WantedAlive
Senior Member
- Messages
- 158
I’m interested to see if all members who’ve had their Urine Organic Acids test to look back to see if their test results resemble a metabolite profile typical of the Warburg effect. For those of you not familiar, the Warburg effect is upregulated glycolysis despite available oxygen and is not unique to cancer, but is also a property of activated inflammatory immune cells as seen in sepsis and burns patients. Metabolic studies of ME/CFS have determined the disease closely resembles systemic inflammatory response syndrome (SIRS), sepsis is essentially SIRS secondary to bacterial infection, SIRS is secondary to non-bacterial infection.
If your test shows very low or undetected Pyruvate, low to normal Lactate, high Citrate and Succinate, and low or undetectable Fumarate, this is a typical profile of the Warburg effect. My understanding is ME/CFS patients have low pyruvate without raised lactate indicating impaired glycolysis, this is very irregular. In fact, low pyruvate doesn’t even get mentioned in the OAT interpretive guide let alone the other metabolites in concert. My GP never picked up on these anomalies with my test. I doubt a cancer patient would reveal this profile, but a sepsis or burns patient probably would due to the systemic metabolic alteration. It begs the question, could this be an adequate biomarker for ME/CFS in the obvious absence of burns or sepsis? Hence, I seek members test results to compare with mine.
My pyruvate was undetectable, lactate low-normal (2nd quintile), citrate and succinate both very high (4th/5th quintile), and fumarate undetectable. I did my test 2 years after ME/CFS onset, at the time I was moderate on the severity scale.
Metabolic studies of ME/CFS indicate pyruvate dehydrogenase inhibition limiting transport of pyruvate into the mitochondria. The remaining fate for pyruvate is lactate, but with lactate also reduced this means glycolytic production of pyruvate must be inhibited. In oncology, this is referred to as “cancer-specific metabolic budgeting system” in which the final step of glycolysis to form pyruvate is downregulated in favour of producing glycolytic intermediates for cellular proliferation. Pyruvate Kinase is the key enzyme in this last step of glycolysis, and it’s M2 isoform (PKM2) is exclusively expressed to help regulate the balance between upstream glycolytic intermediates for proliferation and pyruvate for energy. PK hasn’t been studied in ME/CFS, but I’d bet the house PKM2 is over-expressed to the usual M1 isoform, as is ubiquitous in most cancers and sepsis. Without pyruvate for energy, the cell must resort to fats or amino acids to fuel OXPHOS which is why many of us do better on keto or amino acids. In sepsis, Krebs cycle intermediates citrate is increased for synthesis of lipids and succinate increased to stabilise hypoxia-inducible-factor to maintain aerobic glycolysis and inflammation, though perhaps longer-term or more severe patients may not exhibit this. As I say, I tested mine two years in. The intermediate fumarate is low due to the break in the krebs cycle to sustain high succinate. The same occurs after isocitrate, where alpha-ketoglutarate is supplemented by glutaminolysis.
McGregor believes impaired glycolysis is at the root of ME/CFS and I think he’s bang on the money. Emerging evidence suggests a correlation between increased PKM2 and a pro-inflammatory state. Do we just need to suppress PKM2? Pyruvate is an inhibitor of PKM2, and Davis found pyruvate worked with his nanometer test. Interestingly, pure T3 also suppresses PKM2, is this the reason high dose Pure T3 helped some patients? Shikonin is an inhibitor of PKM2 and could also be tested.
A caveat to this theory is PKM2 overexpression promotes mitochondrial fusion, so what about Prusty’s findings on mitochondrial fragmentation under stress? Interestingly, PKM2 trans-locates to mitochondria under oxidative stress and has been demonstrated to affect mitochondrial fission/fusion mediators. In sepsis, the fission/fusion balance shifts toward fission by upregulation or downregulation of these mediators. This is a field of current research. Is PKM2 trying to compensate a stress-induced fission mediator in ME/CFS? This could be a feedback trap.
Getting back to impaired glycolysis then, do we all show it and is OAT a reasonable diagnostic tool? Please advise how soon after onset you did the test, and how severe you are. It is apparent that more severe patients and maybe more long term patients also have mitochondrial impairment and the krebs cycle intermediates may therefore yield different results.
