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

[Levant]

So if we expect the Warburg effect without having cancer, wouldnt it be worth a try to act on it ? Trying to reduce the PKM 2 ? I found this study very interesting.

https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32756

Its about Benserazide reducing PKM2. It should be really safe to try because it shouldnt do much if you dont need it.

Here's the data from the paper you cited:
Reduction of lactate output...

Upregulation of oxidative phosphorylation...

 

[Badpack]

@sb4 well i think about Benserazide - https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32756

If the cells dont use the normal PDH1 for the citrate cycle and create more lactate while using PDH2 because of the warburg effect, it could be worth a try to reduce PDH2 to bring the body to use the PDH1 again.

 

[sb4]

@sb4 well i think about Benserazide - https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.32756

If the cells dont use the normal PDH1 for the citrate cycle and create more lactate while using PDH2 because of the warburg effect, it could be worth a try to reduce PDH2 to bring the body to use the PDH1 again.

Just so that I understand. PDH is pyruvate dehydrogenase. It has 3 subunits. That paper you linked refers to PKM2 (pyruvate kinase M2). Do you mean PKM2 when you say PDH2?

If so then PKM2 inhibits PDH? But shouldn't PKM1 also inhibit PDH.

Benserazide looks interesting. How safe is it?

 

[Badpack]

Yes i mean PKM2. The study clearly says inhibiting PKM2 with Benserazide doesnt touch PKM1. Which resulted in higher ATP production and less lactate.

PKM1 isozyme is expressed in organs that are strongly dependent upon a high rate of energy regeneration, such as muscle and brain. Which could explain the extreme brain fog and fatigue ppl experience should it change to PKM2.

Benserazide should be as safe as it gets. Its in use for decades as combination therapy for parkinson with L-dopa. And it should do nothing when not needed.

 

[WantedAlive]

When the cfs hit, it was noticeable that something more serious was wrong

@Levant What symptoms did you experience when the CFS ‘hit’? Was this more an acute onset than gradual? It’s really interesting looking at your OAT measures, there are some consistencies with other ME patients, but also differences.

For example, you’re high in the marker 3-methylglutaconic acid. High values indicate a reduced ability to metabolize the amino acid, leucine. This abnormality is found in the genetic disease, methylglutaconic aciduria (such as Barth Syndrome) and in mitochondrial disorders. I can’t find this marker in my OAT test to compare unfortunately.

Another marker 3-hydroxyglutaric acid which you’re high in, the OAT guide indicates genetic disease. This metabolite is associated with glutaric aciduria type I, which is caused by a deficiency of glutaryl CoA dehydrogenase, an enzyme involved in the breakdown of lysine, hydroxylysine, and tryptophan. In this specific disorder, other organic acids such as glutaric and glutaconic acids will be elevated as well. I can’t see evidence of the latter, but your low kynurenic indicates impaired tryptophan metabolism in that pathway at least, which is also thought to exist in ME/CFS.

Also, your elevated levels of glyceric acid in addition to elevated oxalates according to the OAT test guide indicates the presence of the type 2 GRHPR genetic variance. High glyceric levels usually relates to primary hyperoxaluria type 2. In this condition there is a deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHFR). Elevated values may also be due to microbial sources such as yeast (Aspergillus, Penicillium, probably Candida) or due to dietary sources containing glycerol (glycerine).

I hope that offers some further exploration opportunities for you to rule out if they’re at all applicable to you, just in case they’re not ME/CFS related but something you can actually treat. Many of these are hereditary or primary conditions and probably not relevant but may help direct you to a cause. You asked about the three FMT’s I had – they didn’t help me. Perhaps I needed to continue longer, but I’d have expected some improvement by the third dose so that’s why I stopped.

 

[WantedAlive]

So if we expect the Warburg effect without having cancer, wouldnt it be worth a try to act on it ? Trying to reduce the PKM 2 ? I found this study very interesting

@Badpack This raises an interesting dilemma. Might a Warburg-like pathological state be protective in ME/CFS? For example Colon Cancer cells maintain low levels of pyruvate (like we see in ME/CFS) to avoid cell death caused by inhibition of HDAC1/HDAC3 [ref]. Perhaps in ME/CFS, which also exhibits high HDAC1, HDAC2, HDAC3, and the PKM2 enzyme is maintaining low pyruvate production to prevent inhibition of these deacetylases to evade excessive cell death.

