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Mar 30, 2023·edited Mar 31, 2023Author

UPDATE LOG

I sent this out, and when I got home I tested the beer for lactate. So, I rewrote this section:

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I was a drinking an IPA, which is not sour, so should not have more than trace lactate. The lactate meter (NovaBiomedical Lactate Plus) does not clearly state its isomeric specificity, but it should be isomer-specific and not detect bacterial lactate. Bacterial lactate is D-lactate. While D-lactate is made by humans as a detoxification product of methylglyoxal, circulating lactate is mostly L-lactate, which is what is made from glycolysis.

Therefore, this is almost certainly an effect of the alcohol.

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It now reads like this:

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I was a drinking an IPA, which is not sour, so should not have more than trace lactate. The lactate meter (NovaBiomedical Lactate Plus) does not clearly state its isomeric specificity, so it is not clear if it would pick up bacterial lactate.

I tested my beer with the lactate meter (same beer as I used on February 3) and it clocked in at 0.6 mmol/L. The average human has almost 5 liters of blood, 3 liters of which is plasma. 18 ounces of beer is 0.53 liters, which means there were 0.32 millimoles of “lactate” in the beer I drank. If 100% of that entered my bloodstream at once, and was not taken up by any cells or metabolized in any way — which is completely implausible — it would be distributed through 3 liters of plasma and would raise my plasma “lactate” by 0.11 mmol/L.

The beer rose my lactate 26.3 times more than this.

Therefore, this is definitely not an effect of any “lactate” in the beer and is almost certainly an an effect of the alcohol.

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On 12:31 PM March 31, I overhauled the section on my waking glucose and lactate response.

Originally, my comments were these:

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These changes are normal, unsurprising, and unconcerning.

When you eat more glucose, you get better at using glucose, so waking glucose goes down, and since you use more glucose, you make more lactate.

This is consistent with my own findings that repeated glucose tolerance testing leads to massive adaptations in glucose tolerance at a rate near 2.2 grams per day, and is also consistent with what has been shown in randomized controlled trials.

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I reviewed the literature and changed this into two sections, one on lactate, and one on glucose, that now say this:

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From the literature — all exercise science studies — my lactate response appears abnormal. Fasting lactate does not change after shifts to high-carb or low-carb diets lasting two days, four days, 21 days, or 42 days. My waking lactate rose to the higher level within the first days of using higher-dose glucose, so well within the adaptation period allowed for in all of these studies.

I believe this reflects poor clearance of lactate due to an impaired malate-aspartate shuttle as a result of pyruvate carboxylase impairment, ultimately owing to poor biotin status.

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and

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This seems like a healthy response: eat more glucose, get better at using glucose, use more glucose.

I believe the response in the general population is heterogeneous. Since I am not diabetic or overweight, the relevant studies to determine if this is normal would be those done in normal-weight, non-diabetic individuals.

I found two:

In a randomized trial of 6 weeks of high- or low-carb diets in distance runners, fasting glucose was 5.4 mg/dL higher at the end of the trial on the high-carb diet. However, this was not statistically significant, and the standard deviation was 8.6 mg/dL, suggesting the spread could be 17.2 mg/dL in 95% of a large population.

In a randomized trial of 4 weeks of such diets in healthy young, moderately trained males the high-carb diet led to 13.5 mg/dL higher fasting glucose, but again the standard deviation was very high, 29.7 mg/dL, suggesting the spread could be 59.4 mg/dL in 95% of a large population.

Thus, my response is not average, but I believe many people in the minority respond similarly to me.

I suspect this reflects that I have a very healthy insulin response, and very healthy regulation of glucose transporters, hexokinase enzymes, and glycolytic enzymes, which all lead me to be very good at keeping my glucose inside cells.

However, the pyruvate carboxylase step is blocked, so the ultimate fate of glucose is disproportionately lactate rather than to be fully burned for energy.

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Mar 30, 2023Liked by Chris Masterjohn, PhD

Is there any chance you are also manganese deficient as it’s also a cofactor for pyruvate carboxylase? Biotin has been helping me tolerate fat better and has given increased energy but there is still something missing as I just can’t build muscle. I have been working very part time at a not too physically demanding job and have developed myofascial pain syndrome behind my right shoulder blade from repetitive motion. The muscle pain is so intense at times that I can’t sleep. The only thing that stops it is ridiculously high doses of vitamin C 5-10 000 mg a day. Vitamin C is also involved in fat metabolism. I could never take vitamin C before because I would immediately have symptoms of copper deficiency. This is no longer the case since doing the high dose vitamin A. But something is still off because my skin and hair become very dry when using the vitamin C and fatty acids don’t seem to be the solution. Anyways, I’m glad to be using vitamin C for the pain instead of opiates. I will keep following your journey since although there are differences there is also sometimes some overlap. I appreciate your courage and interest in experimenting.

