As we age, we all lose sensitivity to insulin and begin, gradually or rapidly, to poison our bodies with excess sugar in the blood. This happens to almost everyone, and it is only when the symptom is particularly severe that it is diagnosed as (type 2) diabetes. Metformin is a drug that has been used to treat diabetes for 50 years, but it is only recently that epidemiologists have begun to notice that patients on metformin have lower rates of cancer and heart disease. Of course, cancer and heart disease were elevated to begin with in diabetics. But the question has been asked: will metformin provide a benefit for “normal” aging, and lower cancer risk for people who are not diagnosed with diabetes?
Vladimir Anisimov from University of Glasgow has proposed that it’s time to test metformin for its anti-cancer and life extension potential for non-diabetics. He is a biostatistician, an epidemiologist and not a physiologist. But a good part of the reason to think that this might work comes from theory.
Metformin and Caloric Restriction
The only intervention that is known to consistently extend life span across many different species is caloric restriction. Animals seem to be widely adapted to stabilize their populations by suppressing death from aging under conditions of starvation (and raising the internally-programmed death rate when there is plenty of food). How does the individual metabolism detect when it is starving? The signal comes mainly from the insulin metabolism. The body responds to chronically elevated insulin by decreasing sensitivity to insulin, and raising insulin levels yet further in a positive feedback loop that cascades toward death. Metformin interrupts this cycle in a manner similar to lowered food intake. Since most people don’t tolerate chronic hunger very well, a drug that offers the benefits of a lean diet without having to cut calories would be highly prized. Such a drug is called a caloric restriction mimetic, and there is some reason to believe that is what metformin does. (Many people taking metformin experience actual weight loss as well.)
The health benefits of metformin for diabetics are striking, and are not shared by other drugs that treat only the diabetes. Metformin cuts cancer rates by 37%. But cancer is already elevated in diabetics. If the reduction in cancer had been to values below the rates in non-diabetics, then metformin for non-diabetics would seem to be a slam dunk. But in reality this sizable benefit brings cancer rates down just about to their level in non-diabetics, but not further. So the benefits for non-diabetics remain speculative.
Life extension in rats and mice
Over the years, there have been many studies of metformin’s effects on mice and rats. Most show some life extension, and the best result increased life span by 38%. Metformin seems to work better for mice than rats, and better for females than males. Here is a table (from Anisimov) summarizing results in rodents.
|Strain||Sex||Treatment||No. of animals||Life span, days||References|
|Mean||Last 10% of survivors||Maximum|
|C3H/Sn||Female||Control||30||450 ± 23.4||631 ± 11.4||643|||
|Phenformin||24||545 ± 39.2 (+21.1%)||810 ± 0 * (+28.4%)||810 (+26%)|
|FVB/N||Female||Control||34||264 ± 3.5||297 ± 7.3||311|||
|Metformin||32||285 ± 5.2 (+8.0%)||336 ± 2.7 (+13.1%)*||340 (+16.2%)|
|FVB/N||Female||Control||15||285 ± 12||396 ± 0||396|||
|Metformin||20||304 ± 10||352 ± 7||359|
|SHR||Female||Control||50||388 ± 29.2||727 ± 22.5||814|||
|Metformin||50||535 ± 31.9* (+37.9%)||878 ± 6.6* (+20.8%)||898 (+10.3%)|
|NMRI||Female||Control||50||346 ± 11.9||480 ± 9.2||511|||
|Diabenol||50||369 ± 12.9||504 ± 6.4* (+5.9%)||518|
|129/Sv||Male||Control||41||662 ± 27.7||951 ± 32.3||1029|||
|Metformin||46||573 ± 26.5 (-13.4%)*||931 ± 30.4||1044|
|129/Sv||Female||Control||47||706 ± 20.8||910 ± 8.9||930|
|Metformin||48||742 ± 16.3 (+5.1%)||913 ± 19.2||966 (+3.9%)|
|LIO||Female||Control||41||652 ± 27.3||885 ± 11.3||919||[1,73]|
|Phenformin||44||652 ± 28.7||974 ± 16.2** (+10.1%)||1009 (+9.8%)|
|Female||Control||74||687 ± 19.2||925 ± 22.5||1054|||
|Buformin||42||737 ± 26.4 (+7.3%)||1036± 38.9* (+12%)||1112 (+5.5%)|
|Fischer-344||Male||Control||31||796 ± 170||1039 ± 29.6||1065|||
|Metformin||40||815 ± 186||1061 ± 2.5||1062|
The difference with control is significant: * – p < 0.05 ; ** p < 0.01 (Student’s test)
(Phenformin and buformin are chemical sisters of metformin. Metformin is prescribed for people because it has the lowest rate of complications and side effects.)