So far no research has shown impaired glycolysis, but I remain unconvinced until PK enzyme is studied. The expression of PKM2 doesn't shut down pyruvate production, it just limits it to accumulate upstream components for PPP as I understand it. We all appear to exhibit low pyruvate levels and without elevated lactate strongly suggests to me pyruvate production is throttled back.

 

[WantedAlive]

You're saying that the Warburg effect style is happening , but you're also saying glycolysis is inhibited. The definition of the Warburg effect is activation of glycolysis.

@phillybadboy I'm suggesting it MIGHT be happening, hypothetically. To correct any misinterpretation: I'm saying glycolytic production of pyruvate appears to be inhibited, but I'm not saying glycolysis is inhibited. The warburg effect is not just about upregulated glycolysis for energy despite available oxygen for OXPHOS, it can also be about adapting metabolism to shunt upstream components via PPP for cellular proliferation which is where PKM2 enzyme comes into effect as the rate limiting step for pyruvate production. Hope that clarifies.

 

[Badpack]

@WantedAlive Its just a thought experiment. But i believe that the body wants to protect us with the Warburg effect from a threat that doesnt exist. There seems no at hand explanation why it should benefit us and why it should stay.

From the case studies i have seen, cancer patient get a huge relief from their cfs when under treatment. Which often stops with ending the cancer treatment and cfs comes back. This could hint, that acting in these pathways could be very beneficial for us.

We just need to find a parkinson patient with cfs/fatigue symptoms and see if he finds relief in taking l-dopa/Benserazide

 

[sb4]

Its just a thought experiment. But i believe that the body wants to protect us with the Warburg effect from a threat that doesnt exist.

I think this too. Our cells are deliberately adopting a defensive (?) mode and one of the ways it does this is by shuting down PDH.

This would explain why I get benefit from high dose thiamine which then disappears after a few days. It's like my body is combating the thiamine induced upregulation of PDH by further upregulating it's inhibitors.

Having said that on two separate occasions I did a month or so of high doses of DCA which should have upregulated PDH but I noticed nothing. I tried 2 different sources in case one was a dud.

 

[Badpack]

It also explains with i (and a lot of other Cfs patients) never got a real (viral) infection since the start of Cfs. Because they depend on your metabolism. Which clearly doesnt exist.

And i dont believe there is a real infection going on that takes our energy away. Otherwise all of my immunosuppression would have made it worse. But it did nothing. Which also doesnt really speak for autoimmunity. So that leaves me with the believe its a self sufficient circulus vitiosus involving the PDH. Which explains why cancer treatment seems beneficial. Which again brings me to Benserazide right now.

 

[Learner1]

Thanks! That's great info! The naturopath I was being treated by suggested that the elevated oxalates were due to fungal dysbiosis and mould sensitivity, so I've been on diet and supplements for that but without noticeable improvement.
I'll try tackling the oxalate issue directly like you suggest.

Much as I like naturopathic doctors, yours is wrong. Elevated oxalates can lead to fungal dysbiosis, and reducing oxalates can make the fungal issues improve.

Definitely try tackling the oxalate issue - it's near impossible to improve if you don't - they cause a cascade of other problems. It might be wise to check your levels of B6, minerals and antioxidants, which are all depleted by oxalates. And, if you seem to have a sulfur problem, molybdenum can help.

 

[Levant]

@Levant What symptoms did you experience when the CFS ‘hit’? Was this more an acute onset than gradual? It’s really interesting looking at your OAT measures, there are some consistencies with other ME patients, but also differences.

In the month following the organic acids test, I noticed my heart-beat was becoming a bit extreme, I slept less, developed tinnitus and bruxism, and just generally felt a bit hyperactive. But I was pushing myself quite hard at this point and wasn't experiencing any PEM or brain-fog.
At a certain point, it sort of felt like I was having a stroke and the best way I can describe it is that my soul fell out of my arse. I had to lie down on the floor for about an hour, and then just got on with my life as usual - but noticed there was something wrong with the way I my brain was working - I'd occasionally feel spaced-out and thinking didn't seem to come naturally any more, as if I had to put conscious effort into forming thoughts. Physically I was basically fine, but quickly cut back on my exercise and workload subconsciously - and just assumed I'd suddenly become lazy. My brain and body just continued to fall apart over the few months following until I ended up in A&E.