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My manganese levels are on the low side of normal, and I would not discount the possibility they could be low enough to have some adverse effects. However, this is true across the board of most minerals and the most parsimonious explanation is that mineral transport is ATP-dependent and thus all of the minerals are off because of an underlying impairment in ATP production.

My first five weeks of supplementing biotin indicate to me, provisionally, that I had very robust activation of pyruvate carboxylase, but without my respiratory chain being able to keep up. So I think that when my data come in it will probably show that aspartate has returned to normal but I have now unmasked a complex I problem resulting from the ACAD9 mutation. But, we will see very shortly.

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How’s the book coming along Chris?

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Hi Chris - Fantastic detail & open mind. Some of the ‘opposite - of - expected’ occur in me ... high cortisol. High cortisol drives up glucose & flattens ketones during fasting (I’m zero carb OMAD 50 year old 12 % fat woman with 60 min hard workout and 60 min rapid walking each day plus mindfulness, horizon-watching, forest-bathing, but also Type-A INTJ by nature). Example, despite fasting and zero carb life, ketones drop & I feel awful. But if I take herbals that lower cortisol, suddenly I’ve got ketones, and have the fasting energy others talk about. Cortisol is a son of a b*tch that I think has been making everything harder for me. (I’m also celiac. Hashimotos, mthfr, cpet gene allele). - MarySue IRL :)

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This is not normal. If insulin levels are low, which should be the case during fasting, cortisol-induced lipolysis increases ketones.

Sorry for my response to your other comment saying I didn’t know what your previous comment was. I now see it was this one but I saw this second.

I believe you are mixing up cortisol with what Palmer is talking about. Metabolic stress that increases lactate is about having inadequate NADH oxidation via oxygen in respiratory chain to deal with the load of glycolysis.

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Did you think of trying these experiments with biotin sparing amino acids like aspartate with/without protein? Anyway please stop self-annihilating experiments(I am selfish. please for our good) and if at all please do only biotin rich experiments. Most importantly thank you for all the information you provide.

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Hello, I did not annihilate myself. I’m still here :)

Yes I did think of that, but unfortunately I ran out of time.

Especially when I read about the girl who wound up in a wheelchair for life because her father thought she was “cured” of biotin thiamin responsive basal ganglia disease and took her off the supplement, and she was never able to recover from the subsequent crisis, while her younger sister is in good health because the father learned his mistake and never took her off the supplement, that made me more eager to move on from trying to understand all facets of the problem to trying to fix it.

So as much as I wanted to test aspartate in various permutations, four months of experiments was enough. Especially after the glucose adaptation made it so hard to test the effect of protein. More permutations tested in series as glucose adaptations accumulated would have been a minefield to design correctly and could have delayed another 2-6 months.

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Mar 31, 2023Liked by Chris Masterjohn, PhD

Oh...that is great news for me because looks like I my understanding of writings is good. Also thanks for responding. looking forward for more such writings. Btw it kills me that I am still not your subscriber. Definitely going to be.

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Glad you’re getting it! :)

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I have a few thoughts as an outsider with far less expertise than you. Have you considered any of your issues being related to autoimmune issues in the modern sense of leaky gut? I say this because many of your symptoms are also found in people with autoimmune/ gut issues and while you are aware of foods that have triggered some of your past issues, it seems like you still comsume plant foods now that can contribute to autoimmune issues. How do you know those foods are not causing issues or at the very least are not confounders? You don't need obvious symptoms to have gut/ leaky gut/ autoimmune issues. Have you ever measured any leaky gut biomarkers? I would worry about certain foods (wheat, potatoes etc) causing issues in your situation and your investigation. At the very least it could throw everything off. So could your issues be related to autoimmune/ leaky gut/ gut issues rather than a specific biochemical issue or another issue? I would suggest that anyone who is not having perfect bowel movements or perfect digestion has at least some degree of unresolved gut issues. And that's just based off noticeable signs, not unnoticeable ones. Also, have you considered the fact that maybe you need additional nutrients despite no deficiencies? I say this because I personally have found myself needing certain nutrients despite no sign of deficiency. I discussed this in my response to Dave. So even with biomarkers/ genetics that don't indicate deficiencies, maybe you still need (or if not need, could use) more of a certain nutrient. Many are helped by supplements that they don't *need* according to biomarkers and genetics. I would also question whether the standards/ ranges for nutrient adequacy/ deficency are even accurate as research their based on has limitations. And isn't it true that nutrient adequacy/ deficiencies would be based on the individual? So one level of a nutritent may be good for one person but not another.

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Mar 31, 2023·edited Mar 31, 2023Author

I don’t necessarily disagree with you so much as I have the diametrically opposite theoretical framework for thinking about everything you said.

