Using (the Term) 'Lactic Acid' In Physiology Is Dangerous, Should Be Regulated As Drugs

Amazoniac

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As many of my readers know, mainstream science has been catching up on the malefits of excess lactate but continues to erroneously refer to it as lactic acid believing the terms to be interchangeable. Well, in yet another striking example of synchronicity (Synchronicity - Wikipedia), just a few days after posting again that plain thiamine HCl treats... everything, including cases of "lactic acidosis", the article below appeared on my news feed. It corroborates Peat's claim that mainstream consensus lags behind advances in the medical field and decades are needed for a revised concept to gain acceptance. Not only that, but it adds to the evidence that detrimental effects when there's too much lactate are a concern whether it's the acid (exogenous) or base (endogenous) form, they end up being metabolized similarly. Now, when lactic acid is invoked in the context of what takes place in our cellular respiration, the rescuing principle is ignored. In other words, it fails to acknowledge the very purpose for its generation, which is to put protons to use and prevent local acidification while regenerating NAD+ (see attached table), the molecule of life. When I mentioned it to a few doctors (who have adopted me against my will), the responses were nothing but dismissive, it just shows how dogmatic, idiotic, incapacitating, imbecilizing, indoctrinating, rigidifying, misleading, putrid, disgraceful, immoral, miserable, satanic, son of a b****, and damaging the academic shaping of your common white coat can be. :):

@aguilaroja @Drareg @Regina @tankasnowgod

Researchers unravel how humans differ from a pot of yogurt
Lactate, not Lactic Acid, is Produced by Cellular Cytosolic Energy Catabolism

"...it is unfortunate that the authors referred to cellular lactate production as lactic acid, repeatedly associated cellular lactic acid production as a cause of acidosis, and used the term lactic acid within their title. Such repeated use, totaling 50 occurrences of “lactic acid” throughout the entirety of the manuscript, severely detracts from the scientitic quality of their work."

"...there is no such entity as lactic acid in any living cell or physiological system. Indeed, it is impossible, based on the fundamental laws of physics that underpin the disciplines of organic chemistry, metabolic biochemistry, acid-base chemistry, and physiology, for lactic acid to be produced or present in living systems where cellular and tissue pH is regulated to be between 6.0 and 7.45."

"Sun et al. (12) explained cellular lactate production as the conversion of pyruvate to lactic acid (not true), that this was a reaction within glycolysis (not true, although there is debate as to what constitutes the true end of glycolysis, pyruvate or lactate), and that because of the low pKa of lactic acid (pK = 3.86) (true) [although the NIST (8) reference resource has this as pK = 3.67], there was an immediate and near-complete dissociation of lactic acid to lactate and a proton (H+) (p. 453) (not true because in living systems there is no lactic acid to begin with)."

"For glycolysis, there are nine reactions, commencing with the 6-carbon substrate glucose-6-phosphate (G6P) and ending with two 3-carbon pyruvate molecules (see Ref. 9, Table 2, p. R506). The first carboxylic functional group intermediate of glycolysis is produced in the sixth reaction where 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate (see Ref. 9, Fig. 5, p. R507). This is a phosphate transfer reaction, adding the phosphate to ADP forming ATP, with the co-production of 3-phosphoglycerate having an ionized (unprotonated) carboxylic functional group at carbon-3. This is key to understanding the H+ load of glycolysis and H+ metabolic buffering from lactate production. Each glycolytic intermediate following this reaction remains in an ionic form. There is never a glycolytic production of a carboxylic acid since they are all carboxylic ions. This remains true for obvious acid-base reasons from 3-phosphoglycerate to 2-phosphoglycerate to pyruvate and then to lactate. There is no metabolic production of lactic acid or any preceding glycolytic carboxylic ion metabolite, and, as previously explained, lactate production consumes, not releases, ~H+ (see Table 1; also see Ref. 9, Fig. 9, p. R509)."

"From the data of Table 1, it is clear that lactate production consumes a H+ load that is essentially stoichiometric to lactate production, regardless of pH across the cellular pH range. Conversely, as cellular pH declines, pertinent reactions of glycolysis sum to be more net ~H+ releasing. Glycolysis is independently ~H+ releasing, and the ~H+ consumption of lactate production opposes this, and it is unlikely that perfect matching of H+ exchange ever occurs, as is commonly represented in summary metabolic equations of glycolysis [−2 H+ (release)] and lactate production [+2 H+ (consumption)]. Indeed, as a cell becomes more acididic, there is an increasing ~H+ release from glycolysis, whereas that for lactate remains essentially unchanged."

"We understand that the term “lactic acidosis” has been used in clinical research and practice for more than 100 years. With the duration of this use comes considerable engrained misunderstanding and misapplication, and to expect a rapid change from any engrained convention may be unrealistic. However, given that the terminology is wrong based on incorrect understanding of metabolic biochemistry and acid-base chemistry, that clinical practice involves treating illnesses and saving lives from premature mortality, and that correct treatment most often requires a correct understanding of the true mechanisms of disease and symptomology, one would hope that clinical professionals would prefer to base their practice on empirical truths rather than engrained convention."