I'm pretty sure I didn't have M.E. at the time of the organic acids test, though as you've pointed out, I obviously had a boatload of buggery going on metabolically. Weirdly I was pretty functional at that point though, no less functional than I'd been for the previous year anyway.

This is why I'm curious if mitochondrial and metabolic issues in M.E. are truly driving the symptoms, or if there's something more neurological at play.

 

[Levant]

And thanks @WantedAlive for the extra info. Not sure what I'd do to treat this except for treating my cells with a bit of tender loving care.
Also, pity about the FMT, I find it bizarre that it's so life-changing for some cfsers and a non-starter for others.

 

[Levant]

Much as I like naturopathic doctors, yours is wrong. Elevated oxalates can lead to fungal dysbiosis, and reducing oxalates can make the fungal issues improve.

Definitely try tackling the oxalate issue - it's near impossible to improve if you don't - they cause a cascade of other problems. It might be wise to check your levels of B6, minerals and antioxidants, which are all depleted by oxalates. And, if you seem to have a sulfur problem, molybdenum can help.

Thanks @Learner1
You're hired as my new naturopath, congrats

 

[Badpack]

Here is a list of possible PKM2 Inhibitors. Bought some Lapachol. Lets see what happens.

 

[phillybadboy]

Badpack I would strongly advise against anyone taking anything at this time, could be dangerous . I know you're anxious to try things, as so am I . But Lets look into these further and have some disscussions about potential dangers and side effects before we do.

 

[Badpack]

some nice illustration for the better understanding.

 

[Pyrrhus]

New paper about the Warburg Effect in relation to the novel coronavirus:

The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response
https://www.sciencedirect.com/science/article/pii/S030090842030287X
Excerpt:

Highlights
• Enhanced aerobic glycolysis supports replication of many viruses including MERS-CoV.
• PI3K/AKT and MAPK/ERK inhibitors arrest MERS-CoV replication.
• This metabolism likely sustains SARS-CoV-2 replication in host cells, in particular airway cells .
• The Warburg effect also supports activation of endothelial cells and pro-inflammatory cells .

Abstract
Current mortality due to the Covid-19 pandemic (approximately 1.2 million by November 2020) demonstrates the lack of an effective treatment. As replication of many viruses - including MERS-CoV - is supported by enhanced aerobic glycolysis, we hypothesized that SARS-CoV-2 replication in host cells (especially airway cells) is reliant upon altered glucose metabolism. This metabolism is similar to the Warburg effect well studied in cancer.

Counteracting two main pathways (PI3K/AKT and MAPK/ERK signaling) sustaining aerobic glycolysis inhibits MERS-CoV replication and thus, very likely that of SARS-CoV-2, which shares many similarities with MERS-CoV. The Warburg effect appears to be involved in several steps of COVID-19 infection. Once induced by hypoxia, the Warburg effect becomes active in lung endothelial cells, particularly in the presence of atherosclerosis, thereby promoting vasoconstriction and micro thrombosis. Aerobic glycolysis also supports activation of pro-inflammatory cells such as neutrophils and M1 macrophages. As the anti-inflammatory response and reparative process is performed by M2 macrophages reliant on oxidative metabolism, we speculated that the switch to oxidative metabolism in M2 macrophages would not occur at the appropriate time due to an uncontrolled pro-inflammatory cascade.

Aging, mitochondrial senescence and enzyme dysfunction, AMPK downregulation and p53 inactivation could all play a role in this key biochemical event. Understanding the role of the Warburg effect in COVID-19 can be essential to developing molecules reducing infectivity, arresting endothelial cells activation and the pro-inflammatory cascade.

 

[WantedAlive]

The OAT results provided by the handful of PwME in this thread to date exhibit a predominance of low pyruvate without increased lactate. The premise here, with Fluge & Mella demonstrating impaired PDH function would be to expect pyruvate accumulation or increased conversion to lactate, neither of which appears present in ME/CFS and therefore might support a theory of downregulation of pyruvate production by enzyme PKM2.

