Organic Acid Test (OAT) results – do we ALL show the Warburg effect?

[vision blue]

Does anyone have a sample report from a healthy adult we can compare to? of course it's usually the chronically ill that go for the OAT , making comparisons to norms difficult. (Ithought great plains does ship oversees, but perhaps i'm wrong).

I do find the interpretave paragraphs often do not apply to us- they list the most common causes, and i've almost never had one apply.

I've listened to many of their webinars on the oat- i jsut can't remember if they discussed low pryviate- will try to check my notes
(and my OATs later today).

 

[vision blue]

@WantedAlive
ok, was able to dig out my results. Both taken with Great Plains Lab, about 2 years apart. It is different between the two times:

Older one............................................................ Newer one
Pyruvate: low end of norma........................Pyruvate:.Highish normal
Lactate: very low end of normal..............Lactate: .High end of normal)
Citrate about middle of normal range...... Citrate: About middle of normal range ...................................................................................(little.higher than last time)
Succinate very high end of norma;,ost.......Succinate: Very low end of normal range
(almost out of range)
Fumarate low end of normal..........................Fumarate: low end of normal ( a little ...........................................................................................lower than.last time)

In both, lactic higher than pyruvate, more so for older test, but neither has an extreme difference between the two.

Not sure, but neither realy fit? If so, maybe the first one does somewhat? Intersting how different the second one is, especialy succinate. The pyruvate and lactate differnt too, but there, the relation between them is similar, jsut both lowisn in one and highish in the other.

Since this is a biochem pathway I do not know tons about, your expertise certainly appreciated. I remember when i got the second one and compared it to the first i figured i was looking at very common dynamic metaoblism and just one snapshot in time accountinf for differnces. But would love to read your thoughts.

i had listened to webinars there and ddi some digging, but it was when i'd record notes handwritten in marigins. between inc fade and bad handrwriting, cna't make out a lot. thought maybe high succinate may indicate chemical exposure (may have been writing down just tihngs relevent o me) and converted in Complex II initochondria, but can't read to what...useless. i didn't

@Learner1 I'm not stalking you...turns out you posted in two threads i was interested in. I notice here you mention oxalates. I have high oxalates and high ammonia but cannot figure out cause. I eat very low protein and no evidence of a yeast infection (nor pathogenic bacteria in gut). I also do not eat high oxalate foods (or at least did not the years I took the oat).

I'm going to repeat it in the next month or so - if any suggestions on what it would be cool to try from now perhaps to see if makes a difference, i'm game. I need to look through it again to see what I want to test out. I made a concerted effort on a couple of things which did pay off last time.

 

[Learner1]

@Learner1 I'm not stalking you...turns out you posted in two threads i was interested in. I notice here you mention oxalates. I have high oxalates and high ammonia but cannot figure out cause. I eat very low protein and no evidence of a yeast infection (nor pathogenic bacteria in gut). I also do not eat high oxalate foods (or at least did not the years I took the oat).

If you're not eating protein, what are you eating? Plant based foods contain oxalates, animal foods do not.

 

[Pyrrhus]

Out of interest, I've created a rough illustration of this warburg effect showing the krebs-cycle breaks and why Citrate and succinate are elevated, and where PKM2 is and why pyruvate/lactate is likely low.

View attachment 38270

Nice diagram!

I'm curious, which amino acids are broken down to create fumarate?
Just phenylalanine and tyrosine?

 

[WantedAlive]

If we do have low Pyruvate and Lactate, where is all the glucose going? Pentose Phosphate Pathway?
Also could an easy way to test this be ingest a large dose of pyruvate?

@sb4 You're correct. The principle of the Warburg effect being that glycolysis continues to consume glucose but the last step converting to pyruvate is reduced allowing backup of intermediates to pass through the PPP for nucleotide synthesis, cell proliferation, and NADPH. Note also in Armstrong & McGregor’s paper that blood glucose is increased in PwME suggesting glucose excretion in urine is probably also increased.

Ron Davis tested ethyl-pyruvate successfully in his nanometer, but he cautioned not to try this.

 

[WantedAlive]

I'm curious, which amino acids are broken down to create fumarate?
Just phenylalanine and tyrosine?

Aspartate, phenylalanine and tyrosine

Nice diagram!