"It has been encouraging to see many physicians altering their view of a lactic acidosis based on revised explanations consisting of expressions of elevated blood lactate (hyperlactatemia) and an associated (or not) systemic acidosis (3, 5, 7). For example, considerable research of hyperlactatemia occurs for the condition of sepsis (3, 5, 7) and also metformin toxicity (1). For sepsis, hyperlactatemia is predictive of disease severity and premature mortality, with more than a threefold increase in mortality when hyperlactatemia is accompanied by tissue hypo-perfusion (5). The prior conventional interpretation of sepsis-associated hyperlactatemia accompanied by acidosis is framed on belief in a causal connection between the disease state, altered perfusion causing a localized hypoxia, stimulation of glycolysis, and lactic acid-induced metabolic acidosis. This is false knowledge, since there is no such condition as lactic acid-induced metabolic acidosis. The increased lactate presumably occurs due to increased stimulation of energy catabolism, causing increased substrate flux through glycolysis, which will therefore also increase lactate production and/or compromise blood lactate removal. For many patients, there is no accompanied acidosis (3, 5, 7), which is consistent with the metabolic biochemistry of the combined production of lactate and the retained function of mitochondrial respiration, since a continual H+ supply is needed as a substrate for each aspect of energy catabolism. For patients with a systemic acidosis, there could be a localized or systemic inflammatory response that triggers altered mitochondrial function and a metabolic milieu now consistent with metabolic acidosis (3, 7). Such a scenario is more aligned with altered mitochondrial respiration (normally a H+ sink) accompanied by increased glycolytic stimulation, the consequence of the two conditions causing increased net H+ release and an eventual acidosis."
 

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Wilfrid

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Yes, great great post!!!!!
I really enjoy such kind of very informative explanation.
Thanks.
 

lvysaur

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This is nothing new. Mainstream science has been referring to "lactose intolerance" for years, based on a medical test that uses a quarter gallon's worth of lactose. Apart from a few Peaters, (myself included) almost nobody drinks that much milk in one sitting.

It's like saying that if you can't eat 6000 calories then you should starve to death
 

snacks

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As many of my readers know, mainstream science has been catching up on the malefits of excess lactate but continues to erroneously refer to it as lactic acid believing the terms to be interchangeable. Well, in yet another striking example of synchronicity (Synchronicity - Wikipedia), just a few days after posting again that plain thiamine HCl treats... everything, including cases of "lactic acidosis", the article below appeared on my news feed. It corroborates Peat's claim that mainstream consensus lags behind advances in the medical field and decades are needed for a revised concept to gain acceptance. Not only that, but it adds to the evidence that detrimental effects when there's too much lactate are a concern whether it's the acid (exogenous) or base (endogenous) form, they end up being metabolized similarly. Now, when lactic acid is invoked in the context of what takes place in our cellular respiration, the rescuing principle is ignored. In other words, it fails to acknowledge the very purpose for its generation, which is to put protons to use and prevent local acidification while regenerating NAD+ (see attached table), the molecule of life. When I mentioned it to a few doctors (who have adopted me against my will), the responses were nothing but dismissive, it just shows how dogmatic, idiotic, incapacitating, imbecilizing, indoctrinating, rigidifying, misleading, putrid, disgraceful, immoral, miserable, satanic, son of a b****, and damaging the academic shaping of your common white coat can be. :):

@aguilaroja @Drareg @Regina @tankasnowgod

Researchers unravel how humans differ from a pot of yogurt
Lactate, not Lactic Acid, is Produced by Cellular Cytosolic Energy Catabolism

"...it is unfortunate that the authors referred to cellular lactate production as lactic acid, repeatedly associated cellular lactic acid production as a cause of acidosis, and used the term lactic acid within their title. Such repeated use, totaling 50 occurrences of “lactic acid” throughout the entirety of the manuscript, severely detracts from the scientitic quality of their work."

"...there is no such entity as lactic acid in any living cell or physiological system. Indeed, it is impossible, based on the fundamental laws of physics that underpin the disciplines of organic chemistry, metabolic biochemistry, acid-base chemistry, and physiology, for lactic acid to be produced or present in living systems where cellular and tissue pH is regulated to be between 6.0 and 7.45."

"Sun et al. (12) explained cellular lactate production as the conversion of pyruvate to lactic acid (not true), that this was a reaction within glycolysis (not true, although there is debate as to what constitutes the true end of glycolysis, pyruvate or lactate), and that because of the low pKa of lactic acid (pK = 3.86) (true) [although the NIST (8) reference resource has this as pK = 3.67], there was an immediate and near-complete dissociation of lactic acid to lactate and a proton (H+) (p. 453) (not true because in living systems there is no lactic acid to begin with)."

"For glycolysis, there are nine reactions, commencing with the 6-carbon substrate glucose-6-phosphate (G6P) and ending with two 3-carbon pyruvate molecules (see Ref. 9, Table 2, p. R506). The first carboxylic functional group intermediate of glycolysis is produced in the sixth reaction where 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate (see Ref. 9, Fig. 5, p. R507). This is a phosphate transfer reaction, adding the phosphate to ADP forming ATP, with the co-production of 3-phosphoglycerate having an ionized (unprotonated) carboxylic functional group at carbon-3. This is key to understanding the H+ load of glycolysis and H+ metabolic buffering from lactate production. Each glycolytic intermediate following this reaction remains in an ionic form. There is never a glycolytic production of a carboxylic acid since they are all carboxylic ions. This remains true for obvious acid-base reasons from 3-phosphoglycerate to 2-phosphoglycerate to pyruvate and then to lactate. There is no metabolic production of lactic acid or any preceding glycolytic carboxylic ion metabolite, and, as previously explained, lactate production consumes, not releases, ~H+ (see Table 1; also see Ref. 9, Fig. 9, p. R509)."