Despite other researchers finding no impairment in glycolysis, Armstrong & McGregor have indicated inhibition of glycolysis with reduced pyruvate and lactate. Additionally, Armstrong & McGregor reported significantly upregulated histone deacetylase activity for HDAC2 and HDAC3, the relevance here being the Warburg Effect causes a shift in histone acetylation.

The following paper found cancer cells maintain low levels of pyruvate to prevent inhibition of HDAC’s regulated by c-Myc. Constitutively expressed in cancer, c-Myc is involved in activating expression of pro-proliferative genes including T and B-Cell proliferation and has evidence of involvement in lymphoma, leukaemia and several viral-type infections.

Low levels of pyruvate induced by a positive feedback loop protects cholangiocarcinoma cells from apoptosis
https://biosignaling.biomedcentral.com/articles/10.1186/s12964-019-0332-8

Abstract

Background
Cancer cells avidly consume glucose and convert it to lactate, resulting in a low pyruvate level. This phenomenon is known as the Warburg effect, and is important for cell proliferation. Although cMyc has often been described as an oncoprotein that preferentially contributes to the Warburg effect and tumor proliferation, mechanisms of action remain unclear. Histone deacetylase 3 (HDAC3) regulates gene expression by removing acetyl groups from lysine residues, as well as has an oncogenic role in apoptosis and contributes to the proliferation of many cancer cells including cholangiocarcinoma (CCA). HDAC inhibitors display antitumor activity in many cancer cell lines. Cancer cells maintain low levels of pyruvate to prevent inhibition of HDAC but the mechanisms remain elusive. The purpose of our study was to explore the role of cMyc in regulating pyruvate metabolism, as well as to investigate whether the inhibitory effect of pyruvate on HDAC3 could hold promise in the treatment of cancer cells.

Results
We confirmed downregulated pyruvate levels in CCA, and defined that high pyruvate levels correlated with reduced cell proliferation levels. Downregulated pyruvate levels decreased the inhibition to HDAC3 and consequently protected CCA cells from apoptosis. Synergistically upregulated LDHA, PKM2 levels resulted in low levels of pyruvate, as well as poor patient survival. We also found that low levels of pyruvate contributed to proliferation of CCA cells and confirmed that the upstream target is cMyc. Conversely, high activity of HDAC3 stabilized cMyc protein by preferential deacetylating cMyc at K323 site, which further contributed to the low pyruvate levels. Finally, this creates a positive feedback loop that maintained the low levels of pyruvate and promoted CCA proliferation.

Conclusions
Collectively, our findings identify a role for promoting the low pyruvate levels regulated by c-Myc, and its dynamic acetylation in cancer cell proliferation. These targets, as markers for predicting tumor proliferation in patients undergoing clinical treatments, could pave the way towards personalized therapies.

Highlights
We found cMyc decreases pyruvate levels by promoting LDHA and PKM2 levels, this can consequently decrease the inhibition to HDAC3 and protect cancer cells from apoptosis. Conversely, high activity of HDAC3 stabilizes the cMyc protein by preferentially deacetylating cMyc at K323 site, which further contributes to low pyruvate levels. This creates a positive feedback loop that promotes the Warburg effect and cell proliferation of the tumor.

CCA cells consume glucose more avidly and convert it to lactate, resulting in a low pyruvate level, and this is important for cell proliferation. cMyc decreases pyruvate levels by promoting PKM2 and LDHA levels, consequently decreasing the inhibition to HDAC3 and protecting cancer cells from apoptosis. Conversely, high activity of HDAC3 stabilize the cMyc protein by preferential deacetylation of cMyc at the K323 site, which further contributes to low pyruvate levels. This creates a positive feedback loop that promotes the Warburg effect and cell proliferation of CCA.

The therapeutic targets in cancer being explored include HDAC inhibitors potentially preventing the cancer cell protection from apoptosis. In systemic inflammatory diseases which better represent ME/CFS, HDAC inhibitors are also being explored but the balance between acetylation and deacetylation is proving crucial so as to not induce hypo-inflammation.

 

[sb4]

@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?