Mechanism for protection against cancer
There is also “test tube” evidence for metformin’s effect on cancer: Cancer cells are supposed to detect that they are diseased and eliminate themselves harmlessly and promptly via a mechanism called apoptosis. Cancer can’t become cancer until this mechanism is suppressed, mutated away so that the cancer cells don’t automatically commit suicide. In lab studies of cell cultures, cancer cells respond to metformin by restoring the apoptosis mechanism that was suppressed when they became cancerous in the first place. Metformin shrinks tumors by inducing cancer cells to commit suicide. On this basis, metformin is just beginning to be tried as a treatment for cancer patients, with first application to breast cancer.
Complications and risks from metformin are unusual, but they do exist. The main one is called lactic acidosis – a rare but serious disease that is almost unknown outside metformin patients. A conscientious doctor who prescribes metformin will counsel the patient to be alert to the symptoms.
Research study would be most beneficial – but who will pay the bill?
For those who are overweight in middle age or pre-diabetic, there is much to recommend metformin. But are there benefits for middle-aged people who are not in this category? The only way to know for sure is through double-blind clinical trials with at least several thousands of patients. But who will fund such a study? Metformin is a cheap, generic prescription, decades out of patent. There is no company with the motivation to invest in it.
Even if such a study is begun, it will require ten years at best before we know anything. In the meantime, a few avid life extensionists are taking the chance and asking their doctors for a prescription, or even self-medicating through on-line pharmacies. Perhaps we will learn from their experience.
For basic information about healthy living for a long life,
see the author’s permanent page at AgingAdvice.org.
This was a fantastic article.
I would be curious if you could expand on this quote:
“Animals seem to be widely adapted to stabilize their populations by suppressing death from aging under conditions of starvation (and raising the internally-programmed death rate when there is plenty of food).”
Do you know where I might be able to read more about this mechanism?
The Demographic Theory of Aging is my contribution to the field. I believe that it is on the basis of population stabilization that aging has evolved.
Try this article for a technical introduction: http://www.springerlink.com/index/60524W6348670770.pdf
I was lucky enough to find a doctor who had knowledge about the anti-aging benefits of Metformin. I have been on it for 3 yrs, did lose some weight. The Metformin has kept my fasting glucose between 75 – 80; I have studied deprenyl and consider it another anti-aging drug that I would like to take. I have sent literature to my consultant doctor. If he says No, how can I “self-medicate” with an on-line pharmacy? I use a Canadian pharmacy that requires a prescription.
I’ve just started taking Deprenyl in the form of 2.5mg every other day Selegeline imported from India. I am fortunate enough to have a doctor who supports the experiment, and wrote me a prescription. Even though the dosage I’m taking is “sub-clinical”, I am experiencing some noticeable mood alterations. I’m sleeping less and not tired. I’m a little more impulsive, less deliberative, more optimistic and less worried about the future. Is my judgment distorted, or am I just in a good mood? I will ask trusted friends for their honest opinion.
How many mg do u take per day
Dreprenyl works great for my mood. I’ve been taking it 5 days per week during several years. I believe I discovered it reading some articles from David Pearce.
Later on, thanks to 23andme, I discovered that my genes produce very low dopamine. Deprenyl helps to keep its level up, and this probably explains the positive effect it has on me.
Do find that your body became tolerant after awhile, so you needed higher doses?
yes, I think one becomes tolerant. Anyway, I wouldn’t go to higher doses because of the danger of U response. I take 5-6 days/week 5mg in the morning and 5 in the afternoon. And from time to time I’m one or two weeks taking nothing.
2009 U.S. study possibly linking accelerated senility to metformin.
Thank you, Rayske – this is an ambiguity in the data, and a complication I had not uncovered.
