to be activated, they’ll increase their expression of vitamin D receptors to take in vitamin D. The vitamin supports differentiation of cells which cancer cells have trouble with and works against metastasis and works anti-proliferation.
Many research results show positive effect of endogenous ketone production while undergoing cancer treatment. This is clear in petri dish, mice and rat studies and also in human studies and has been shown to slow and even stop progression.
Getting the ketone production high enough suppresses glucose output from the liver. This lowers substrate availability for the cancer cells. A ketogenic diet also keeps insulin very low which is needed for curcumin to be effective.
Cancer cachexia is in part serving as a source of glucose. A ketogenic diet will oppose skeletal muscle breakdown preventing or slowing down cachexia.
All inflammatory markers go down on a ketogenic diet. This is important as the cancer treatment (radiation/chemo) will cause higher levels of inflammation putting a burden on your body. This inflammation will raise triglyceride levels giving cancer cells the building blocks to proliferate.
A very important extra is that it also helps stimulate the activation of T-cells and NK-cells through better oxygenation of the tumor microenvironment. BHB also helps T-cells to build up a better glycogen reserve to have a better burst growth in case of pathogens. Being treated with radiation and/or chemo will affect your immune system making you more vulnerable for disease so you need this re-enforcement.
One of the main reasons normal cells are protected is because they are able to adapt to the high fat diet. Cancer cells have a problem with this. Melatonin, ketones and curcumin all optimize fat metabolism essentially shifting the environment into one that is detrimental for cancer.
“Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury.” – Miyauchi T, Uchida Y, Kadono K, Hirao H, Kawasoe J, Watanabe T, Ueda S, Okajima H, Terajima H, Uemoto S – 2019 – https://www.ncbi.nlm.nih.gov/pubmed/31196960
The MCT oil is very easily converted to ketones. Together with the bulletproof coffee and the ketogenic diet, we’ll be able to stimulate a high enough level of beta-hydroxybutyrate (BHB). The butter, cream and coffee itself all either deliver fats that can be easily converted to BHB or, in case of the caffeine, it stimulates fat release which also helps raise BHB. If you can measure your blood level of BHB then we want to aim for above 1 mmol. Higher is better but let’s say don’t let it get much higher than 5~6 mmol measuring fasted in the morning.
So MCT and the bulletproof coffee essentially help the ketogenic diet to raise BHB.
Meat and fish are high in proteins. These proteins, when eaten, are broken down into amino acids. A number of these amino acids serve as a signal in the body to stimulate growth via insulin secretion but also directly, sensed in the cell via mTOR. While there is nothing wrong with growth in itself, during cancer treatment we want to avoid any stimulation of growth as it is overstimulated in cancer cells.
We want to be able to kill the cancer cells at a higher rate then the growth of new cancer cells. Otherwise the tumor can never shrink. When insulin is raised, even only modestly by protein intake then insulin is raised across the whole body, also in the cancer cells.
We can’t afford not to eat protein but taking in protein together with fat causes a reduced speed of absorption with a lowered peak activation of insulin so being on a high fat diet will greatly help to reduce the insulinogenic impact.
Below are some pictures from my brother-in-law. He jumped from one day to the next on this diet and was able to adapt within the guidelines. This is to give you an idea of what to eat. There are plenty of resources on the internet but some are not always so strict on carbs because they don’t have cancer in mind.
It basically comes down to a wide variety of vegetables and a source of animal protein such as fish, chicken, pork, beef etc.. mixed in with a lot of fat. When I say a lot of fat, I literally mean 70% and upwards of your total caloric intake. Fat is your friend.
A small note on the vegetables. Some are high in carbohydrates and are therefore completely excluded such as any type of potato and legumes. Other vegetables such as carrots and parsnip are relatively high. They can be put on the plate but in lower quantities. Keep in mind, we do not want to stimulate insulin with protein but neither with carbohydrates.
Especially the combination of carbohydrates with protein is very potent at stimulating insulin. This is very bad and to be avoided at all cost.
The protocol can be overwhelming at first but once you’ve settled in it is actually not that big of a deal. Once you are comfortable with it you can always step it up a notch. Below are a few topics which deserve attention and can be applied when physical energy permits, when the mental state allows for it. They can be applied at a delayed stage as well but I recommend to start as early as possible and maintain it as long as possible, without forcing yourself! No stress, if you don’t feel like it then don’t. I do find them worth to consider.
Not oxygen supply but acute oxygen deprivation will help stimulate the body to adapt to a low oxygen state. Hypoxia actually stimulates autophagy (which insulin prevents). There are breathing exercises that will create acute hypoxia to which the body will react by creating more capillaries and increase hematocrit and hemoglobin so that more oxygen can be carried and distributed within the body. Follow the link or search on my page for “breathing” and you’ll find an exercise I have composed to get you started. It was posted in December 2019.
Together with curcumin, ketogenic diet and melatonin, being active moves the whole body into the same optimization for fat metabolism. Aerobic activity helps to get adapted and keep those muscles insulin sensitive and receptive to glucose. In the event that glucose and/or insulin would rise, we need the skeletal muscles there to buffer as much as possible.
A tumor is also dependent on lactate. By performing aerobic activity you stimulate the circulation of plasma, possibly helping to clear the lactate from the tumor environment. Lactate suppresses immune function and is involved in spreading (metastasis) of the cancer and is converted to useful metabolites by other cells and shared again with cancer cells.
Don’t overdo the exercise though. Making it too intense also puts a burden on your immune system. Keep it light to moderate, minimum 30 minutes and preferably around an hour every day. The heart rate should go up but you shouldn’t loose your breath while talking.
Similar to exercise we can make sure glucose is taken up by brown and white fat and our skeletal muscles through cold exposure. The cells will try to generate heat using glucose increasing their uptake and consumption. There are 2 common ways to do this and that is taking cold showers and/or taking ice baths. The level of exposure that is needed is not always clear, this for both duration and temperature. I have adopted a habit of always taking cold showers.
The immune system and building muscle requires a lot of zinc so my basic recommendation would be to monitor zinc status and make sure you are not low. Aim for being at least in the middle of the reference range but don’t stress over it. Take a zinc supplement if needed. Increasing your vitamin D level will also increase the absorption rate of zinc.
Inonotus obliquus (Chaga mushroom)
All interventions are aimed at enhancing fat metabolism and shifting away from glucose metabolism together with lowering glucose availability.
Chaga has been researched and shows potent anti-cancer abilities. Its action is also targeted to enhance fat metabolism.
“Continuous intake of the Chaga mushroom (Inonotus obliquus) aqueous extract suppresses cancer progression and maintains body temperature in mice” – Satoru Arata, Jun Watanabe, Masako Maeda, Masato Yamamoto, Hideto Matsuhashi, Mamiko Mochizuki, Nobuyuki Kagami, Kazuho Honda, and Masahiro Inagaki – 2016 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946216/
With all these extras you now have a range of additional tools to use in case you have the energy and feel you can take up an extra arsenal of cancer suppressing adjuvants.
I want to keep this section light but informative enough so you can think about how to prevent getting cancer in the first place.
I would describe cancer as a state of forced growth. This is because a lot of the hallmarks of cancer, the so called oncogenes, deformed mitochondria, lactate production etc… are all normal (!) for a growing cell. It doesn’t make it cancer. What makes it cancer, to my view, is that it can’t get out of this growth state.