Thanks! Not sure it resembles ME/CFS, but my OAT seemed to correlate with the TCA breaks illustrated. I had a very acute sepsis-like onset.

 

[WantedAlive]

@vision blue Thanks for posting and your request for 'expertise'...I must declare I'm no expert. @Learner1 has had more experience with professionals in this field. Your measures don't show anything out of a normal range, so difficult to make a comment. Do you have any other metabolites out of normal? They might offer some clues that can be interpreted from the guides.

 

[sb4]

Ron Davis tested ethyl-pyruvate successfully in his nanometer, but he cautioned not to try this.

I have already tried ethyl pyruvate but in very low amounts. The seller of the product reasoned that the ethyl group allows it to stick around longer, where it activated PDH but doesn't actually get used up by it. I noticed I was more hungry when using it for the first few days but that effect seemed to fade.

 

[vision blue]

@WantedAlive . This is a great thread but wondering about something. What your saying about impaired glycolosis in ME is different than what I've been reading. I thought the metabolomic studies of CFS/ME have been finding there is no impairment in either glycolosis or krebbs cycle, but rather the link between the two. So that pyruvate (output of glycolosis) cannot be used as fuel for the kreb cycle- so no product of coq a or whatever that is. And that CFS folk, becasue they don't use the pyruvate to form the co q a needed for krebs convert they pyruvite to lactate. (You did say that but then went on to say you thought glycolosis itself also impoared) Therefor, cfs folk (in the standard account of what's gone wroing with pyruvite donverting to lactate cause can't be used as a substrate in krebs) build up lactic acid much sooner in excercise, for example. My understaning of the warburg effect is not low pyruvate as I think you said - perhaps you were speaking quickly? . (though i imainge smoe folk could be so good at converting to lactate that pyrvuate doesn't show up?) . So e.g. when i first looked at my data i concluded nor a warburg based on what you said, but further reading suggests otherwise.

I've had what appears to me to be a big change in glycolosis and serine production - suddenly hugely upregulated, and i'm getting concerned it may reflect a cancer. Its intersting you say can also occur in immune states- though if it has to be so extreme as to be sepsis, then I certainly dont' have that.

i may do a seperate post on it

by the way, i asked a question on histidine curious to see what others have found if youre interested in more metabolomics discussion.

ok, looks like you had more posts, so will look now.

 

[vision blue]

If you're not eating protein, what are you eating? Plant based foods contain oxalates, animal foods do not.

Eat way to many carbs but probably a better answer to your question is that I was speaking to hastily in attempt to be brief. I'm making the mistake of aggregrating oxaalte with other sources of acid (i have high ammonia in urine and pretty acidi urine yet my intake of protein is low (and my usual low AA levels in urine reflect this). So one of my intersts in uric acid was getting to the bottom of my high ammonia and acidic urine. But perhaps is not productive to do it this way.

 

[vision blue]

@sb4 The principle of the Warburg effect being that glycolysis continues to consume glucose but the last step converting to pyruvate is reduced ..

I'm still unclear where this comes from. Here's a quote on the warburg effect:

"The Warburg Effect refers to the phenomenon that occurs in most cancer cells where instead of generating energy with a low rate of glycolysis followed by oxidizing pyruvate via the Krebs cycle in the mitochondria, the pyruvate from a high rate of glycolysis undergoes lactic acid fermentation in the cytosol."
It's from pubchem and there are alot of siilar sites https://pubchem.ncbi.nlm.nih.gov/pathway/PathBank:SMP0000654

This suggests pyruvate is produced but then it gets converted to lactic acid/lactate rather than being able to be used for krebs cycle, like noted aelarer.
What am i missing? that is, in the view of warburg priciniple youre mentioning, less pyruvate is produced but in what i'm reading of warburm principle, just as much pyruvate is produced.

In regards to my own situation where that glycolosis suddently increased, i think will create a post on it which i hope you can look at (expecially once we get clarity on warburg!

 

[Learner1]

Eat way to many carbs but probably a better answer to your question is that I was speaking to hastily in attempt to be brief. I'm making the mistake of aggregrating oxaalte with other sources of acid (i have high ammonia in urine and pretty acidi urine yet my intake of protein is low (and my usual low AA levels in urine reflect this). So one of my intersts in uric acid was getting to the bottom of my high ammonia and acidic urine. But perhaps is not productive to do it this way.