First of all, the people who are helped by supplements with no data to support the need have not figured anything at all out about why.

In other words, this is true, yet meaningless in my framework because I am operating systematically to determine causes and effects precisely, and not operating on trial and error.

Second, on autoimmunity, I see this as universally an effect rather than a cause and believe it is never the root cause of anything. The fact that medicine sees it as a final diagnosis is largely a product of medicine having no understanding of its causes nor way to address the causes, and my favored hypotheses to explain autoimmunity (tissue damage, fat-soluble vitamin deficiency, and poor innate/adaptive rhythm during infection) are very different from those in the paleosphere and carnivore sphere.

That said, my ANA transiently went up after COVID, then went normal. I have spent 1.5 years gluten free and it provided no value to my health at all and in fact made it worse. My stools are very good if I am not newly adapting to lactose after time off and when I am not doing glucose tolerance tests above 60 g.

I am ambivalent about the plant foods and I do not dispute at all I run lowish in numerous nutrients, but I am controlling my diet so that my experiments are interpretable, and so that I arrive at final conclusions on the effects of my supplementation.

Sure, I could have added a bunch of random supplements and then maybe something would have gotten better, but then I would know nothing about why or which one did what and then a year later I would wonder why I was wasting money on them, start cutting things out, and persist in some endless cycle of trying things and not improving my understanding of anything.

Hence, the controlled experiments described in this series.

Thank you for adding your thoughts!

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Chris, I am curious about the subject you brought up about reactive hypoglycemia, as I struggle with that as well. It seems strange the body would react as if the blood sugar is much lower than it is. Do you have any thoughts on why this is? Maybe this question is more suitable for an AMA, if so let me know.

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I’m not sure what you’re asking. Reactive hypoglycemia is for the blood sugar to drop, not for the body to act as if it has dropped.

Which one are you asking about?

If your blood sugar is normal and you feel hypoglycemic, the correct conclusion is how you feel is not caused by your blood sugar.

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Mar 31, 2023·edited Mar 31, 2023

My understanding was reactive hypo-g was feeling like your blood sugar was lower than it was.

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No. That is not reactive hypoglycemia.

Reactive hypoglycemia is your blood sugar spiking and then dropping because the insulin from the spike overcompensated.

If you feel like your blood sugar is lower than it is, this is called being wrong about your blood sugar. The solution is to stop thinking your blood sugar is low and move on to a different hypothesis of why you feel that way.

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Which was the nature of my question. Do you have any theories?

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You said biotin helps, so it’s either biotin deficiency or an impairment in a biotin-dependent enzyme that is treatable with biotin, as at least part of it.

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I have felt this very thing and I needed calcium and magnesium. No doctor could figure this out. Sometimes I would get temporary chills/ shivers/ heat flashes/ shakiness/ weakness/ racing heart rate. Sugar often fixed symptoms temporarily but once I supplemented enough calcium and magnesium, these issues mostly went away. And for proof that sugar was never what I needed, once I got these electrolytes down, I was able to do a very strict keto diet for many months including at times being in such a high deficit that I was losing more than 1 lb of fat a day. So while in the short run sugar would often fix my symptoms, it clearly was not because I needed sugar. This is why I would call this "pseudo-hypoglycemia" where it seemed like I was hypoglycemic (where sugar helped symptoms temporarily) but I was technically not hypoglycemic. I don't think I had any clear signs/ biomarkers of deficiencies which is part of why I wrote what I wrote in my response to Chris. Maybe he needs something that he is not deficient in. And for me, it seems like food containing these minerals does not help me nearly as much as supplements. So even if I eat plenty of magnesium, I still need to supplement as if the food sources of magnesium are not acting like the pure supplemental forms. I also wonder if these supplements are helping me because I need them or because they are influencing other biochemical pathways that end up helping me. I wonder if Chris needs something regardless of what his biomarkers and genetics indicates. Dave, we can certainly connect with each other in case my experiences could help you.

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I think there is a serious problem with you calling this “pseudo-hypoglycemia.”

This just reinforces the wrong belief that these are tell-tale signs of hypoglycemia.

I considered my under-eating symptoms “hypoglycemia” until I deliberately provoked them and measured my blood sugar.

It was not low.

Therefore, I was wrong.

I wasn’t “pseudo-right.”

I was simply wrong.

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Sounds like you were far too parasympathetic dominant or anabolic. Magnesium is the most catabolic mineral and the reason it's considered a 'calming' mineral is because people lean far too anabolic and it helps raise their electrolytes so that they aren't crashing all night and waking up. But for people who lean far too catabolic magnesium makes their insomnia worse! And so with the anabolic side you will be having low electrolytes because of poor digestion or inability to extract nutrients out of the food from low hcl and sluggish gallbladder. If ever magnesium causes insomnia you will know it has now pushed you far too catabolic.