So how do we get into this state? There are many causal factors of which genetic mutation can be one of them but it is unlikely to be the only causal factor apart from some rare cases. Detrimental genetic mutations are on the rare side.
Consider it like fire, you need a fuel, a heat source (for example a spark) and oxygen. None of them alone cause fire but we all think of fuel as THE single component that causes it.
For cancer, you preferably need a low oxygen environment (fructose will do just fine!), you need a growth stimulating environment (high carb -> insulin, check). You can add a higher omega-6 (seed oils) to push away the protective effect of DHA and you now have… the standard American diet (SAD) diet.. as a good basis to increase your risk. SAD but true.
Now it is just a matter of time under this highly inflammatory state to get the right (epi)genetic change that will push a cell over the edge to become locked into this growth state. It almost universally results in an augmented expression of PI3K (stimulate growth) and/or PTEN (suppresses growth) ablation hence the protocol targets PI3K. PTEN is there to control PI3K so both an over-activation of PI3K or reduction in PTEN activity can set you on the path to cancer. This over-activation or suppression both can come from a genetic modification but this modification results from a disturbed metabolism.
There are 2 fields of thought which is the genetics origin and the metabolism origin as causes for cancer. Analogous to the fire, both have a role to play. Without the genetic mutation you don’t get a lock-in in growth but without the disturbed metabolism you can’t create the genetic mutation that easily (unless for those rare cases).
The book of David Sinclair was helpful in this because he explained that our cells have a mechanism that supports either growth or repair but can’t do both. By stimulating growth which insulin does powerfully, you don’t give the cell time to do repair of damage, particularly to the DNA.
The damage is caused by the growth so that’s why there is always a swing needed from growth to repair and back. This cycle comes automatically from feeding and not feeding but under conditions of high insulin and lack of oxygen we end up in a state continuously stimulating growth or at least a state where we can’t get sufficient DNA repair done. At some point the right strings (DNA mutations) are touched and lock the cell in growth permanently.
Now restoring sufficient oxygen is not going to help us out anymore and low insulin is also not going to be sufficient to resolve the cancer cell but the above described protocol targets everything possible to kill this growth and resolve the cancer.
If you found this information useful, if you managed to improve your outcome or your loved one using this information, please consider a donation to show your appreciation.
Why a theory behind obesity? Isn’t it just CICO? I’ll use a simple analogy.
You find a little puddle of water so you start mopping it up but then it comes back so you do some more mopping. The puddle of water keeps coming back and bigger if you don’t do any mopping so people tell you to do more mopping and faster. You’re not doing enough to get rid of the puddle!
But if you would look at the root cause, a leaking tap, then you know you have to fix the tap and then clean up the puddle with a last mopping.
CICO is the mopping and my theory shows you how to fix the tap.
First we will have a look where the name HyProCICO comes from which sums up the whole theory in a quick easy name.
To make the information digestible I’ll first describe the theory and then go into the details to provide the backing for the theory.
I will also have a Testing section that shows some scenarios where I simply explain the findings based on my theory. Here and there supported by some reference material.
But before we get into that final Testing chapter there is first a section on the different types of leaking taps that can lead to obesity.
So the sections are:
The name that I have given to the theory refers to the hypothalamusthat does the sensing of energy and amino acids to satisfy energy needs and protect the protein in the body from being used for energy. It will do this by regulating simultaneously both Caloric Intake and Caloric Output.
You’ll find that the theory is actually quite straightforward and doesn’t require much explaining but the ongoing debate in the (scientific) dietary communities shows this root cause is somehow missing from their view.
It will not be a complete theory. It doesn’t cover all regulation that takes place. I’m primarily looking at the most important components in relation to obesity. The hypothalamus is a central organ in this theory but this organ does so much more than the aspects touched here.
There are 2 main aspects that drive food intake. A first is the requirement for energy and a second is driven by the need for sufficient amino acids.
The brain – energy
The brain is a highly energy hungry organ. It senses how much energy is circulating in the blood via the hypothalamus. Energy includes more than just glucose. Since the brain can also run on beta-hydroxybutyrate (BHB) it measures or responds at least to the energy level through the totality of glucose and BHB but possibly also fatty acids.
The totality of energy may be the driver to stimulate hunger… However, it is possible that the level of glucose itself will drive control over what energy is freed up.
When the glucose level becomes inadequate, insulin must lower and glucagon must increase to enable the freeing of fat and conversion into ketones. The hypothalamus controls these hormones through the nervous system.
The brain – amino acids
Not only energy is required in sufficient quantity. Protein requirements also need to be met within the body to make sure cells can be maintained, misfolded or damaged protein can be cleared etc. both for the brain and the rest of the body.
As such the hypothalamus senses circulating amino acids and will stimulate feeding behavior when levels go down.
The energy sources
What happens if there is not enough energy? From the hypothalamus, nerve signals and hormones are secreted to regulate energy release from within the body storage, energy consumption by the body and external energy intake into the body.
We keep a fairly steady temperature production but it can be turned down a notch to save energy. Some people feel the urge to move or exercise a lot or can’t sit still while others don’t budge. Reducing the urge to move can also help preserve energy.
The theory will not go into the aspects of increasing or reducing energy expenditure although the regulation of it is part of why obesity establishes itself. I will briefly reference to these aspects under “The details – Energy Control”.
The amino acid sources
Amino acids become available through our diet by eating protein or are partially coming from recycled proteins within our body. Some of the amino acids will be lost into gluconeogenesis (GNG), no matter their source.
If levels drop below a certain threshold then feeding must be stimulated.
What if we can’t find food? What if on top of that our energy reserves are low (liver glycogen, stored fat)? As a last resort, our protein mass (skin, skeletal muscle, organs) will be broken down to continue providing energy to the brain. This is a situation that must be prevented. We have both an energy level to protect as well as an amino acid level. The brain needs both to function.
So on one hand we have the energy need of the brain that must be met and on the other hand we have the protection of protein.
If the brain senses low energy it will stimulate hunger. If the energy level is not restored, it will break down protein for energy.
The detected low energy level points out that we don’t have much reserve left so the brain better starts stimulating hunger to avoid being starved itself.
In a similar way we find that amino acids dropping in level will stimulate hunger.
What this means is that we have 2 components that both must be available in sufficient levels. We may have sufficient energy but if amino acids are low, we’ll still be stimulated to eat. Vice versa our amino acids level can be sufficient but energy may be low, also stimulating us to eat.
When there is a low level of energy sensed, the GNG process will be stimulated helping to convert circulating amino acids to glucose so low energy can lead to low amino acids. This is an important aspect when looking into obesity. It also helps explain loss of protein mass while still having sufficient fat mass when the sensing goes awkward.
So much for the theory, let’s now have a look at the science behind all of it.
A paper released just recently has found neurons that stimulate glucagon or inhibit glucagon release based upon the glucose level sensed.
In our high-carb diet based society there is little research into the role of ketones and generally only considered as a negative element such as in diabetic ketoacidosis. Therefor we get statements like the following:
during energy deficit such as fasting specific hypothalamic glucose sensing neurons become sensitized to decreased glucose
Become sensitized to decreased glucose or equally satisfied with ketones as with glucose?
What I do suspect but cannot verify is that the stimulation of hunger must be dependent on the total energy but that the level of glucose specifically creates a shift to more lipolysis when its level is going down. I could not find any papers that have looked at this specific aspect.