I don't think so. See this thread:

https://forums.phoenixrising.me/threads/oxalates.79925/

 

[WantedAlive]

This suggests pyruvate is produced but then it gets converted to lactic acid/lactate rather than being able to be used for krebs cycle, like noted aelarer.
What am i missing? that is, in the view of warburg priciniple youre mentioning, less pyruvate is produced but in what i'm reading of warburm principle, just as much pyruvate is produced.

Of course, it's true pyruvate is still being produced, and in the Warburg Effect there is upregulated conversion of pyruvate to lactate as you say. With this, you would expect to see a lower than normal pyruvate-to-lactate ratio. The reason for this is thought to control intracellular pH beneficial to cell division and replication.

However, the other important aspect of the Warburg Effect is to provide glycolytic intermediates through the pentose phosphate pathway (PPP) necessary for nucleotide synthesis, cell proliferation and NADPH. You can't have cell proliferation without the building blocks. So even if glucose intake may be increased and glycolysis upregulated, the ratio of glucose-to-pyruvate production is reduced and those spare glycolytic intermediates are redirected through the PPP.

In theory therefore, the reason we see low pyruvate in OAT is because it is being converted to lactate. However, if pyruvate was being produced at normal levels, then you would expect to see high lactate levels, but that's not the case - lactate levels are low to normal. This must mean pyruvate production is sub-normal.

I thought the metabolomic studies of CFS/ME have been finding there is no impairment in either glycolosis or krebbs cycle

The jury is out on glycolysis impairment, Armstrong McGregor suspecting impairment, others saying there isn't. I believe there needs to be deeper research on this as it's not certain. The TCA cycle appears to be fueled by amino acid catabolism, and the electron transport chain has been found to have an impaired complex V (ATP Synthase).

The Warburg Effect is common in cancer and normal proliferating cells, even in embryonic development. Its a surprisingly common finding, not just in cancer but many non-cancerous diseases as well. I do believe we are seeing the Warburg Effect in ME/CFS, but if so, the real question is why?

 

[Learner1]

This must mean pyruvate production is sub-normal.

I've seen dozens of patients' tests. Not all have low pyruvate, but some do. This is what Genova Diagnostics says the causes of low pyruvate can be:

Three processes, then, are responsible
for adequate pyruvate:
(1) glycolysis (glucose to pyruvate),
(2) glycogenolysis (breakdown of glucose stored as glycogen),
(3) gluconeogenesis (making glucose from non-carbohydrate nutrients).

The rate-limiting problems for glycolysis can be-

• Insulin deficiency, which reduces activity of glucokinase
• Insulin/glucagon dysregulation, which impairs both glycogenesis and glycogenolysis
• Deficiency of magnesium, the activator of phosphokinase enzymes needed for glycolysis and gluconeogenesis
• Excessive aluminum, which binds phosphate and inhibits phosphokinase enzymes
• Excessive antimony, which inhibits phosphofructokinase
• Excessive iodine, which may inhibit glyceraldehyde dehydrogenase
• Excessive fluorine or fluoride, which inhibits enolase (forms phosphoenol pyruvate)

Glycogenolysis, to free up stored glucose, can be inhibited by Insufficient glucagon or epinephrine, both of which stimulate the phosphorylase enzyme that controls glycogenolysis. This is particularly important in the morning, upon arising; thus if pyruvic acid is low in first-morning urine, low blood sugar due to impaired glycogenolysis is likely. This could be due to insufficient glucagon secretion (such as in pancreatic insufficiency) or to inadequate catecholamines (resulting from inadequate nutrient precursors such as phenylalanine and tyrosine, adrenal medullary insufficiency, or impaired ability of platelets to carry the catecholamines, as in platelet clumping.)

Gluconeogenesis is an unlikely reason for low pyruvate in first morning urine. This process usually becomes critical in activities requiring extended periods of physical exercise and endurance.


So, of all of the reasons above, many ME/CFS patients are either low in magnesium, have insulin dysregulation, adrenal insuffiency, and/or shortage of phenylalanine, tyrosine and/or catecholamines like epinepherine, any of which can cause low pyruvate.

