Metformin Is A Mitochondrial Toxin And Raises Lactate

haidut

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This study lists some of the possible reasons drugs like Metformin are to be avoided and why Peat has cautioned against it even without explicitly saying what he has against it.

Etiology and therapeutic approach to elevated lactate


"...One of the first biguanides, phenformin, was withdrawn from the US market in 1976 because of the common occurrence of elevated lactate. [136] Today, metformin is the only biguanide used clinically for the management of diabetes mellitus. Metformin is thought to increase the risk of elevated lactate, but the correlation remains controversial. The proposed mechanism includes inhibition of gluconeogenesis and mitochondrial impairment.[104]".
 
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Blossom

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Peata said:
I finally stopped Metformin last month.
Congratulations Peata!
 

Agent207

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Metformin is thought to increase the risk of elevated lactate, but the correlation remains controversial. The proposed mechanism includes inhibition of gluconeogenesis and mitochondrial impairment.

Recently a major Cochrane meta-analysis concluded that there was no increased risk of the development of elevated lactate for metformin compared to non-metformin treatment, however this may reflect usage in selected study populations and not necessarily those with overdoses or use in renal insufficiency, for example.137 The estimated rate of confirmed elevated lactate (lactate >5 mmol/L) was reported to be around 5 cases per 100,000 patients based on numbers from the Food and Drug Administration (FDA) from 1996.103 Patients with diabetes who develop this complication are often ill and have numerous comorbid issues, such as renal insufficiency and congestive heart failure. The elevated lactate observed in metformin users may be related to an exacerbation of their chronic disease or another acute insult and is not necessarily related to metformin.104,139 Pure metformin-associated elevated lactate is often seen with accumulation due to kidney failure, liver failure or overdose. In cases with renal failure, the suggested treatment is hemodialysis, which will correct the metabolic acidosis and remove metformin.104

Persistent lactate elevation may indicate unrecognized ischemic bowel, an uncontrolled source of infection, inadequate flow (either from inadequate intravascular volume or inadequate cardiac contractility), concomitant pharmacologic insult (e.g., associated metformin-induced mitochondrial injury in a septic patient with renal failure)


A little biased title... the study clears at various times the intrinsecal rol of failures on other organs like kidneys or liver for the absolute conclusion you state wthout taking into acount. Yet they say the relation remains controversial. There are some studies showing benefits from metformin.

Metformin improves healthspan and lifespan in mice

"Several studies provide evidence that metformin partially inhibits complex I of the electron transport chain (ETC) with subsequent alteration of the mitochondrial performance, but the molecular mechanisms underlying this process have not been characterized in detail21–23. Thus, metformin may compromise ATP production in mitochondria leading to an increase of the AMP/ATP ratio. As a consequence of energy depletion, glycolysis is induced to maintain cellular metabolism. Even though mitochondrial poisons increase oxidative cellular damage by mechanisms involving increased reactive oxygen species24,25, there is no evidence that metformin induces the generation of reactive oxygen species and/or accumulation of oxidative damage26,27. In fact, the transcription factor SKN-1/Nrf2 is activated upon metformin treatment, resulting in increased expression of antioxidant genes in cells and animal models10. Reduced accumulation of oxidative damage may contribute to the inhibitory effects of metformin treatment in carcinogenesis models"
 

haidut

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Agent207 said:
post 111979 Metformin is thought to increase the risk of elevated lactate, but the correlation remains controversial. The proposed mechanism includes inhibition of gluconeogenesis and mitochondrial impairment.

Recently a major Cochrane meta-analysis concluded that there was no increased risk of the development of elevated lactate for metformin compared to non-metformin treatment, however this may reflect usage in selected study populations and not necessarily those with overdoses or use in renal insufficiency, for example.137 The estimated rate of confirmed elevated lactate (lactate >5 mmol/L) was reported to be around 5 cases per 100,000 patients based on numbers from the Food and Drug Administration (FDA) from 1996.103 Patients with diabetes who develop this complication are often ill and have numerous comorbid issues, such as renal insufficiency and congestive heart failure. The elevated lactate observed in metformin users may be related to an exacerbation of their chronic disease or another acute insult and is not necessarily related to metformin.104,139 Pure metformin-associated elevated lactate is often seen with accumulation due to kidney failure, liver failure or overdose. In cases with renal failure, the suggested treatment is hemodialysis, which will correct the metabolic acidosis and remove metformin.104

Persistent lactate elevation may indicate unrecognized ischemic bowel, an uncontrolled source of infection, inadequate flow (either from inadequate intravascular volume or inadequate cardiac contractility), concomitant pharmacologic insult (e.g., associated metformin-induced mitochondrial injury in a septic patient with renal failure)


A little biased title... the study clears at various times the intrinsecal rol of failures on other organs like kidneys or liver for the absolute conclusion you state wthout taking into acount. Yet they say the relation remains controversial. There are some studies showing benefits from metformin.