What we can be certain about is that the brain doesn’t just look at glucose. It can also detect the level of fatty acids and ketones. The capillaries in the hypothalamus region are more ‘leaky’. Presumably to have a better and faster sensing of actual circulating levels.
There is indirect evidence that shows ketones could be part of sensing the totality in energy. Research shows us a reduction in ghrelin when administering ketone esters. But ketones could also have a different, more direct or modulating effect on ghrelin production. Either way, BHB contributes to signaling that energy is available.
Central administration of leucine has also been used and shown to activate hypothalamic mTOR leading to a reduction in feeding. Interesting is that leptine also stimulates mTOR in these same cells explaining the reduction in feeding behavior from leptin.
The hypothalamus can also activate the adrenals to release cytokines which will help increase lipolysis in the adipocytes.
I’ll let the next paper speak for itself:
The arcuate nucleus (ARC) of the hypothalamus contains at least two crucial populations of neurons that continuously monitor signals reflecting energy status and promote the appropriate behavioral and metabolic responses to changes in energy demand. Neurons making pro-opiomelanocortin (POMC) decrease food intake and increase energy expenditure through activation of G protein-coupled melanocortin receptors (MCR) via the release of a-melanocyte-stimulating hormone (aMSH). Until recently, the prevailing idea was that the neighboring neurons expressing the orexigenic neuropeptides, agouti-related protein (AgRP) and neuropeptide Y (NPY) (NPY/AgRP neurons) increased feeding and decrease energy expenditure primarily by opposing the anorexigenic/catabolic actions of the POMC through both the competitive inhibition of melanocortin tone at the postsynaptic level and via directed inhibition of POMC firing rate (Fig. 1)
You see here how energy shortage is reacted on by increasing feeding and decrease energy expenditure and energy abundance lowers food intake and increases energy expenditure.
Now you can understand why weight loss strategies that reduce food intake and demand increase in energy expenditure through activity are completely contradictory to how the body wants to regulates itself ! We think it is all about the energy we eat while it is about the energy that the brain senses. Feeding and decreasing energy expenditure belong to each other, satiety and increased energy expenditure belong to each other.
The following picture is created to show the role of leptin but it gives a good overview of the hypothalamus and several of its structural elements. Mainly the tanycytes which are the sensors, their presence close to the fenestrated capillaries and how tanycytes affects NPY and POMC.
In a mouse test they injected BHB to make it directly available to the hypothalamus but they noted an increase in feeding behavior. That goes against my theory because we’re injecting even more energy than what already circulates so if anything they should be less hungry.
This is a good case of why research leads to wrong conclusions and thus creates confusion. Luckily though, they investigated thoroughly and even confirmed in their discussion that there was a downregulation of glucose AND MCT transporters in the blood-brain-barrier (through which BHB can get into the brain). With lower energy sensed by the hypothalamus due to lowered glucose and BHB you stimulate feeding behavior. Just like the theory predicts.
It would be interesting to find out why such injection has lead to reduction in MCT.
Ghrelin is a hormone secreted in the stomach and said to induce hunger. Research shows us that it depends on NPY and AgRP which are secreted by the hypothalamus. At least one of these 2 elements is needed for ghrelin’s effect.
Ghrelin is highest before a meal and lowest after. As such it is a hormone that signals digestion of food. By signaling that there is nothing in the digestion, through raising ghrelin levels, it gives the hypothalamus a sense that there is no incoming energy or amino acids. And this also means that there is room to stimulate dietary intake.
A mouse knockout model of the ghrelin receptor in the hypothalamus leads to increase in energy expenditure and ablation of obesity. This simulates a signal that food is being digested thus energy and amino acids will be coming in so it increases energy expenditure.
The theory shows a mechanism in which there is a well balanced sensing and regulation. As long as the total energy is OK and amino acids are OK then there is no issue.
When it comes to energy, in order to stimulate hunger and create a surplus in body weight, we must have a chronic situation where there is sufficient energy available but 1) the energy in the circulation is ‘under representing’ what is available OR 2) there is a problem in the sensing or representation of the circulating energy in the hypothalamus.
For various reasons it is possible that energy is not released sufficiently so there is a reduced level of energy in the blood circulation.
The sensing is a never-ending process depending on the continuous passage of blood. Any reduction or increase in blood flow can drive less or more energy to the hypothalamus. Any issue in processing that energy level in the hypothalamus cells will lead to a wrong correction.
When the sensing detects low energy, it will stimulate feeding. No matter how much energy is available in storage.
When it comes to amino acids, a low sensed level can lead to a surplus intake if the dietary protein are low while the energetic value of the food is high. Food with low protein content will not be able to raise the circulating amino acid levels enough so more food needs to be eaten to come up with a sufficient level of amino acids.
A paper from Kevin Hall indicates this by having compared ultra-processed food with unprocessed food. Free intake of food resulted in a perfect match of protein intake (490 kcal/d) between the 2 groups. With energy sufficiently available, it was the protein that drove the intake in this study.
So what are some of the various cases apart from protein dilution in the meal?
I’ve already covered the detrimental roles that fructose play in health and pointed out its link with obesity but let’s focus in on its specific action on the hypothalamus.
As highlighted earlier, the signaling works through the activation of mTOR for which sufficient ATP needs to be available. Glucose, BHB, fatty acid all ensures sufficient ATP. Fructose however depletes the ATP in the cells when it gets metabolized. That will lead to activation of AMPK which is kind of the opposite of mTOR.
The reduction of ATP causes a signal of reduced energy availability. The body responds by increasing hunger and lowering energy expenditure.
Fructose can be taken up from the diet but it can also be produced endogenously. When fructose is metabolized, it leads to an increase uric acid. Uric acid itself activates aldose reductase which is responsible for converting glucose to fructose so fructose has a positive feedback loop whereby fructose ingestion and metabolism further increases fructose production and metabolism.
Insulin is also involved in the energy signaling and regulation by the hypothalamus. Insulin is a known activator of mTOR so it will stimulate the sense of energy excess leading to satiety and energy expenditure. The cells in the hypothalamus express insulin receptors. It is possible that the metabolism of fructose within these same hypothalamus cells creates a similar insulin resistance as happens in the liver.
Pointing out further the effect of fructose metabolism, when fructose is absorbed in liquid form and in high enough quantity and frequently, it will lead to insulin resistance causing high secretion of insulin for prolonged time. This appearance of insulin resistance can be seen as an indication that fructose is metabolized in the body and is thus able to reach the brain where its metabolic effect is indicated above.
As we saw before under fructose, ATP depletion caused activation of AMPK. 2DG, by hindering glucose metabolism in the hypothalamus also causes a reduction in ATP with a resulting increase in AMPK, stimulating an increase in glucagon and corticosterones.
The long term usage of antidepressants is associated with weight gain. When I bumped into this I first wanted to check if they are feeling more hungry. And indeed, it is even used as a combo in underweight elderly to handle their depression and weight at the same time.
So could there be any influence of antidepressants on the glucose sensing in the hypothalamus? It turns out that the drug citalopram, an SSRI antidepressant, reduces the blood flow in the hypothalamus.
Do we find citalopram associated with weight gain?
Celexa (citalopram) has been associated with slight weight gain, but it’s thought that the drug itself doesn’t cause this effect. Rather, the weight increase is likely due to improved appetite from taking the drug. A better appetite can cause you to eat more, leading to increased body weight.