"From the data of Table 1, it is clear that lactate production consumes a H+ load that is essentially stoichiometric to lactate production, regardless of pH across the cellular pH range. Conversely, as cellular pH declines, pertinent reactions of glycolysis sum to be more net ~H+ releasing. Glycolysis is independently ~H+ releasing, and the ~H+ consumption of lactate production opposes this, and it is unlikely that perfect matching of H+ exchange ever occurs, as is commonly represented in summary metabolic equations of glycolysis [−2 H+ (release)] and lactate production [+2 H+ (consumption)]. Indeed, as a cell becomes more acididic, there is an increasing ~H+ release from glycolysis, whereas that for lactate remains essentially unchanged."

"We understand that the term “lactic acidosis” has been used in clinical research and practice for more than 100 years. With the duration of this use comes considerable engrained misunderstanding and misapplication, and to expect a rapid change from any engrained convention may be unrealistic. However, given that the terminology is wrong based on incorrect understanding of metabolic biochemistry and acid-base chemistry, that clinical practice involves treating illnesses and saving lives from premature mortality, and that correct treatment most often requires a correct understanding of the true mechanisms of disease and symptomology, one would hope that clinical professionals would prefer to base their practice on empirical truths rather than engrained convention."

"It has been encouraging to see many physicians altering their view of a lactic acidosis based on revised explanations consisting of expressions of elevated blood lactate (hyperlactatemia) and an associated (or not) systemic acidosis (3, 5, 7). For example, considerable research of hyperlactatemia occurs for the condition of sepsis (3, 5, 7) and also metformin toxicity (1). For sepsis, hyperlactatemia is predictive of disease severity and premature mortality, with more than a threefold increase in mortality when hyperlactatemia is accompanied by tissue hypo-perfusion (5). The prior conventional interpretation of sepsis-associated hyperlactatemia accompanied by acidosis is framed on belief in a causal connection between the disease state, altered perfusion causing a localized hypoxia, stimulation of glycolysis, and lactic acid-induced metabolic acidosis. This is false knowledge, since there is no such condition as lactic acid-induced metabolic acidosis. The increased lactate presumably occurs due to increased stimulation of energy catabolism, causing increased substrate flux through glycolysis, which will therefore also increase lactate production and/or compromise blood lactate removal. For many patients, there is no accompanied acidosis (3, 5, 7), which is consistent with the metabolic biochemistry of the combined production of lactate and the retained function of mitochondrial respiration, since a continual H+ supply is needed as a substrate for each aspect of energy catabolism. For patients with a systemic acidosis, there could be a localized or systemic inflammatory response that triggers altered mitochondrial function and a metabolic milieu now consistent with metabolic acidosis (3, 7). Such a scenario is more aligned with altered mitochondrial respiration (normally a H+ sink) accompanied by increased glycolytic stimulation, the consequence of the two conditions causing increased net H+ release and an eventual acidosis."

Google and other sites spying on you 25/8 isnt synchronicity
 

haidut

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it just shows how dogmatic, idiotic, incapacitating, imbecilizing, indoctrinating, rigidifying, misleading, putrid, disgraceful, immoral, miserable, satanic, son of a b****, and damaging the academic shaping of your common white coat can be.

Lol, love the intro!
OK, I see their point that one should immediately jump to conclusions that elevated lactate is to be blamed for acidosis as it is not causing it directly since lactate is not lactic acid, and in fact (initially) lactate generation serves as a sink for H+, which protects from the acidosis. However, hyperlactemia blocks the further movement/consumption of incoming H+ (from glycolysis) along the metabolic pathway PDH->Krebs->ETC due to the lower pyruvate/lactate ratio as a result of accumulating lactate. So, while the initial step triggering the acidosis is likely elevated FFA in the bloodstream (which also leads to a drop in mitochondrial NAD/NADH) the buildup of lactate itself also contributes to the acidosis by contributing to the inhibition of the link (by activating PDK and thus suppressing PDH) between glycolysis and OXPHOS, as well as by activation of HIF1a, which further exacerbates the mitochondrial dysfunction and thus promotes acidosis. And if that was not bad enough, lactate can promote a functional hypoxia-like response independently of HIF1a.
TLDR: Lactate generation is an emergency response to excessive buildup of H+ (reductive state) and initially protects from the acidosis associated with this reductive state. However, this emergency mechanism quickly becomes overwhelmed and pathological if activated for too long, and eventually may become the main driver of the acidosis (due to its powerful inhibition of OXPHOS), surpassing even the direct effects of increased FAO/FFA. A reasonable treatment approach should address BOTH the elevated FFA/FAO and elevated lactate. Especially in cancer, as lactate is by now a known oncometabolite (see study below), not just a benign sign of a metabolic dysfunction (e.g. Warburg "Effect"). After a while it turns from Warburg Effect into a Warburg Cause with relevance for virtually every disease and not just cancer.
Case Report: Lactic acidosis in diabetic ketoacidosis
Randle cycle - Wikipedia
"...The impairment of glucose metabolism by fatty acid oxidation is mediated by the short-term inhibition of several glycolytic processes. The extent of inhibition increases along the glycolytic pathway, being most severe at the level of pyruvate dehydrogenase and less severe at the level of glucose uptake and 6-phosphofructo-1-kinase (PFK-1).[5] This sequence occurs because of the initial event, triggered by fatty acid oxidation, is an increase in the mitochondrial ratios of [acetyl-CoA]/[CoA] and [NADH]/[NAD+]. These both serve to inhibit pyruvate dehydrogenase activity.[7] It has been proposed that these changes lead to an accumulation of cytosolic citrate, which in turn inhibits PFK-1, followed by an increase in glucose 6-phosphate, which eventually inhibits hexokinase."
Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells
https://www.cell.com/cell/pdfExtended/S0092-8674(15)00264-0
https://2019.febscongress.org/abstract_preview.aspx?idAbstractEnc=4424170094095099096093424170
"...Finally, analysis of the hepatocellular carcinoma cohort from The Cancer Genome Atlas revealed that low LDHB/LDHA ratio was significantly associated with poor prognostic outcomes and high gene set enrichment of glycolysis hallmarks, and negatively correlated with PDK1 and 2, supporting a close link between LDHB suppression and PDK/PDH axis. These results suggest that LDHB suppression is a key mechanism in glycolysis enhancement, and critically involved in the maintenance and propagation of mitochondrial dysfunction via lactate release in liver cancer progression."
 