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Mar 31, 2023·edited Mar 31, 2023Author

I don't think a catabolic/anabolic spectrum is useful. The average person has too much fat and not enough muscle. They have the wrong anabolism and the wrong catabolism relative to the ideal.

Magnesium can be calming from multiple ways, including being the off-switch for NMDA glutamate receptors, and being a more or less co-factor for ATP, since energy itself is calming, and the low-energy state is not a calm state, but rather a disordered state that has no distinction between being "revved up" or "calm," that one might consider an endless stream of purposeless jitteriness.

Since Anonymous did not take any useful measurements, none of us can do more than guess at what happened.

Since carbohydrate helped Anonymous at first, I suspect they simply cured a frank intracellular magnesium deficiency. Carbohydrate and insulin help bring magnesium into cells, which would be very helpful in a state of frank magnesium deficiency, but not needed once the deficiency has been corrected.

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I'm speaking about terms Dr Emanuel Revici used. Not whether someone has lots of muscle compared to fat. In an overly anabolic state, the body does not use oxygen to make energy as appropriately as the body is intended to. This imbalance can cause constipation by sending too much of the body's water to the kidneys and not enough to the bowels, making the stool harder and more difficult to move. It can also cause a person to have to pee a lot (due to increased volume) and they will often have to get up in the middle of the night to pee. A wide variety of other problems can also occur if a person stays in that rest and rebuild state most of the time and is not moving back into the active catabolic state during the day. To help the body operate correctly, we need to oscillate back and forth from the anabolic state at night while we sleep to a catabolic state during the day, while we’re active. So taking mag and calcium is helping to correct this imbalance and is not about whether they are solving the frank deficiency. Revici said magnesium is experimentally catabolic and calcium is strongly catabolic. So yes magnesium is necessary for proper energy production.

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Thanks. Unfortunately, my calcium already runs high(ish) and I've never really noticed any effect from supplementing magnesium. Sometimes I might even feel a little worse after taking it. I will say, though, I think my megadosed biotin is helping me fast more. It hasn't completely eliminated fasting crashes, but it takes a lot longer to get there. For the last many years before biotin I couldn't fast at all because of reactive hypo... (or at least my definition of it; ie. feeling like the b.s. is lower than it is). Biotin really moves the bowel, too, which has always been an issue for me. Thanks for the feedback though.

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Moving the bowel is an energy dependent process.

If biotin helps your fasting tolerance but you do not become hypoglycemic when you fast, biotin is helping you make more ATP and this is normalizing your gut function.

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Do you think a possible alternative explanation is that the body views the large dose as toxic and initiates a diuretic effect in the bowel to excrete the excess? Did the toxicology studies include fecal measurements of biotin? I'm sure all of this was thought about already, I'm just curious.

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Hi Dr. CMJ and community,

I too seem to have the paradoxical rise in lactate the longer I fast. The past 2 mornings my waking fasting lactate was lower than my fasting lactate taken later in the morning (yesterday: 7:00am 1.9mmol/l; 11:50am 3.2mmol/l. Today: 7:00am 1.1mmol/l; 9:30am 3.6mmol/l; then 10min after mixed bfast 3.1mmol/l). This pattern is consistent. Does this pattern point to a genetic issue? Or could it be a nutrient deficiency(s)?

My waking fasting lactate is higher than 1.0 more often than not on my Nova lactate meter whether or not I've had any alcohol within the past few days. Most of the reasons for elevated lactate you listed in a different article seem unlikely to me. I've tried high dose thiamine, but that seemed to raise fasting lactate. Waking urine PH is usually ~5.5, but goes up to ~6.5 after a meal. My glucose and ketone readings seem pretty normal.

Do you have any initial suggestions for diet/supplements to address my high fasting lactate and paradoxical rise in lactate the longer I fast? Or is this not enough info to provide a suggestion?

I'm on the BioOpt waitlist, but just seeing if there's something obvious I could try to address this in the meantime.

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Very interesting to see the bodyweight impact on your symptom presence/severity! Might you be able to estimate your bodyfat percentage when you were between 153 and 159 lb?

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It's always 20% when I do DEXA.

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Jan 10Liked by Chris Masterjohn, PhD

Thanks for confirming! Mine also hovers around 20 percent, plus or minus 4%.

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Chris - Right in line with what I said before, look at Chris Palmer's lactate spike comments at 1:30-1:35 of this Tim Ferris interview. All stress-related and true-er in fit exercisers like you and me. https://youtu.be/JVl1X0fb1uA

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I don’t have baseline higher than normal lactate. He’s talking about metabolic stress, not psychological stress. I’m not sure what previous comment you’re relating this to. Thanks for sending along the interview.

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