Since you wrote this, there are now a lot of PubMed articles on Metformin reducing cancer risk, plus extending life span for ovarian cancer patients and others cancer patients. Allantoin is a natural Metformin mimic with the same benefits. http://www.sigmaaldrich.com/catalog/papers/22147657 Plasma glucose lowering action of allantoin is induced by activation of imidazoline 1-2 receptors in streptozotocin induced diabetic rats
Thank you, Carol. It seems that allantoin is one more orphaned drug, under-studied because unpatentable. For now, I’m going with metformin, because so much is known about its safety and its effectiveness, based on hundreds of millions of patient-years. I don’t automatically think that because allantoin is a naturally-occurring compound it must be safer. But many people do prefer a natural product and this will be welcome news.
I agree that you need Metformin if you are diabetic and you need the plasma glucose lowering action to improve your health, and, there is no need to try Allantoin as Metformin is already on the market and approved by the FDA with tons of clinical research backing it up. Diabetics on Metformin have lower cancer risks and people with cancer find Metformin will extend their life. I meant to add a last line that Allantoin is a natural source to lower plasma glucose levels that is found naturally in yams which was really the purpose of my comment. But, I pressed send too fast.
http://www.sciencedirect.com/science/article/pii/S0308814605000099 “Quantitative analysis of allantoin and allantoic acid in yam tuber, mucilage, skin and bulbil of the Dioscorea species.”
So, my friend with ovarian cancer does not have high blood sugar, so her oncologist will not prescribe Metformin for her (even though PubMed says Metformin will extend ovarian cancer patients’ life span) because Metformin has not gone through clinical trials for ovarian cancer treatment and Metformin is not in the Ovarian Cancer Protocol. It is hard to ask your doctor for a prescription for a medicine and he will just automatically write you a prescription, especially if it is off label. Many doctors are not happy when anyone researches health topics online, like lay people are practicing medicine on ourselves without a license. My primary care physician says he does not take vitamins and doesn’t believe in vitamins or supplements. I have normal fasting glucose levels and my doctor will refuse to offer me Metformin for longevity reasons or to lower cancer risk because my tests indicate I am not in danger with super high plasma glucose levels, even though Metformin has a low risk of causing hypoglycemia. I have read the research on Metformin myself, and I am very impressed with it for AMPk activation, and so, for this reason. I am happy knowing that when I eat a yam (and the skin has the highest Allantoin content), drink comfrey tea, eat sugar beets, wheat sprouts or sprinkle wheat germ on my berries and yogurt that I am lowering my blood glucose levels because these foods- yam, comfrey, sugar beets, wheat sprouts, wheat germ- all contain Allantoin which naturally lowers blood sugar levels, thus lowering my cancer risks by turning on healthy genes and pathways in my body in a similar fashion to Metformin. Do we need to look at Allantoin as an alternative medicine that needs to go through clinical trials and needs to be sold by pharmaceutical companies or supplement companies? We can enjoy natural healthy foods in our meals that offer us the same health benefits.
I was reading https://en.wikipedia.org/wiki/AMP-activated_protein_kinase “Recent research  has implicated overproduction of AMPK in the genesis of Alzheimer’s disease. This has raised theoretical concern over the safety of Metformin” an AMPK activator and a drug for Type 2 diabetes. (Metformin (Glucophage) lowers fasting glucose levels without causing hypoglycemia for patients with type 2 diabetes mellitus.)
Click on the research link below which explains how they discovered overproduction of AMPK by the body is linked to killing off Dendrites (from Greek δένδρον déndron, “tree”)(also dendron) are the branched projections of a neuron that act to propagate the electrochemical stimulation received from other neural cells.