Metformin improves healthspan and lifespan in mice

"Several studies provide evidence that metformin partially inhibits complex I of the electron transport chain (ETC) with subsequent alteration of the mitochondrial performance, but the molecular mechanisms underlying this process have not been characterized in detail21–23. Thus, metformin may compromise ATP production in mitochondria leading to an increase of the AMP/ATP ratio. As a consequence of energy depletion, glycolysis is induced to maintain cellular metabolism. Even though mitochondrial poisons increase oxidative cellular damage by mechanisms involving increased reactive oxygen species24,25, there is no evidence that metformin induces the generation of reactive oxygen species and/or accumulation of oxidative damage26,27. In fact, the transcription factor SKN-1/Nrf2 is activated upon metformin treatment, resulting in increased expression of antioxidant genes in cells and animal models10. Reduced accumulation of oxidative damage may contribute to the inhibitory effects of metformin treatment in carcinogenesis models"

Ask any ER doctor about metformin and he/she will tell you this is one of the first things to rule out when somebody presents with ketoacidosis or lactic acidosis. Chronic alcoholism is the other big factor. So, no, for ER people the link is quite far from controversial. Metformin also lowers the NAD/NADH ratio and this alone should tell you how "good" metformin is for your metabolism. Its main mechanism is to simulate starvation, so definitely not something you want to take chronically.
 
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haidut

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Agent207 said:
post 112026 I know metformin has it sides and may be risky for taking it long time even in healthy persons. This study focus more on the the mitochondrial impairment,
http://onlinelibrary.wiley.com/doi/10.1111/jdi.12328/pdf

What do you suggest for improving insulin sensitivity?

Taking 4g-6g of sodium salicylate for 2 weeks fully reverses even established diabetes. Given how quickly it works, the actual reversal of pathology, and the relative safety (especially if combined with vitamin K) I think this is something every person with insulin resistance issues should try before going to drugs like metformin. GABA agonists like taurine, theanine, and some flavonoids are also highly beneficial. Blocking serotonin or cortisol fully reverses insulin resistance. Things like DHEA, vitamin A, cascara, lapacho, etc all inhibit cortisol synthesis and all have studies showing benefit for insulin resistance. Things like bromocriptine, lisuride, cabergoline, mirtazapine, cyproheptadine also have studies showing reversal of insulin resistance and even diabetes. Btw, bromocriptine is approved as diabetes type II drug in the USA.
https://en.wikipedia.org/wiki/Bromocriptine
"...In 2009, bromocriptine mesylate was approved by the FDA for treatment of type 2 diabetes under the trade name Cycloset (VeroScience). It is currently unknown how this drug improves glycemic control, but it has been shown to reduce HbA1c by ~0.5 percentage points."
So, given all these options I don't see why someone would go for something as dangerous as metformin.
 
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Agent207

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Thanks Haidut; interesting the bromocriptine rol on reducing HbA1c, but I wonder the time necessary for that effect considering its side on cardiac fibrosis used longtime..
 

haidut

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Agent207 said:
post 112055 Thanks Haidut; interesting the bromocriptine rol on reducing HbA1c, but I wonder the time necessary for that effect considering its side on cardiac fibrosis used longtime..

At the doses approved for diabetes (2.5mg daily) it would be extremely unlikely to get a fibrotic effect even if you take bromocriptine for life. Cabergoline is a much more dangerous drug and even in low doses. Fibrosis with bromocriptine has only been noted after reaching doses of 30mg daily, which is a dose used only for Parkinson and not realistic for pretty much everybody on the forum.
 
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haidut

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Peata said:
post 112062
Blossom said:
post 46729
Peata said:
I finally stopped Metformin last month.
Congratulations Peata!