Amazoniac

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Lol, love the intro!
OK, I see their point that one should immediately jump to conclusions that elevated lactate is to be blamed for acidosis as it is not causing it directly since lactate is not lactic acid, and in fact (initially) lactate generation serves as a sink for H+, which protects from the acidosis. However, hyperlactemia blocks the further movement/consumption of incoming H+ (from glycolysis) along the metabolic pathway PDH->Krebs->ETC due to the lower pyruvate/lactate ratio as a result of accumulating lactate. So, while the initial step triggering the acidosis is likely elevated FFA in the bloodstream (which also leads to a drop in mitochondrial NAD/NADH) the buildup of lactate itself also contributes to the acidosis by contributing to the inhibition of the link (by activating PDK and thus suppressing PDH) between glycolysis and OXPHOS, as well as by activation of HIF1a, which further exacerbates the mitochondrial dysfunction and thus promotes acidosis. And if that was not bad enough, lactate can promote a functional hypoxia-like response independently of HIF1a.
TLDR: Lactate generation is an emergency response to excessive buildup of H+ (reductive state) and initially protects from the acidosis associated with this reductive state. However, this emergency mechanism quickly becomes overwhelmed and pathological if activated for too long, and eventually may become the main driver of the acidosis (due to its powerful inhibition of OXPHOS), surpassing even the direct effects of increased FAO/FFA. A reasonable treatment approach should address BOTH the elevated FFA/FAO and elevated lactate. Especially in cancer, as lactate is by now a known oncometabolite (see study below), not just a benign sign of a metabolic dysfunction (e.g. Warburg "Effect"). After a while it turns from Warburg Effect into a Warburg Cause with relevance for virtually every disease and not just cancer.
Case Report: Lactic acidosis in diabetic ketoacidosis
Randle cycle - Wikipedia
"...The impairment of glucose metabolism by fatty acid oxidation is mediated by the short-term inhibition of several glycolytic processes. The extent of inhibition increases along the glycolytic pathway, being most severe at the level of pyruvate dehydrogenase and less severe at the level of glucose uptake and 6-phosphofructo-1-kinase (PFK-1).[5] This sequence occurs because of the initial event, triggered by fatty acid oxidation, is an increase in the mitochondrial ratios of [acetyl-CoA]/[CoA] and [NADH]/[NAD+]. These both serve to inhibit pyruvate dehydrogenase activity.[7] It has been proposed that these changes lead to an accumulation of cytosolic citrate, which in turn inhibits PFK-1, followed by an increase in glucose 6-phosphate, which eventually inhibits hexokinase."
Is Lactate an Oncometabolite? Evidence Supporting a Role for Lactate in the Regulation of Transcriptional Activity of Cancer-Related Genes in MCF7 Breast Cancer Cells
https://www.cell.com/cell/pdfExtended/S0092-8674(15)00264-0
https://2019.febscongress.org/abstract_preview.aspx?idAbstractEnc=4424170094095099096093424170
"...Finally, analysis of the hepatocellular carcinoma cohort from The Cancer Genome Atlas revealed that low LDHB/LDHA ratio was significantly associated with poor prognostic outcomes and high gene set enrichment of glycolysis hallmarks, and negatively correlated with PDK1 and 2, supporting a close link between LDHB suppression and PDK/PDH axis. These results suggest that LDHB suppression is a key mechanism in glycolysis enhancement, and critically involved in the maintenance and propagation of mitochondrial dysfunction via lactate release in liver cancer progression."
Jorge!

Blocking break down of fuel is part of the rescuing program due to lack of reagents, not doing this would only require more lactate if its clearance is normal.

One criticism is that in spite of appearing to be a net-neutral reaction (the hydrogen iods that are taken up, will then be released), recovering is costly, which means that it's only acceptable as a temporary buffer. It transfers the burden, with the liver taking the hit. When it hasn't been overwhelm'd, lactate can alkalinize to the same extent as other solutions (possibly at the expense of liver wealth):
- Three myths about Plasmalyte, Normosol, and LR | EMCrit (ignore the rest)

And lactic acid won't be occuring either way because the hydrogen iods dissociate in the physiological pH range.