Because I remember from hearsay that lack of sleep can cause weight gain I thought this would be interesting to check out. The story is more complex here because it is specific to sleep and temperature regulation is important since we can’t simply put on an extra cover when we are cold.
A study in rats does show melatonin induces a reduction in blood flow in all areas including in the hypothalamus. But is it representative for humans?
Such a brain wide reduction in blood flow would also result in a reduction of oxygen supply. In addition it also lowers energy signaling from all other hormones such as leptin, ghrelin, insulin etc.. Interesting…
Melatonin is produced during the whole night and during our sleep the body temperature drops. How is this temperature regulated at night?
During our sleep, temperature is diverted from the core to the skin through vasodilation. This probably evolved in our evolution that way to protect us from too cold ambient temperatures with death or frost bite from cold during sleep.
We find that melatonin increases BAT and beige activity which are known to create heat by uncoupled metabolism which means consuming energy just for the sake of producing warmth. It is possible that melatonin acts directly on the fat cells so it doesn’t work through the hypothalamus.
This is perfect to keep warm during the night and would explain the reduction in brain blood flow to simulate energy shortage, thereby releasing more energy which then can be used for the heat generation.
The hypothalamus can also induce thermogenesis but this is part of energy expenditure and falls under sensing sufficient energy and is also stimulated by cold sensation signals (like a cold shower).
The level to which our temperature can drop will make a difference in how much energy needs to be spent to keep us warm.
What we see in obese subjects, a high energy evening meal causes less weight reduction versus an isocaloric daily intake where the largest portion is taken during the morning.
I’m trying to look at a diverse list of scenarios to see if I can explain the outcome using the theory. In such a way you’ll be able to understand how I see the model working and allows you to refute or ask questions. My theory does need validation.
Glycogen Storage Disease type III (GSD3)
A first example is GSD3 where they report a prevalence of enlarged liver (hepatomegaly) of 98%. This disease has a problem with breaking down glycogen into glucose to release it into the circulation. It also shows us that there is not really a fixed ceiling for storing glucose in the liver. The liver adapts growing larger to store more.
The patients are intolerant to fasting. They can generate ketones but their glucose levels are too low (because they cannot free it up fast enough from the liver) despite the ketones they may produce.
One of their symptoms is (chronic) hunger. With their reduced available glucose, it could be beneficial if they are on a high fat diet to generate more ketones and as such provide the necessary circulating energy.
Linked to GSD3 but actually the opposite we find in Inuits. They have a mutation that reduces their ketone production capacity. Where GSD3 cannot provide enough glucose, we find in the Inuits affected by this mutation that they cannot provide sufficient ketones.
Not only does the high protein allows them to maintain glucose level but in addition is the fat helping them with keeping warm in the arctic climate.
I couldn’t find any clear references but traditional eskimos are said to have enlarged livers and eat a high level of protein. If this is correct, it would fit the theory in such a way that there must be an increased capacity to produce glucose for a longer period of time throughout fasting in compensation for a reduced ketones production capacity.
If anyone can contribute to finding good references towards the protein intake and the liver size then I would be very grateful.
Their traditional food does seem to provide a large amount of protein. I see numbers around 133~166gr of protein for adult males (20-60y) while they have an average height of around 165 cm. That would support a high protein consumption.
A study tested the effects of hunger, appetite and weight loss in 2 different groups. A first group on a low carb high protein diet (30%p; 4%c; 66%f) and another group on a medium carb high protein diet (30%p; 35%c; 35%f). They were fed ad libitum. To understand the results make sure you have also read my article on gluconeogenesis being a supply driven process.
What happens here is that the high protein intake helps to replenish the glucose level in the liver for both groups. The difference however is that the low carb group has lower meal-triggered insulin release. This allows the low carb group to release more fat for energy which leads to ketone production.
The medium carb group has a very high insulin secretion due to being combined with high protein. This is how incretins work out (check out the video under “Regulation”). This raises the excursions into hypoglycemia post absorption. In such a phase the hypothalamus may react with hunger stimulation.
Both low ghrelin and high leptin should signal to the hypothalamus that there is abundance of energy so it should lead to a reduction in appetite and increase energy expenditure.
Active research in this field has defined the term leptin resistance. One of the mechanisms could be that leptin has a reduced capability to cross the blood brain barrier (BBB) and as such cannot provide its signaling. This has been shown in mice by leptin administration directly in the brain, bypassing the BBB. What causes this issue in crossing the BBB is under investigation. There are also thoughts regarding disturbed signaling because the hypothalamus could get inflammed when metabolising fructose due to the stress of low ATP availability.
When it comes to ghrelin, it is probably a non-factor. Meaning that high ghrelin can induce hunger but it does not mean that low ghrelin induces satiety nor that high ghrelin is needed to induce hunger. Activation of AMPK is already sufficient to release NPY so although low ghrelin may signal digestion is going on, if AMPK is activated for some reason then hunger is stimulated.
Obese insulin sensitive and obese insulin resistant
There are obese people who develop insulin resistance as you would expect from high fructose consumption. Yet there are also those who remain sensitive.
I’m missing quite some data on these people but in the following study something caught my eye. The obese sensitive people have significant lower fasting triglycerides. What this may mean is that the fat which is produced in the liver from fructose is quicker cleared and moved out of the liver. This would prevent NAFLD and insulin resistance.
They may have a quicker response to the fructose induced lowering of insulin and increase in glucagon. By quicker releasing the fat from the liver there is less chance of building it up to cause restance.
The fat however is created and needs to be stored elsewhere.
The development of a fetus during a period with inadequate maternal protein consumption has consequences for the offspring. This has been tested in Sprague-Dawley rats. What is interesting about this experiment is that the offspring rats had an increase in hunger, consuming more calories, yet at a lower body weight which the authors suspect is due to increased energy expenditure. This is a very big difference in energy expenditure. It is not eat more and weigh the same, but eat more and weigh less.
Qasem RJ, Li J, Tang HM, Pontiggia L, D’mello AP. Maternal protein restriction during pregnancy and lactation alters central leptin signalling, increases food intake, and decreases bone mass in 1 year old rat offspring. Clin Exp Pharmacol Physiol. 2016;43(4):494‐502. doi:10.1111/1440-1681.12545 https://pubmed.ncbi.nlm.nih.gov/26763577/
So what is going on? The following study gives us a glimps of what may have taken place. They looked at hypothalamic cells in the fetus of maternally protein restricted rats. Most of the upregulated genes are involved in the mitochondrial complex. I suspect this is not only in the hypothalamus but system wide and is done to increase mitochondrial mass with the purpose of increasing the protein protection by enhancing fatty acid metabolism.
Frapin M, Guignard S, Meistermann D, et al. Maternal Protein Restriction in Rats Alters the Expression of Genes Involved in Mitochondrial Metabolism and Epitranscriptomics in Fetal Hypothalamus. Nutrients. 2020;12(5):E1464. Published 2020 May 19. doi:10.3390/nu12051464 https://pubmed.ncbi.nlm.nih.gov/32438566/
Further changes noted in the offsprings is an enhanced gluconeogenesis capability. Improving the ability of the liver to increase glycogen storage and maintain glucose output is another way to protect protein from serving as a glucose substrate.
A very recent study, also from Kevin Hall, comparing high carb with low carb ad lib intake shows again the need to meet sufficient amino acid levels. This time however there was not an equal intake of dietary protein so what happened?