Thanks. My dr. has pushed for me to go back on it everytime I'm there.

Why wouldn't your doctor prescribe bromocriptine instead? If it is approved for diabetes II and there is no contraindication in your case, your doctor has no legal right to deny you that drug or push for metformin. He can voice an opinion of preference for metformin but if there are other approved drugs that you are medically eligible for, he has to prescribe or fire himself and send you to another doctor.
 
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Blossom

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Peata said:
post 112062
Blossom said:
post 46729
Peata said:
I finally stopped Metformin last month.
Congratulations Peata!

Thanks. My dr. has pushed for me to go back on it everytime I'm there.
Sorry you are experiencing that from your doctor Peata. IIRC you were prescribed metformin for PCOS. It sounds like your doctor might be buying into the pharmaceutical marketing propaganda and basing his opinion on that instead of the latest science on how the drug actually works. Ultimately it's your choice, your body and your life so I agree with haidut about firing that doctor if he doesn't respect your decision to not take metformin. It's also your money and I think sometimes doctors forget that we are paying them to help us either directly or indirectly. :)
 
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Agent207

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What about Na-RALA + biotin? looks solid and safer long term than bromocriptine... (if you're not overloaded with Hg)
 
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metformin also damages the stomach and intestinal lining and reduces "intrinsic factor" preventing proper vitamin B12 metabolism. It is linked to peripheral neuropathy in a VERY high number of cases, which is often misdiagnosed as diabetic neuropathy.
 

NathanK

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Probably the best Metformin breakdown paper in general that I've read to date
http://www.sciencedirect.com/science/ar ... 2812000552
Fatty acids revert the inhibition of respiration caused by the antidiabetic drug metformin to facilitate their mitochondrial β-oxidation ☆
We found that metformin inhibited mitochondrial respiration, although ATP levels remained constant as the decrease in mitochondrial production was compensated by an increase in glycolysis. While AMP/ATP ratios were unaffected by metformin, phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase augmented.

"...we found that fatty acids caused a striking rapid reversal in the inhibition of respiration which may explain the failure of metformin to inhibit their oxidation. We hypothesize that metformin favors the oxidation of fatty acids, but that it prevents pyruvate oxidation. Moreover, we propose that metformin favors the oxidation of fatty acids to facilitate the removal of plasma fatty acids and improve the lipid profile in the diabetic patient.
 

burtlancast

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haidut said:
post 46614 This study lists some of the possible reasons drugs like Metformin are to be avoided and why Peat has cautioned against it even without explicitly saying what he has against it.
.

Ray has been saying it all along ( interview about diabetes type 1):

HD: ok, I just want to mention one of these drugs medications that I know quite a few people have been on, and probably are still using, amongst others, but metformin as a diabetes medication?

RP: Yeah, phenformin was the first form of that, that was used widely in the 50’s and 60’s. But it was killing a very high proportion of people: they were dying much earlier than they would have with no treatment at all. It was causing lactic acidosis, by causing the mitochondria to be unable to oxidize glucose. Which is exactly the problem of diabetes. So that got a bad reputation, and it was replaced by metformin which was reputed to not cause lactic acidosis. But even on pubmed if you look up metformin and lactic acid, you’ll see, I don't know, there must be more than 100 articles warning about the production of lactic acidosis with this standard very common treatment. And, it works, where it works, partly by poisoning the mitochondria, so the cells are forced to produce lactic acid. And so it lowers the blood sugar by wasting the glucose, turning it to lactic acid. But it also has some other effects which accounts for why everyone doesn't die quickly from lactic acidosis; apparently it has some slightly protective anti-inflammatory effects.
 
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Peata

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Why wouldn't your doctor prescribe bromocriptine instead? If it is approved for diabetes II and there is no contraindication in your case, your doctor has no legal right to deny you that drug or push for metformin. He can voice an opinion of preference for metformin but if there are other approved drugs that you are medically eligible for, he has to prescribe or fire himself and send you to another doctor.

I am supposed to go see him next week and will ask him about bromocriptine.
 

Katty

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I am supposed to go see him next week and will ask him about bromocriptine.
@Peata
Hey Peata,
I know this is an older thread. Wondering if you ended up talking to your Dr about bromocriptine. If so, what did he say?
 
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