Вашите открития са толкова големи, че сензационизмът и пристрастията се преодоляват (ентусиазмът е условен токсин). Винаги сте били вдъхновение.
 
Last edited:

haidut

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Jorge!

Blocking break down of fuel is part of the rescuing program due to lack of reagents, not doing this would only require more lactate if its clearance is normal.

One criticism is that in spite of appearing to be a net-neutral reaction (the hydrogen iods that are taken up, will then be released), recovering is costly, which means that it's only acceptable as a temporary buffer. It transfers the burden, with the liver taking the hit. When it hasn't been overwhelm'd, lactate can alkalinize to the same extent as other solutions (possibly at the expense of liver wealth):
- Three myths about Plasmalyte, Normosol, and LR | EMCrit (ignore the rest)

And lactic acid won't be occuring either way because the hydrogen iods dissociate in the physiological pH range.

Вашите открития са толкова големи, че сензационизмът и пристрастията се преодоляват (ентусиазмът е условен токсин). Винаги сте били вдъхновение.

Agreed, no lactic acid, only lactate. As you said - the liver takes the biggest hit and if somebody has some form of say NAFLD/NASH/etc (e.g. more than 2/3 of Western population) then lactate quickly becomes non-benign, right? Also, the Cori cycle is energetically expensive, it consumes 6 ATP molecules per iteration so considering glycolysis produces 2 ATP there is a net "loss" of 4 ATP. If this continues long enough, the lack of ATP leads to structural changes in the cell (leakage, disintegration) and once the cellular debris starts to increase in the bloodstream all kinds of other problems pop up. I guess it is still a lesser evil rather than allowing acidosis to form right away but something has to consume those H+ coming out of glycolysis. Lactate is the first (only?) emergency mechanism and if it gets elevated sufficiently, it does become a problem and even contributes to the very thing it was supposed to prevent at the beginning (acidosis).
Oh, one last thing. Lactate itself is toxic to cells when glucose availability is low, so even a mild buildup of lactate in somebody on low-carb diet or during exhaustive exercise can be a problem even if it is part of the normal physiological reaction of preventing acidosis and the liver is still not overwhelmed.
Just my 2c.

P.S. Your Bulgarian is really good! Who is teaching you, if I may ask? I doubt Google translate works that well :):
 

Amazoniac

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Agreed, no lactic acid, only lactate. As you said - the liver takes the biggest hit and if somebody has some form of say NAFLD/NASH/etc (e.g. more than 2/3 of Western population) then lactate quickly becomes non-benign, right? Also, the Cori cycle is energetically expensive, it consumes 6 ATP molecules per iteration so considering glycolysis produces 2 ATP there is a net "loss" of 4 ATP. If this continues long enough, the lack of ATP leads to structural changes in the cell (leakage, disintegration) and once the cellular debris starts to increase in the bloodstream all kinds of other problems pop up. I guess it is still a lesser evil rather than allowing acidosis to form right away but something has to consume those H+ coming out of glycolysis. Lactate is the first (only?) emergency mechanism and if it gets elevated sufficiently, it does become a problem and even contributes to the very thing it was supposed to prevent at the beginning (acidosis).
Oh, one last thing. Lactate itself is toxic to cells when glucose availability is low, so even a mild buildup of lactate in somebody on low-carb diet or during exhaustive exercise can be a problem even if it is part of the normal physiological reaction of preventing acidosis and the liver is still not overwhelmed.
Just my 2c.

P.S. Your Bulgarian is really good! Who is teaching you, if I may ask? I doubt Google translate works that well :):
I cycle language translations like the body does with lactate, it allows refinement.

I was avoiding mentioning Cori to prevent technicalitosis, yet was thinking along the same lines, what meant by 'recovering being costly'. However, I now decided to consult my anesthesiology book for knowing that it's al dere .This lactate chart that we're used to see is for a cycle that closes with the reformation of glucose, which is the energy-consuming step; up until the recovery of pyruvate there's only the reduction of NAD. Prior to turning overwhelming, those 2 ATP used in the process can be neglected because it's just normal break down of glucose before impairment.

- Gluconeogensis | NYU School of Medicine

upload_2020-8-28_13-12-26.png

upload_2020-8-28_13-12-31.png
upload_2020-8-28_13-12-35.png

The liver could simply proceed metabolizing pyruvate locally and prioritize utilization of existing/circulating glucose to other cells to avoid the convolution.

Lactate is also a way of displacing a molecule that can't be processed at the time, not just clearing acidity. If it was just acidity, there would be the known buffers ,part here :
- "The Primary Sources Of Acidity In The Diet Are Sulfur-containing AAs, Salt, And Phosphoric Acid"
- Creatine

Came across this today:
- Physiology and clinical aspects of the extracellular bicarbonate pool: plea for cognizant use of HCO3-
Abstract said:
Objective: Derived from literature data the function of bicarbonate (HCO3-) is described together with its extracellular pool, the regulating organs, and the clinical variations.

Data sources and selection criteria: The medical German and English literature was reviewed. No special literature retrieval was performed. Results from measurements at the author's laboratory were used.