The previous study from Hall (see “Obesity”) had a different distribution in macronutrients. Here the much higher carb offers more protection from protein catabolism by providing a large amount of glucose and stimulation of insulin. Insulin protects the muscle from breakdown and the high glucose makes sure the liver can supply a steady stream of glucose to satisfy the needs of the brain.
OK but why did the low carb diet led to such a high intake? By taking out carbs from the diet, the liver glycogen lowers. This lowers glucose availability. The brain will react by lowering insulin and increasing glucagon. This will lead to a higher level of GNG whereby also the circulating amino acids are converted to glucose.
BHB can compensate for the lower glucose but the production of BHB is not immediately increased. To cover this transition until BHB production is high enough, protein need to fill in as a source of energy (glucose) so there is a temporary need to increase protein intake to help supply the circulating glucose and circulating amino acids.
The body does not want to give up its own protein so it will increase hunger feeling. This will lead to an increase in food intake whereby the food intake will directly cover the glucose requirements. The food contains little carbs so the protein in the food will for a part be converted to glucose while at the same time the dietary protein also have to serve as a supply to maintain amino acid levels.
In the first week we see an immediate jump up in dietary intake. During the first days BHB production is too low to help compensate for the drop in glucose. As BHB ramps up throughout the week we see the intake reduce. In the second week we see a marked lower intake versus the first week now that BHB has reached a meaningful level.
There is still a difference in caloric intake because the protein in the diet are not sufficient to keep the circulating amino acids up. GNG is high for the low carb diet and there is very little glucose from the diet. A longer study is required to see how this further evolves. This study has helped us view what happens during the first 2 weeks when transitioning into a low carb diet.
Preprint reference: “A plant-based, low-fat diet decreases ad libitum energy intake compared to an animal-based, ketogenic diet: An inpatient randomized controlled trial” https://osf.io/preprints/nutrixiv/rdjfb/
Once the transition period is over, it will be easier for the body to obtain energy from BHB through fat metabolism and glucose through the GNG process. There is a system wide adaptation whereby the brain will start making ketones, the skeletal muscle will use more fat for energy etc..
The whole system has to adapt to rearrange how it provides sufficient energy to the brain and thereby finds a new equilibrium to spare amino acids.
To further support the “transition period” with more evidence, the following study shows a longer trial of 30 days whereby we see an accelerating fat loss after 15 days. It was also conducted by Kevin Hall et all.
It was also noted that there was increase urinary nitrogen. As I explained, the lack of sufficient compensation by BHB during the transition will result in the breakdown of protein.
Urinary nitrogen excretion increased by 1.5 ± 0.4 g/d (Table 3; P = 0.0008) during the KD phase and indicated significantly increased protein utilization. The time course of the changes in urinary nitrogen excretion showed that the increased protein utilization occurred within the first week of the KD and persisted until day 11 (not shown).
Further support for the transition effect comes from a study where they tested the low carb effects of exercise across a very short duration. Via phenylalanine they found a greater oxidation of the amino acid showing that if you are not sufficiently transitioned, low liver glycogen will result in low glucose and therefor a greater amino acid conversion to glucose via GNG.
In an experiment to overfeed people we see that calories do matter to gain weight. But what the referenced study did was gradually increase overfeeding (20%, 40%, 60%) with each time a period of ad lib food intake to satiety. In the ad lib period after the 60%, the subjects naturally started to eat less calories than at baseline.
None of their allowed drinks contained any liquid sugar or fructose allowing for the automatic regulation of energy intake and expenditure.
Finally the authors conclude:
regulation must be dominated by hypothalamic modulation of energy intake. This result supports present conclusions from genetic studies in which all known causes of human obesity are related to defects in the regulation of appetite.
Siervo M, Frühbeck G, Dixon A, et al. Efficiency of autoregulatory homeostatic responses to imposed caloric excess in lean men [published correction appears in Am J Physiol Endocrinol Metab. 2008 Apr;294(4):E808]. Am J Physiol Endocrinol Metab. 2008;294(2):E416‐E424. doi:10.1152/ajpendo.00573.2007 https://pubmed.ncbi.nlm.nih.gov/18042669/
Migraine (added 1 dec 2020)
Today (1 dec 2020) I bumped against a post on Twitter explaining why you can get hungry when you have a migraine. Because of this theory I immediately suspected an impact on hypothalamic blood flow so a great case to test the theory.
As it turns out, this year a paper came out showing a reduction in blood flow in the hypothalamus. It perfectly demonstrates how the hypothalamus is the central organ that detects energy and responds accordingly.
Why the blood flow decreases is unfortunately not revealed.
Our results reflect that immediately prior to a migraine headache, resting regional cerebral blood flow decreases in the lateral hypothalamus. In addition, resting functional connectivity strength decreased between the lateral hypothalamus and important regions of the pain processing pathway, such as the midbrain periaqueductal gray, dorsal pons, rostral ventromedial medulla and cingulate cortex, only during this critical period before a migraine headache.
There was a study done in rats to find out the effect of lauric acid, a medium-chain fatty acid. They wanted to study the anti-obesogenic properties of lauric acid. They noticed a modulation of NPY and AGRP in the hypothalamus showing there is a reduction in hunger stimulation.
The mRNA expression levels of the anorexic neuropeptide POMC in the hypothalamus between the LT group and the other groups were not different, while the gene expression levels of the orexigenic neuropeptides NPY and AGRP decreased significantly in the LT group.
The hypothalamus, based on what it detects will control the vagus nerve to control the pancreas in releasing glucagon and insulin. The following experiment shows that when stimulating the vagus nerve, it will lead to a higher metabolism and more weight loss in an isocaloric setting.
This drug is injected and successfully treats diabetes and causes weight loss. What does it do? It’s a GLP-1 receptor agonist, basically it mimicks GLP-1 that is normally released as food comes in and tells us that we have eaten enough.
We see that it reduces the response to highly desirable food so the mental desire for food is influenced by physical factors with signals passing through the hypothalamus.
“GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial” https://pubmed.ncbi.nlm.nih.gov/26831302/
How it achieves the increase in weight reduction is through increasing metabolism by stimulating T4 secretion.
The evidence is now quite broad but let me add one final element. Central administration of bile acid in the brain, presumably signaling incoming food and more specifically fat, signals energy and is responded to by stimulating the sympathetic nervous system. This increases the metabolic rate through various ways leading to reduced weight accumulation, up to weight loss itself.
As you can see, the hypothalamus is central to the regulation and it acts based upon all the different inputs that tell us something about the energetic status of the whole body.
I hope it is clear with this article that obesity is not simply a matter of calories. Yes a calorie is a calorie and under controlled equal caloric feeding you may not gain weight but such controlled feeding is not our natural world.
When people get obese, we need to think in terms of energy and amino acid sensing. It’s the sensing that needs to be fixed, not how much we actually have available. We have no long lasting will power over this sensing, we can fight it but eventually succumb to the automated regulation.
When the brain signals hunger and lowers metabolism… eating less and moving more is completely opposite of what the body wants to achieve and only further aggravates the signal if we don’t fix the underlaying problem.
We need to work with the system, not against it:
Protect your protein by having a sufficient supply of circulating amino acids
Avoid any other issue outlined above that would interfere with the correct sensing of energy or would interfere with releasing sufficient energy from the storage places
Take care of these problems and the body will auto-regulate itself towards a more lean and active individual.