If your test shows very low or undetected Pyruvate, low to normal Lactate, high Citrate and Succinate, and low or undetectable Fumarate, this is a typical profile of the Warburg effect. My understanding is ME/CFS patients have low pyruvate without raised lactate indicating impaired glycolysis, this is very irregular. In fact, low pyruvate doesn’t even get mentioned in the OAT interpretive guide let alone the other metabolites in concert. My GP never picked up on these anomalies with my test. I doubt a cancer patient would reveal this profile, but a sepsis or burns patient probably would due to the systemic metabolic alteration. It begs the question, could this be an adequate biomarker for ME/CFS in the obvious absence of burns or sepsis? Hence, I seek members test results to compare with mine.
My pyruvate was undetectable, lactate low-normal (2nd quintile), citrate and succinate both very high (4th/5th quintile), and fumarate undetectable. I did my test 2 years after ME/CFS onset, at the time I was moderate on the severity scale.
Metabolic studies of ME/CFS indicate pyruvate dehydrogenase inhibition limiting transport of pyruvate into the mitochondria. The remaining fate for pyruvate is lactate, but with lactate also reduced this means glycolytic production of pyruvate must be inhibited. In oncology, this is referred to as “cancer-specific metabolic budgeting system” in which the final step of glycolysis to form pyruvate is downregulated in favour of producing glycolytic intermediates for cellular proliferation. Pyruvate Kinase is the key enzyme in this last step of glycolysis, and it’s M2 isoform (PKM2) is exclusively expressed to help regulate the balance between upstream glycolytic intermediates for proliferation and pyruvate for energy. PK hasn’t been studied in ME/CFS, but I’d bet the house PKM2 is over-expressed to the usual M1 isoform, as is ubiquitous in most cancers and sepsis. Without pyruvate for energy, the cell must resort to fats or amino acids to fuel OXPHOS which is why many of us do better on keto or amino acids. In sepsis, Krebs cycle intermediates citrate is increased for synthesis of lipids and succinate increased to stabilise hypoxia-inducible-factor to maintain aerobic glycolysis and inflammation, though perhaps longer-term or more severe patients may not exhibit this. As I say, I tested mine two years in. The intermediate fumarate is low due to the break in the krebs cycle to sustain high succinate. The same occurs after isocitrate, where alpha-ketoglutarate is supplemented by glutaminolysis.
McGregor believes impaired glycolysis is at the root of ME/CFS and I think he’s bang on the money. Emerging evidence suggests a correlation between increased PKM2 and a pro-inflammatory state. Do we just need to suppress PKM2? Pyruvate is an inhibitor of PKM2, and Davis found pyruvate worked with his nanometer test. Interestingly, pure T3 also suppresses PKM2, is this the reason high dose Pure T3 helped some patients? Shikonin is an inhibitor of PKM2 and could also be tested.
A caveat to this theory is PKM2 overexpression promotes mitochondrial fusion, so what about Prusty’s findings on mitochondrial fragmentation under stress? Interestingly, PKM2 trans-locates to mitochondria under oxidative stress and has been demonstrated to affect mitochondrial fission/fusion mediators. In sepsis, the fission/fusion balance shifts toward fission by upregulation or downregulation of these mediators. This is a field of current research. Is PKM2 trying to compensate a stress-induced fission mediator in ME/CFS? This could be a feedback trap.
Getting back to impaired glycolysis then, do we all show it and is OAT a reasonable diagnostic tool? Please advise how soon after onset you did the test, and how severe you are. It is apparent that more severe patients and maybe more long term patients also have mitochondrial impairment and the krebs cycle intermediates may therefore yield different results.
I did Genova Diagnostics test, they use slightly different metabolites and measures to your test, who was yours done through? I might read up on their guide to compare the measures with what Genova uses (mcg/mg creatinine). While your citric wasn't high, your aconitic was low suggesting a slight 'break' in the cycle. Can I ask what severity you were when you did the test and were you a fast or slow ME/CFS onset? I'm wondering if a sudden onset might show in these results compared to a slow onset. This is all rather intriguing.