Results: HCO3- may be described as the most potential nonrespiratory buffer base. For a 65 kg patient, the extracellular HCO3- pool amounts to approximately 350 mmol with a maximum tolerance limit of +/- 200 mmol. An influx of H+ ions (acidosis) and/or a reduction in the pCO2 (hyperventilation) will reduce this pool, whereas alkalosis and hypoventilation will enlarge it. The lungs (in close cooperation with the erythrocytes), liver and kidneys all contribute to the regulation of this HCO3- pool. The paramount organ for this regulation seems to be the liver, since it is able, even within a period of only a few hours, to eliminate much larger amounts of H+ ions (and correspondingly release HCO3-) than the kidneys are able to eliminate even under extreme conditions. It is primarily the liver which regulates the size of the HCO3- pool through the metabolism of the so-called metabolizable anions (bases) such as acetate, lactate, malate and citrate. The metabolism of these anions in the form of acetic, lactic, malic or citric acid requires (per mol) 1 mol H+ (acetate, lactate), 2 mol H+ (malate) or even 3 mol H+ (citrate), with the corresponding release of HCO3-. Iatrogenic alterations in the HCO3- pool occur more frequently than previously assumed. Infusion solutions may lead to a dilution acidosis (dilution of HCO3-), an infusion acidosis (addition of H+) or an infusion alkalosis (administration of metabolizable anions).

Conclusion: An improvement in the declaration accompanying infusion solutions is recommended according to their actual pH-dependent composition. In particular, the concepts of base excess (BE, mmol/l) and BE pot. (mmol/l) should be introduced, in order to give an indication of potential alterations in the HCO3- pool after infusion and metabolism. This also applies to blood derivatives, where transfusion acidosis as well as alkalosis may occur, and in hemodialysis and peritoneal dialysis where the occurrence of acidosis and alkalosis during therapy need to be reckoned with.
 
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haidut

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The liver could simply proceed metabolizing pyruvate locally and prioritize utilization of existing/circulating glucose to other cells to avoid the convolution.

Hmm, so I guess we don't want the Cori cycle functioning too well as that would reduce the NAD back to NADH thus nullifying the benefits of generating the lactate in the first place as an emergency sink for H+ from glycolysis. I think the Cori cycle is tightly-regulated for that reason - i.e. prevent consuming the NAD that is crucial for at least glycolysis working and the cell staying alive. That means lactate will tend to accumulate in cases of deficient OXPHOS, which is what is actually seen clinically. So, we are back to the same issue - how do we handle excess lactate holding H+? As the last study you posted says, liver does the bulk of the work (about 70% of lactate consumption), the kidneys do the other 30%, but even a healthy liver will probably not handle all the lactate thrown at it in order to conserve NAD. So, in the face of deficient OXPHOS it seems the only solution to accumulating lactate is something that can oxidize it directly - i.e. methylene blue, quinones, etc. One could also use HCO3, but as the last study you posted also says that could be dangerous and cause alkalosis if it is not properly calculated.
 

Amazoniac

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Hmm, so I guess we don't want the Cori cycle functioning too well as that would reduce the NAD back to NADH thus nullifying the benefits of generating the lactate in the first place as an emergency sink for H+ from glycolysis. I think the Cori cycle is tightly-regulated for that reason - i.e. prevent consuming the NAD that is crucial for at least glycolysis working and the cell staying alive. That means lactate will tend to accumulate in cases of deficient OXPHOS, which is what is actually seen clinically. So, we are back to the same issue - how do we handle excess lactate holding H+? As the last study you posted says, liver does the bulk of the work (about 70% of lactate consumption), the kidneys do the other 30%, but even a healthy liver will probably not handle all the lactate thrown at it in order to conserve NAD. So, in the face of deficient OXPHOS it seems the only solution to accumulating lactate is something that can oxidize it directly - i.e. methylene blue, quinones, etc. One could also use HCO3, but as the last study you posted also says that could be dangerous and cause alkalosis if it is not properly calculated.
But that will take place after relocation to organs with greater capacities to handle the excess, it's indeed choosing the least harmful option. Dealing with the reduction of NAD has to happen to recover pyruvate, afterwards it's a matter of using as fuel or promoting storage. Another representation of the selected part of the figure above:


Other than the obvious (not requiring lactate generation in the first place), anything that can oxidize NAD should be useful once lactate has been created. It's taxing on the liver (and kidneys as you mentioned), but I suspect that the acidity in and of itself is not the main concern because there are multiple backup systems to normalize this aspect, it's the buildup of reduced NAD that's the issue, it has to be regenerated as fast as it's being consumed. Excess lactate must deplete oxidized NAD in the liver just like alcohol does (all dehydrogenases).

As you know, there are other factors that will dictate the fate of puruvate, not just the state and availability of NAD or thiamide. For example, too much downstream metabolites like acetyl or citrate signal supstrate overload, it makes no sense to forward metabolism unless they is diverted to storage.

- Pyruvate dehydrogenase complex: structure, steps, mechanism, regulation (!)

"The first reaction is essentially identical to pyruvate decarboxylase reaction (EC 4.1.1.1), which carries out a non-oxidative decarboxylation in glucose fermentation to ethanol. What differs is the fate of the hydroxyethyl group bound to thiamine pyrophosphate that, in the reaction catalyzed by pyruvate dehydrogenase is transferred to the next enzyme in the sequence, dihydrolipoyl transacetylase, whereas in the reaction catalyzed by pyruvate decarboxylase is converted into acetaldehyde."