For most people, taking out fructose will solve much of the problem so consider this number 1 on the priority list.
Note: No doubt that there are other causes that can lead to obesity but they likely will all show somehow to influence the described mechanism and may not always be fixable when they cannot be adapted for by lifestyle changes.
I won’t know until I have antigen testing done but I’m fairly sure I was infected with the SARS-COV-v2 aka COVID-19 at the starting of March. Last year I was also diagnosed with lymphoma. The connection between the 2 is that the lymphatic system is involved in the defense against infectious pathogens. If you have cancer in your lymph nodes then viruses become a potential aggravating factor. This is something I experienced as the affected lymph nodes became more sensitive during the COVID-19 infection and on the latest PET-scan showed increased activity. Naturally my interest is sparked in this area.
So with that introduction, the main reason to write about vitamin D is because of its role in the immune function and because that is of interest to the general public. For me there is an extra motivation due to the lymphoma. So join me in the exploration and let’s see what we can dig up.
The research is split up into observational, interventions and cellular studies so that we can have a better overview and see how they relate to each other.
Vitamin D is an enhancer in reactions and helps to either upscale or downscale effects. It affects the expression of over 2000 genes.
In the “Structure” section you’ll see about the half life of the different molecules and at the bottom section you’ll see about supplementation. This makes research tricky if it is not followed up and measured properly. The way the dosing is done can already create no noticeable effect so I won’t be looking into those kind of studies.
If you already know the ins and outs of vitamin D then you can skip the next section but I want to introduce high level the different forms and at the end I’ll show what I consider good supplementation strategies and why. If you don’t do it right, you could be throwing money in the toilet (or donate it to me to keep this site up and running 😉 ).
As most people know, vitamin D3(D3) is produced in the skin through UVB exposure. There is also vitamin D2 but I’ll not get into that. D3 is cholecalciferol and is what you find in most supplements. It has a half life of around 24 hours or even a bit shorter.
D3 is converted in the liver to 25-hydroxyvitamin D which I’ll refer to as 25D from now on. This is what is measured in your blood panel by your doctor and it is also known as calcifediol or calcidiol. It has a half life of several weeks. You will see that in most of the scientific literature, this is what is reported on and measured to find association with clinical outcomes etc..
25D is not yet the active form though. It needs to be further converted to 1,25 dihydroxycholecalciferol(1,25D) also known as calcitriol. This is done by both the kidneys and virtually every cell in your body. Its half life is in the range of a few hours at most.
Important about observational data is that we look at 25D status before disease appears. If 25D is affected by a disease itself then it doesn’t make sense to claim any links on the diseased state due to 25D status.
First too give some idea about blood levels of 25D, a level of 20 ng/mL (x2.5 -> 50 nmol/L) is reported to be adequate by this paper to prevent respiratory infections. Whether this is correct is another question but it allows you to map your own 25D level to this reference.
When looking at athletes, measuring 25D before and after and record their incidences of illness and severity symptoms related to respiratory infections during winter. They also measured cathelicidin which we’ll come back to under the “Mechanisms” section. At the start the median 25D (total so including the small fraction of D2) was 57 nmol/L and at the end, after 4 months, dropped to 47 nmol/L. The groups were divided as follows:
12-30 nmol/L (deficient) -> 4.8-12 ng/mL
30-50 nmol/L (inadequate) -> 12-20 ng/mL
50-120 nmol/L (adequate) -> 20-48 ng/mL
>120 nmol/L (optimal) -> >48 ng/mL
Everything tracks along their 25D status according to nr of infections, severity and duration.
I want to highlight from this study the following 2 graphs because they relate to the ‘cytokine storm‘ that has been mentioned so much in relation to the severity of symptoms during a COVID-19 infection. They took blood samples and tested the cytokine reactions in the lab.
As you can see, those with sufficient vitamin D levels are able to produce more cytokines. Keep this in mind when reading further below the “Immune cells” section.
The next study did a similar thing except they measured 25D every month and had respiratory infections evaluated by the investigators. The investigators were blinded from the 25D status. Again we see a correlation in incidence, severity and duration based on 25D status. The researchers also conclude that levels of 38ng/mL or above should be maintained.
There were only 18 subjects >= 38 ng/mL so the sample is relatively small compared to the 180 who were below. Note though that the 18 subjects were the ones who still had a high 25D status at the end of the study. At the beginning there were 32 people. So at the end of those 18, 83.3% in the high 25D group survived the observation period without infection compared to 55% in the low 25D group.
One more follow up study this time in Canadian children shows us again the same observation. They found 25D status to be correlated with respiratory infection (and age). Levels of <70 nmol/L (28 ng/mL) increased the risk with 50% and levels <50 nmol/L (20 ng/mL)increased the risk with 70%.
For interventions we can look at what the effect is of supplementation (either supplementation or increased sun exposure) and how that prevents disease but we can also look at a diseased state and see if supplementation helps you recover more quickly. It is very well possible that only one of these scenario’s is effective. We’ll see.
A major review finds a reduction in death when D3 is administered together with calcium. That is interesting but is that due to improvement in immune function and thus prevention from infection-caused death or more due to reduction in fracture etc.. so no conclusions from this one yet.
The task would be too big but you would have to go through all the trials in the review and see what dosage was used and how frequently administered. Not only intake but you’d also have to assess to what levels the subjects their 25D was improved. There is a lot of variation and that influences the reported results.
A first RCT shows quicker recovery when supplementing with 25D. Interesting as usually D3 is supplemented. This is probably done to overcome issues with the liver in the conversion of D3 to 25D. Both the duration and the severity were reduced with a supplementation of 10 microgram/day (400 IU/d). Because it was double-blind placebo controlled, we don’t know by how much this raised patients’ 25D levels. They did report that about 59% started with a deficiency of levels below 30 ng/mL.
The next intervention was in school children (6-15 y) and noticed a reduction in Influenza infections versus the placebo group. They were given 1200 IU/d and the trial was run from December to March. Although a reduction is noted, we have no clue on their starting and ending 25D status.
In a special group of patients with frequent respiratory infections or antibody deficiency they gave 4000 IU/d for 1 year. Their baseline level of 25D was around 50 nmol/L (20ng/mL). The daily intake resulted in an increase towards 133 nmol/L (53,2 ng/mL). They went into the details to detect differences in bacteria and fungi and found primarily Staphylococcus aureus and fungi to be reduced. The end result is a reduction in infection burden as we see throughout all the studies.
As a third category we can see what we find in the lab. What do we find as effect at cellular level and does that fit within our observations and interventions?
For the actual mechanisms we’ll need to look at the active form 1,25D.
The active form 1,25D keeps the epitehlial cells and endothelial cells better clustered together, decreasing permeability so keeping a tight junction. We see this reflected in the blood-brain-barrier and also in the gut.
In the gut they tested the effect using lipopolysaccharides (LPS). LPS causes an increase in gut permeability allowing pathogens, from which the LPS originates, to enter the body. We see here a fight between LPS trying to downregulate the vitamin D receptors (VDR) while 1,25D restores it.
“1,25-Dihydroxyvitamin D3 preserves intestinal epithelial barrier function from TNF-α induced injury via suppression of NF-kB p65 mediated MLCK-P-MLC signaling pathway.” https://europepmc.org/article/med/25838204
Both the D3 supplementation and production in the skin from the sun causes the skin to produce cathelicidin. This is like our endogenous antibiotics production but the effects are more wide and modulate our immune system as shown in the image. For more information you can check the reference but I wanted to highlight specifically the antimicrobial function.