http://www.eurekalert.org/pub_releases/2013-04/sri-sri040513.php “Scripps Research Institute scientists help unravel central mystery of Alzheimer’s disease ”
Then I read this from Scripps Institute and was shocked! Overproduction of AMPK causes Alzheimers! I thought AMPK activation was great- increasing autophagy, removing waste and reducing inflammation, increasing SIRT 1 expression, and then to activate AMPK-you need exercise and calorie restriction and you need to raise leptin levels and thyroid levels and to activate AMPK, you need to supplement with ginger, resveratrol, alpha lipoic acid, bitter melon, curry, berberine, fisetin, garlic, genistein, green tea, gymnostemma pentaphyllum, quercetin, metformin, exercise, garlic, trans tilloroside, thyroid, sage, juniperus chinensis, grapefruit, pomegranate, sage, Methotrexate or synephrine. Many AMPK activators are also Sirt1 activators. Sirt1 activators which you need to treat cancer and type 2 diabetes are ephedrine, caffeine, quercetin, resveratrol, fasting, CR, alternate day fasting, fisetin, butein, piceatannol, the antidiabetic drug Pioglitizone, DHA, leucine, NAD. http://www.greenray4ever.com/AMPK.html#AMPKACTIVATINGNUTRACEUTICALS
To neuroscientist Suzanne de la Monte, MD, of Brown University, Alzheimer’s disease is really a metabolic disease that affects the brain. The links are so close that she has begun referring to Alzheimer’s disease as Type 3 diabetes.Brain cells use glucose as fuel, and insulin tells these cells to slurp up glucose in the blood. De la Monte’s big insight was that brain cells can develop insulin resistance, just like other cells in the body.”Any organ can be affected by insulin resistance,” de la Monte says. “You can have it in the liver- we call that non-alcoholic fatty liver disease. If you get it in the kidney, we call it renal disease. If you get it in the brain, we call it Alzheimer’s. Her research over the past few years has revealed that this creates a toxic environment for the brain, leading to the harmful buildup of proteins and neuron death seen in Alzheimer’s. In addition to telling us more about how Alzheimer’s can be prevented through healthy diet and exercise, it could also help potentially treat the disease. Preliminary studies have shown that inhaled insulin can help reduce symptoms of Alzheimer’s dementia.
Today, I am going crazy because I discovered . You need to increase AMPK and Leptin to reduce Alzheimers.
http://www.medscape.com/viewarticle/761825_4 SIRT1-mediated Attenuation of Aβ and Tau Pathology, The pathogenesis of Alzheimer’s disease is characterized by marked increase in oxidative stress and mitochondrial damage, significant neuroinflammation, increased calcium signalling, amyloid-β (Aβ) oligomerization and fibrillation, and tau hyperphosphorylation.[25,26] Evidence regarding the neuroprotective effects of sirtuins in Alzheimer’s disease stems from current research focussing on SIRT1 [20•]. In-vitro activation of SIRT1 by either NAD+ or resveratrol can significantly reduce the levels of oligomerized Aβ by switching the processing of amyloid precursor protein (APP) by increasing the production of alpha-secretase.[25,26] Moreover, overexpression of SIRT1 also prevented the activation of microglia by fibrillar Aβ, therefore reducing the release of neurotoxic chemokines, cytokines and nitric oxide from activated microglia through inhibition of the nuclear factor-kappaB (NFκB) signalling pathway.
Recently, a double transgenic mouse model overexpressing both APP and SIRT1 showed reduced Aβ formation compared with APP transgenic mice only. Moreover, increased Alzheimer’s disease-like brain abnormalities and increased behavioural dysfunction have been observed in SIRT1-deficient APP mice.[17•] The antiamyloidogenic effects of SIRT1 are mediated by the direct activation of the alpha-secretase gene ADAM10 by binding to its promoter. SIRT1-induced activation of ADAM10 can also activate the Notch signalling pathway, by cleavage of the Notch receptor, which promotes neuronal repair. This can free an intracellular Notch domain that forms a transcription complex that upregulates the transcription of genes necessary for the promotion of neurogenesis.[28••] Recently, leptin has been shown to modulate Alzheimer’s disease pathology by activation of the AMP-activated protein kinase (AMPK).[29•] Greco et al.[29•] recently showed that leptin can boost cellular metabolism by activating AMPK and SIRT1 to reduce Aβ and tau phosphorylation. Considering the significance of leptin deficiency in contributing to the neuronal imbalance observed in Alzheimer’s disease, there has been renewed interest in the use of leptin as a legitimate treatment for Alzheimer’s disease.
As well, injection of resveratrol in P25 transgenic mice showed a reduction in hippocampal degeneration, improved cognitive function and lowered acetylation levels of SIRT1-binding proteins such as p53. Overexpression of SIRT1 using a lentivirus also improved hippocampal integrity, mimicking the neuroprotective effects of resveratrol injections.
PET images using the Pittsburgh compound B have shown that Aβ deposition is colocalized with regions of the brain that metabolize glucose by aerobic glycolysis in normal, young brains.[31•] These regions are dependent on the optimal conversion of glucose 6-phosphate to pyruvate, which is essential for the proliferation of neuronal cells and serves as a rapid source of energy production. Aerobic glycolysis is also associated with altered NAD+ recycling. As SIRT1 activity requires adequate levels of NAD+, it is not surprising that the development of Aβ pathology might be related to alterations in aerobic glycolysis in the Alzheimer’s disease brain, inhibiting SIRT1 activity by lowering the NAD/NADH ratio, and therefore shifting APP processing to promote amyloidogenic activity.[33,34]
https://en.wikipedia.org/wiki/Metformin Metformin has also been reported to decrease the blood levels of thyroid-stimulating hormone in people with hypothyroidism .
https://www.ncbi.nlm.nih.gov/pubmed/16926377 (Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice.)