"[..]in the liver, to avoid wasting energy, glyucolysis and gluconeogenesis are reciprocally regulated so that when one pathway is active, the other slows down. As explained in the article on gluconeogenesis, during evolution this was achieved by selecting different enzymes to catalyze the essentially irreversible reactions of the two pathways, whose activity are regulated separately. Indeed, if these reactions proceeded simultaneously at high speed, they would create a futile cycle or substrate cycle. A such fine regulation could not be achieved if a single enzyme operates in both directions."​

In Prolactinese, 'kinases' are referred to as 'phosphaccretases'.

Extra lactate appears to be decently and immediately metabolized towards energy release in compromised cases too, it's entering cellular respiration because the response is close to taking other organic acids salts, but the story may change when tissues are forming a lot of it 25/8 (nacks, 2020) because of the cost to it.

If the lactate cycle were to close, at least there must be a delay in reformation of glucose, otherwise it would make no sense to clear excess pyruvate as lactate from tissues, send it to the liver (and partners), resynthesize glucose in an expensive process and return it.

- The role of bicarbonate precursors in balanced fluids during haemorrhagic shock with and without compromised liver function (rats)

"Acetate was metabolized effectively in this study, regardless of liver failure or severe shock. This confirms that acetate is metabolized elsewhere or that limited hepatic function is sufficient to support bicarbonate generation. Acetate can be metabolized in several extrahepatic tissues, including the muscles, brain, myocardium, and renal cortex, because they all have the required enzymes.[15,17] Therefore, acetate is subject to less accumulation in states of shock with impaired liver function."

"As expected, lactate concentrations increased during haemorrhagic shock. Measured lactate concentrations were influenced by the additional lactate supplied by resuscitation with RL [Ringer's Lactate]. In addition, PLR [Partial Liver Resection; 70%] reduced the capacity of lactate to be metabolized, as shown by the trend increase in urine lactate. It may have a negative impact on the acid–base balance when it accumulates. Nevertheless, RL was superior to normal saline in terms of correcting the acid–base status, even in the presence of liver failure. This result was consistent with the literature.[31]"

"Measurements were made at baseline (BL),
60 min after initiation of haemorrhagic shock (Shock),
and at the end of the experiment,
which was 60 min after starting resuscitation (R60)."

upload_2020-8-29_7-14-30.png


upload_2020-8-29_7-14-39.png
 
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Rick K

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As many of my readers know, mainstream science has been catching up on the malefits of excess lactate but continues to erroneously refer to it as lactic acid believing the terms to be interchangeable. Well, in yet another striking example of synchronicity (Synchronicity - Wikipedia), just a few days after posting again that plain thiamine HCl treats... everything, including cases of "lactic acidosis", the article below appeared on my news feed. It corroborates Peat's claim that mainstream consensus lags behind advances in the medical field and decades are needed for a revised concept to gain acceptance. Not only that, but it adds to the evidence that detrimental effects when there's too much lactate are a concern whether it's the acid (exogenous) or base (endogenous) form, they end up being metabolized similarly. Now, when lactic acid is invoked in the context of what takes place in our cellular respiration, the rescuing principle is ignored. In other words, it fails to acknowledge the very purpose for its generation, which is to put protons to use and prevent local acidification while regenerating NAD+ (see attached table), the molecule of life. When I mentioned it to a few doctors (who have adopted me against my will), the responses were nothing but dismissive, it just shows how dogmatic, idiotic, incapacitating, imbecilizing, indoctrinating, rigidifying, misleading, putrid, disgraceful, immoral, miserable, satanic, son of a b****, and damaging the academic shaping of your common white coat can be. :):

@aguilaroja @Drareg @Regina @tankasnowgod

Researchers unravel how humans differ from a pot of yogurt
Lactate, not Lactic Acid, is Produced by Cellular Cytosolic Energy Catabolism

"...it is unfortunate that the authors referred to cellular lactate production as lactic acid, repeatedly associated cellular lactic acid production as a cause of acidosis, and used the term lactic acid within their title. Such repeated use, totaling 50 occurrences of “lactic acid” throughout the entirety of the manuscript, severely detracts from the scientitic quality of their work."

"...there is no such entity as lactic acid in any living cell or physiological system. Indeed, it is impossible, based on the fundamental laws of physics that underpin the disciplines of organic chemistry, metabolic biochemistry, acid-base chemistry, and physiology, for lactic acid to be produced or present in living systems where cellular and tissue pH is regulated to be between 6.0 and 7.45."

"Sun et al. (12) explained cellular lactate production as the conversion of pyruvate to lactic acid (not true), that this was a reaction within glycolysis (not true, although there is debate as to what constitutes the true end of glycolysis, pyruvate or lactate), and that because of the low pKa of lactic acid (pK = 3.86) (true) [although the NIST (8) reference resource has this as pK = 3.67], there was an immediate and near-complete dissociation of lactic acid to lactate and a proton (H+) (p. 453) (not true because in living systems there is no lactic acid to begin with)."

"For glycolysis, there are nine reactions, commencing with the 6-carbon substrate glucose-6-phosphate (G6P) and ending with two 3-carbon pyruvate molecules (see Ref. 9, Table 2, p. R506). The first carboxylic functional group intermediate of glycolysis is produced in the sixth reaction where 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate (see Ref. 9, Fig. 5, p. R507). This is a phosphate transfer reaction, adding the phosphate to ADP forming ATP, with the co-production of 3-phosphoglycerate having an ionized (unprotonated) carboxylic functional group at carbon-3. This is key to understanding the H+ load of glycolysis and H+ metabolic buffering from lactate production. Each glycolytic intermediate following this reaction remains in an ionic form. There is never a glycolytic production of a carboxylic acid since they are all carboxylic ions. This remains true for obvious acid-base reasons from 3-phosphoglycerate to 2-phosphoglycerate to pyruvate and then to lactate. There is no metabolic production of lactic acid or any preceding glycolytic carboxylic ion metabolite, and, as previously explained, lactate production consumes, not releases, ~H+ (see Table 1; also see Ref. 9, Fig. 9, p. R509)."