First a quick word of explanation. What we have seen with COVID-19 is that the immune response is prolonged in the more severe cases. The so called “cytokine storm” is a severe and prolonged response of the immune cells which are tasked to destroy infected cells. In the lungs, the endothelial cells are the first in line to be infected and destroyed by the immune cells but that leads to leakage of plasma into the aeveoli, restricting the ability to breath.
What we want is an immune system that can respond quickly by very fast proliferation so that enough immune cells are created to handle the infected cells but also fast to stop the virus from spreading and infecting many cells. This is the defense that is needed. We also want a quick turn-down of this proliferation once the threat has been handled to avoid excessive damage.
If the initial response is not fast and strong enough, we risk a more prolonged fight because the virus is able to spread more, causing a prolonged increase in immune cells and destruction of infected cells increasing the overall damage.
A first good indication of modulation by vitamin D is the presence of a receptor for it. 2 review paper shows us that the immune cells (monocytes, macrophages, dendritic cells (DCs), T-lymphocytes and B-lymphocytes) have VDR’s to produce their own 1,25D showing that vitamin D is an active player in these cells.
In order to replicate fast, the immune cells require ATP via the cytosolic glycolysis. This happens in T-cells when an anti-gen is presented. Glycolysis means that the ATP has to come from glucose.
Unfortunately I could not find tests on immune cells but we can have a look at cancer cells and embrionic cells, which both are cells that proliferate at a rapid rate, to have an idea what 1,25D may mean. We see in a cancer-specific cell line that the active 1,25D is able to reduce glycolysis. In an embryonic kidney cell line it is able to modulate the reductive state. I’m interpreting here but what it means, according to my insight, is that it will support the capability to switch back from glycolysis to oxygen phosphorilation. This is important for a cell to stop the proliferation.
Not only can it help to induce differentiation, it can also help to prevent differentiation. This is an example of how 1,25D provides a supportive modulatory role. In the paper below, the preventive action improves encephalomyelitis, an autoimmune disorder potentially linked to T17 cells.
One of the reasons vitamin D could be improving autoimmune diseases is because it modulates dendritic cells (DCs) in such a way that it reduces T cell response. DCs are the cells that present antigens to T cells who then respond to this antigen by fast proliferation.
This effect on DCs seems contrary to the fast and strong (but short) response needed from the immune system but what I suspect is going on is that it doesn’t disable DCs ability overall but is probably fine tuning DCs more towards pathogens somehow.
We find improvement in immune function with higher 25D levels so it must have a beneficial effect somehow.
Although not directly about vitamin D, I found a presentation that talks about how incorrect adaptation in metabolism of the T cells can lead to several diseases.
Taken together, it shows that vitamin D is important in potentiating a correct adaptation in immune cell metabolism to provide the right type of response.
The cell cultures reveal interesting modulatory roles primarily in the differentiation, possibly by regulating the way energy is metabolised. The papers show the highly complex world of immunology.
Not only is there direct effect in the way immune cells behave but also in the protective barriers such as the epithelial lining in the gut and vasculature do we see its involvement together with an antibiotic production.
The observation and intervention sections show us, in line with the cell cultures that vitamin D status, measured through 25D, does make a difference and is important to maintain an optimal state. What that level should be is debated but it is clear that there is no upper limit defined as of which there are no more positive effects observed.
There is toxicity possible but for that you need to go higher than what you would receive from the sun. Our skin darkens in response to sun exposure and this lowers the D3 production but with supplementation we don’t have this automatic protection. But we are talking about regular intake of 500 000 IU for a longer period whereby the toxic effects are easily reversed by stopping the supplementation.
The exercise has been done reviewing the dosage used and timings. The best approach seems to be on a daily basis. The reason for that is because you are normally supplementing with D3 which has a half life of 24 hours roughly. This means that if you take a big bolus once a month of say 100 000 IU, the next day your body has 50 000 IU left, the day after 25 000 IU etc.. After 7 days you have about 1562 IU left. In contrast if you take 2000 IU every day then you only get 60 000 IU per month but it will be much more effective.
This is also reflected in a review of randomized control trials regarding respiratory infections:
There is evidence that daily administration is more effective than high-dose bolus administration [OR = 0.48 (95 % CI 0.30–0.77) vs. OR = 0.87 (95 % CI 0.67–1.14)]
Personally I decided to take multiple dosages of 1 000 IU spread across the day. Whatever the dosage you take, I would suggest to spread it from early morning to late afternoon. This is 1) to anticipate on the liver conversion capacity of D3 to 25D and 2) to avoid any negative effect on sleep.
I would suggest not to take D3 in the evening. I could not find any papers showing an immediate influence on melatonin production but out of precaution I think it is better to mimick the natural production we would have from the sun. A light dose in the morning, the heaviest dose at noon when the sun is the highest and a light dose again in late afternoon.
There are papers that looked at 25D and sleep and find correlation between bad sleep and 25D deficiency. There is also a paper looking at MS patients reporting reduction in sleep. However they looked at metabolites in urine rather than sleep or direct melatonin production so we can’t really derive much from those results. Due to the long life I don’t consider 25D having an immediate effect related to intake and melatonin.
Anecdotes and even a very thorough n=1 experiment indicate it is best not taken at night. My way of intake likely will be synergistic with the circadian rhythm.
If I know I will exercise then I’ll take an extra dose. It has been shown that exercise increases 25D production during and post exercise. I suspect that this is due to the increase in blood flow pushing more D3 through the liver. Whatever the cause, we want our 25D status up so this is a good way to make most use of your D3 intake (or sunshine).
I came across a couple of resources and started to appreciate how different fructose is from glucose. In the low carb community, carbohydrates are obviously avoided or at least high amounts of it as they are generally considered bad. I support this approach but when we zoom in on fructose we notice that it is not so much glucose that is causing all typical chronic diseases but fructose.
Sugar is associated with metabolic syndrome (hypertension, insulin resistance, Type 2 Diabetes, NAFLD, cancer, …) as well as brain-related issues such as Alzheimer’s, dementia, Parkinson etc.. but what is it about sugar that makes us succumb to disease? Being half glucose half fructose, there are only 2 components to look into.
Can it really be glucose? We do have populations that have been eating high amounts of rice, wheat, potatoes… products that are all high in starch which get broken down into glucose and absorbed into our body. Yet metabolic syndrome is something that started to appear and evolved since the 1900’s.
What I will show you here is how fructose is causal to a lot of these diseases so that you understand it is fructose specifically that needs to be kept out of the diet. I do not recommend high starchy foods (glucose) either due to other factors but that is not the focus of this article.
Immediately some people will reflect on fruit because that is what we usually associate with fructose. The danger from fructose comes from a combination of quantity and speed so there is less to worry about as most fruit comes in a package of fiber that needs to be munched down so that speed and quantity is low. However, if you take down for example 3 or 4 oranges in one go then you’re no better off than drinking a glass of sugar sweetened beverage (SSB).
As a starter I would advice to listen to the Attia podcast with Rick Johnson, M.D. , researcher of fructose since many years. The podcast is packed with knowledge, it has opened my mind on fructose. I’ve used it to find research papers to support the link with the diseases I’m listing below.