The jury is out on glycolysis impairment, Armstrong McGregor suspecting impairment, others saying there isn't. I believe there needs to be deeper research on this as it's not certain.

I think it differs from patient to patient, and that's what McGregor told me, that there are subsets of patients with different problems.

The TCA cycle appears to be fueled by amino acid catabolism, and the electron transport chain has been found to have an impaired complex V (ATP Synthase).

The MitoSwab people told me they've seen the typical pattern in ME/CFS patients is low complex I and high complex IV. Unfortunately, they don't measure complex V.

Impaired complex I can be due to peroxynitrite production, which many of us have. They told be complex IV will be hyperactive to try to compensate for complex I, however, though I've been able to increase complex I, my complex iV is still hyperactive, but I don't know if this is typical.

 

[Martin aka paused||M.E.]

@sb4
Ron Davis tested ethyl-pyruvate successfully in his nanometer, but he cautioned not to try this.

like many I’m low in pyruvate and just had the idea to take it. Did he say why that could be dangerous?

 

[sb4]

like many I’m low in pyruvate and just had the idea to take it. Did he say why that could be dangerous?

Not sure what he would have said but I think the idea behind ethyl pyruvate is that the ethyl group allows the pyruvate to stay around in the cell much longer without getting used up. In this extra time it is still activating PDH.

When I took it I noticed an increase in hunger for the first couple of days, can't remember now wether it did much for other symptoms, but the effect seemed to fade away after a few days. Perhaps the body builds tolerance.

 

[Pyrrhus]

Related discussion on the Warburg Effect (AKA aerobic glycolysis):

Enhanced aerobic glycolysis [...] by Epstein-Barr virus latent membrane protein 1
https://forums.phoenixrising.me/thr...n-barr-virus-latent-membrane-protein-1.58953/

 

[Pyrrhus]

Here is a new paper on the Warburg Effect (AKA aerobic glycolysis)

Increased demand for NAD+ relative to ATP drives aerobic glycolysis (Luengo et al., 2021)
https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30904-7
Excerpt:

Highlights
• PDH activation suppresses cell proliferation by reducing the NAD+/NADH ratio
• Insufficient ATP demand slows mitochondria NAD+ regeneration in proliferating cells
• Uncoupling mitochondrial respiration from ATP synthesis can increase proliferation
• Aerobic glycolysis reflects increased cell demand for NAD+ relative to ATP turnover

Summary
Aerobic glycolysis, or preferential fermentation of glucose-derived pyruvate to lactate despite available oxygen, is associated with proliferation across many organisms and conditions. To better understand that association, we examined the metabolic consequence of activating the pyruvate dehydrogenase complex (PDH) to increase pyruvate oxidation at the expense of fermentation. We find that increasing PDH activity impairs cell proliferation by reducing the NAD+/NADH ratio. This change in NAD+/NADH is caused by increased mitochondrial membrane potential that impairs mitochondrial electron transport and NAD+ regeneration. Uncoupling respiration from ATP synthesis or increasing ATP hydrolysis restores NAD+/NADH homeostasis and proliferation even when glucose oxidation is increased. These data suggest that when demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP.

 

[Learner1]

Here is a new paper on the Warburg Effect (AKA aerobic glycolysis)

Increased demand for NAD+ relative to ATP drives aerobic glycolysis (Luengo et al., 2021)
https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30904-7
Excerpt:
...
These data suggest that when demand for NAD+ to support oxidation reactions exceeds the rate of ATP turnover in cells, NAD+ regeneration by mitochondrial respiration becomes constrained, promoting fermentation, despite available oxygen. This argues that cells engage in aerobic glycolysis when the demand for NAD+ is in excess of the demand for ATP.

So, how would we test to see if it's happening to us? Things my testing and experience have shown:

• Depleted NAD+ as evidenced by energy increase from NAD+ or NMN
• Lack of use of beta oxidation, preferential use of glycolysis, both lying flat on a table for 20 minutes as well as with anything effort in exercise
• High glutaric acid and low myoglobin which gave been linked to impaired fatty acid oxidation

 

[vision blue]

like many I’m low in pyruvate and just had the idea to take it. Did he say why that could be dangerous?

Hi. When you say you are low in pyruvate, are you high or low in lactate? (and are you measuring through urine or blood). Thanks.