"From the data of Table 1, it is clear that lactate production consumes a H+ load that is essentially stoichiometric to lactate production, regardless of pH across the cellular pH range. Conversely, as cellular pH declines, pertinent reactions of glycolysis sum to be more net ~H+ releasing. Glycolysis is independently ~H+ releasing, and the ~H+ consumption of lactate production opposes this, and it is unlikely that perfect matching of H+ exchange ever occurs, as is commonly represented in summary metabolic equations of glycolysis [−2 H+ (release)] and lactate production [+2 H+ (consumption)]. Indeed, as a cell becomes more acididic, there is an increasing ~H+ release from glycolysis, whereas that for lactate remains essentially unchanged."

"We understand that the term “lactic acidosis” has been used in clinical research and practice for more than 100 years. With the duration of this use comes considerable engrained misunderstanding and misapplication, and to expect a rapid change from any engrained convention may be unrealistic. However, given that the terminology is wrong based on incorrect understanding of metabolic biochemistry and acid-base chemistry, that clinical practice involves treating illnesses and saving lives from premature mortality, and that correct treatment most often requires a correct understanding of the true mechanisms of disease and symptomology, one would hope that clinical professionals would prefer to base their practice on empirical truths rather than engrained convention."

"It has been encouraging to see many physicians altering their view of a lactic acidosis based on revised explanations consisting of expressions of elevated blood lactate (hyperlactatemia) and an associated (or not) systemic acidosis (3, 5, 7). For example, considerable research of hyperlactatemia occurs for the condition of sepsis (3, 5, 7) and also metformin toxicity (1). For sepsis, hyperlactatemia is predictive of disease severity and premature mortality, with more than a threefold increase in mortality when hyperlactatemia is accompanied by tissue hypo-perfusion (5). The prior conventional interpretation of sepsis-associated hyperlactatemia accompanied by acidosis is framed on belief in a causal connection between the disease state, altered perfusion causing a localized hypoxia, stimulation of glycolysis, and lactic acid-induced metabolic acidosis. This is false knowledge, since there is no such condition as lactic acid-induced metabolic acidosis. The increased lactate presumably occurs due to increased stimulation of energy catabolism, causing increased substrate flux through glycolysis, which will therefore also increase lactate production and/or compromise blood lactate removal. For many patients, there is no accompanied acidosis (3, 5, 7), which is consistent with the metabolic biochemistry of the combined production of lactate and the retained function of mitochondrial respiration, since a continual H+ supply is needed as a substrate for each aspect of energy catabolism. For patients with a systemic acidosis, there could be a localized or systemic inflammatory response that triggers altered mitochondrial function and a metabolic milieu now consistent with metabolic acidosis (3, 7). Such a scenario is more aligned with altered mitochondrial respiration (normally a H+ sink) accompanied by increased glycolytic stimulation, the consequence of the two conditions causing increased net H+ release and an eventual acidosis."
it just shows how dogmatic, idiotic, incapacitating, imbecilizing, indoctrinating, rigidifying, misleading, putrid, disgraceful, immoral, miserable, satanic, son of a b****, and damaging the academic shaping of your common white coat can be. :):
You give them far too much credit. :) I wouldn't take my sickly azalea to this grotesque underclass of egotistical, empirical buffoons.
 

Rex_Squiggly

New Member
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Sep 11, 2017
Messages
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So uh, for us smoothbrains--does this mean yogurt is not as bad as we thought or even worse than we thought?
 

GelatinGoblin

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Apr 15, 2020
Messages
813
it just shows how dogmatic, idiotic, incapacitating, imbecilizing, indoctrinating, rigidifying, misleading, putrid, disgraceful, immoral, miserable, satanic, son of a b****, and damaging the academic shaping of your common white coat can be. :):
You give them far too much credit. :) I wouldn't take my sickly azalea to this grotesque underclass of egotistical, empirical buffoons.

I feel you... Rage against doctors is real :(
 

Amazoniac

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Thread starter
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Sep 10, 2014
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Not Uganda
Breaking news: our Bulgarian supercentenarian adds the red color before underlining (it's counterintuitive for it to work this way).

Anyway, Cori isn't an appropriate name for a cycle, but it is for a dog -- Cori! Cori! -- that you could teach tricks. The good can do a variation of the classic roll:


There are only two advantages that I can think of in honoring someone by naming the discovery after the person:
- Not risking specifying a function for something that may have it broad.
- Leaving such mark is no modest reward, should encourage others to seek similar great feats.

Narrowing of function can be avoided by naming the discovery with something that relates to it, such as what it looks like or resembles; anything that hints at it is going to be more useful than having a bunch of terms that have no practical value (Randle, Krebs, Pasteur, Crabtree, Bohr, Haldane, and so on), it's honoring one person to burden the rest.

When it was a cooperative work (Jarisch-Herxheimer), an entity may be flushed down the toilet for the catchy name. The Coris:
- Cori cycle - Wikipedia
 
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