Insulin Resistance (IR)
A first topic I already covered in another article where I explain about the differences in Insulin Resistance based on fructose versus low carb. It comes down to fructose metabolism causing a buildup of diacylglycerol or DAG. The effect of it is that it prevents insulin signaling.
To show you that the effect of fructose is real and already known since a long time. The paper below tested a hypocaloric diet with different liquid forms (glucose, galactose and fructose) in 14 days. They discuss other papers where they have seen every time that hypocaloric diets increase the insulin receptor in different cell types. This is an effect attributed to the hypocaloric content. What they noted was that in case of fructose there was no such increase in insulin receptors.
Closely linked to IR we have NAFLD. The accumulating fat from the fructose metabolism in the liver causes IR but if it further aggravates then it develops into NAFLD.
There is a specific mechanism activated in response to the high fructose availability and that is carbohydrate response element–binding protein (ChREBP). This mechanism increases cholesterol synthesis but it also stimulates de novo lipogenesis. That is unfortunate because it is the buildup of fat that is causing the problems so creating more fat is the last thing needed.
I suspect that fructose has a similar profile to glucose to stimulate ChREBP. This is how excess in glucose is handled. There is a second pathway via SREBP1c but this is insulin mediated. ChREBP downregulates SREBP2 yet in how far that is different from SREBP1 is unknown to me at the moment. It is possible that with IR already build up, insulin won’t be able to activate SREBP1 much.
What is important here is that when de novo lipogenesis is activated, it also converts glucose to fat. So not only does fructose get turned into fat in the liver, it also stimulates the conversion of glucose to fat in the liver.
Glucose and fructose have differential effect on the brain apart from the regions where there is overlap. What is interesting to see is that fructose causes a reduction in blood flow in the region that is affected by Alzheimer’sdisease.
Hippocampal atrophy is part of Alzheimer’s disease. What does fructose do in a mouse study? Likely as a result of the reduced blood flow it could cause hypoxia and of course the hypoperfusion leading to insufficient nutrition with atrophy as a consequence.
Fructose consumption reduced the levels of the neuronal nuclear protein NeuN, Myelin Basic Protein, and the axonal growth-associated protein 43, concomitant with a decline in hippocampal weight.
There are different mechanisms proposed to how fructose affects the regulation of appetite. It doesn’t mean that there is only one correct. It could very well be that all the different mechanisms are at play at the same time. I won’t go into detail listing all the possibilities but you can scan through the papers if you want to know more.
What is clear from the different research papers is that fructose causes increased food intake while glucose has a satiating effect.
One of the ways obesity is stimulated is by having a high response of insulin which suppresses plasma glucose below baseline resulting in a sense of hunger. Fructose exaggerates the insulin response to glucose so that it will lead to a suppression of glucose below baseline.
How can fructose lead to hypertension? It is clear that animals respond badly to fructose.
Animal studies have shown that high-fructose diets up-regulate sodium and chloride transporters, resulting in a state of salt overload that increases blood pressure. Excess fructose has also been found to activate vasoconstrictors, inactivate vasodilators, and over-stimulate the sympathetic nervous system.
But not only animals respond bad to it. After reviewing the NHANES data and adjusting for many confounders they found fructose independently associated in US adults without (!!) a history of hypertension. Blood pressure was reviewed in adults who were not diagnosed with hypertension before the study started.
After adjustment for demographics; comorbidities; physical activity; total kilocalorie intake; and dietary confounders such as total carbohydrate, alcohol, salt, and vitamin C intake, an increased fructose intake of ≥74 g/d independently and significantly associated with higher odds of elevated BP levels: It led to a 26, 30, and 77% higher risk for BP cutoffs of ≥135/85, ≥140/90, and ≥160/100 mmHg, respectively. These results suggest that high fructose intake, in the form of added sugar, independently associates with higher BP levels among US adults without a history of hypertension.
Also here we see a different effect and again not a good one. I’ll just directly quote from the article abstract.
In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle–triglyceride and –cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.
It shouldn’t be a surprise to see here that insulin sensitivity went down and visceral fat went up. This was covered in the sections above.
So we have an increase in small dense LDL, oxidized LDL and triglycerides. There are communities of researchers who think less of LDL as a marker for atherosclerosis but I think you’ll find almost nobody who doesn’t agree on small dense LDL, (excessively) oxidized LDL and high triglycerides as dangerous markers for increased heart disease.
A study on rats shows how the damage builds up with fructose.
Under light microscopy, the kidneys of the HFD group revealed amyloid deposits in Kimmelstiel-Wilson-like nodules and the walls of the large caliber blood vessels, early-stage atherosclerosis with visible ruptures and scarring, hydropic change (vacuolar degeneration) in the epithelial cells covering the proximal tubules, and increased eosinophilia in the distant tubules when compared to the control group.
One of the causes for kidney failure is the increase in uric acid which is also a cause for kidney stones. The consumption of fructose has a fast response in uric acid production as you can see in the image under (A), the plasma uric acid. The 2 lines at the bottom are the 2 controls.
This study is in rats but for now there is no reason to suspect a differential effect in humans. What happens here is that fructose causes a lower serum level of 1,25(OH)2D3. This is the active form of vitamin D. The result is that the serum level of calcium doesn’t increase while it was expected and does take place under glucose instead of fructose feeding.
The volume of papers on the effects of fructose that I referenced above are just a small sample of what you can find. The links with the diseases are strong but is our health policy targeting avoidance of fructose? No.
It is just a guess but I think policy makers and their advisors don’t want fructose to be demonized because it is part of ‘healthy’ fruit.
I don’t want to demonize fruit either. It causes no harm when it is part of a meal or under small amounts such as in berries but I don’t consider fruit necessary.
Fruit not necessary? What about the anti-oxidants, vitamines etc.. I hear you ask. Join me for a minute in my imagination where I get dropped in a European wood far from civilization and I have to survive in the vast area, allowed to eat all the fruit I can find.
First of all, I won’t find fruit unless I’m there at the right time of the year. How necessary can it have been in our evolution?
Secondly, when I do find fruit wild in nature, it are berries. Not the monstrous sized apples etc. We cultivated them to be huge. We didn’t go through evolution with access to large fruits, perhaps apart from a few exceptions. At least not in Europe.
Thirdly, when I do succeed to find a source of berries, I’ll be in competition with the rest of the animals who all want to obtain some fructose. They also enjoy the sweet taste.
Fourthly, when I manage to find that source of berries, they are not all ripe at the same time. The 1 or 2 handful that I’ll be able to get the first time will result in about maximum a handful for the next set of days.
If you are lucky you’ll find a berry field at the right time and score some more but the point is that we cannot expect to have evolved on fruit being an important part of our diet because we simply didn’t have access to sufficient quantities for them to make a difference.
Even if it provided us a little edge on survival, today we have no need to build up a fat reserve using fructose to survive winter. Certainly not in the quantities it is consumed today. And we consume a lot through sugar which is half fructose half glucose.
The problem is most apparent when drinking fructose-containing liquids (fruit juice, sugar sweetened beverages).
If I can recommend only one thing for people to improve their health then it is to avoid sugar in their diet. The most important to cut out are those fruit juices and sugar sweetened beverages. If you can or as a second phase, cut out sugar entirely from your diet.
You’ll significantly reduce your risk of all the above mentioned diseases.
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.