AMPK and thyroid hormone regulate some similar processes. Knowing these similarities, Winder and Hardie et al. designed an experiment to see if AMPK was influenced by thyroid hormone. They found that all of the subunits of AMPK were increased in skeletal muscle, especially in the soleus and red quadriceps, with thyroid hormone treatment. There was also an increase in phospho-ACC, a marker of AMPK activity.
So, what do you think? I am not a scientist, but I like reading your blog and a few other longevity blogs. I just recently became a little confused about the Scripps Research and am wondering about benefits of AMPK activation after all, and I would like an educated person’s take.
What is your private email as I would like to send you one long comment on 3 blog topics? My letter will comment on a combination of your blogs on sleep, the hypothalamus, and the blog on molecules of self destruction because they might all be related.
Thank you- David PS. Above, you may not have noticed I also mentioned Berberine as an AMPk activator. I already bought it for my friend with other AMPk activating supplements that she might try for her ovarian cancer. The reason that I mentioned Allatoin is that it is another natural Metformin mimic usually not mentioned. So, here is my big question, personally, I don’t have any disease yet, and it seems by gene activation, I may unwittingly be choosing my own death- cancer (I can hold it off), heart disease (I can hold it off), Alzheimers (Not sure now how to try to hold it off????- to AMPk activate or not???? and if not, then cancer/heart disease could get a foot hold?), immune failure (I can try to hold that off) or eventual cell senescence (I can try to hold that off with hTERT activators and DNA repair activators). The big question I have is for Alzheimers- to activate AMPk or not activate AMPk? as Scripps research now implicates AMPk as the culprit in Alzheimers disease while other opposite research says that AMPk activation is needed as Alzheimers is diabetes of the brain or a deficiency of leptin hormone which also activates AMPk . Scripps research on AMPk over-activation as the cause of Alzheimers seems to be very shocking to me. In my mind, I need help figuring this out from a scientist. Please help me understand better.
Thank you- David PS. Above, you may not have noticed I also mentioned Berberine as an AMPk activator. I already bought it for my friend with other AMPk activating supplements that she might try for her ovarian cancer. The reason that I mentioned Allatoin is that it is another natural Metformin mimic usually not mentioned. So, here is my big question, personally, I don’t have any disease yet, and it seems by gene activation, I may unwittingly be choosing my own death- cancer (I can hold it off), heart disease (I can hold it off), Alzheimers (Not sure now how to try to hold it off????- to AMPk activate or not???? and if not, then cancer/heart disease could get a foot hold?), immune failure (I can try to hold that off) or eventual cell senescence (I can try to hold that off with hTERT activators and DNA repair activators). The big question I have is for Alzheimers- to activate AMPk or not activate AMPk? as Scripps research now implicates AMPk as the culprit in Alzheimers disease while other opposite research says that AMPk activation is needed as Alzheimers is diabetes of the brain or a deficiency of leptin hormone which also activates AMPk . Scripps research on AMPk over-activation as the cause of Alzheimers seems to be very shocking to me. In my mind, I need help figuring this out from a scientist. Please help me understand this better.
I don’t think we can choose our mode of death. All we can do is to modify the odds. Our genes and other circumstances of our lives will have their effect as well as other imponderables.
To lower risk of Alzheimer’s, consider curcumin (from the spice turmeric) and fish oil and daily ibuprofen or aspirin if you are over 50.
Thank you everyone.
Am a nondiabetic taking metformin off label.
Singed in to get follow up and new posts.
There is some evidence of a link between metformin and Alzheimer’s. This is disturbing, but the link is not strong and I don’t think it is necessarily a deal-breaker.
A question for those conspiracy-lovers
Why has the FDA (and big pharma) allowed human trials of Metformin for life extension and antiaging?
Maybe it reduces cancer as they have no cure for it yet and usually kills in a few years
So they can keep them alive longer to sell them many other drugs as they age?
If Big Pharma is interested in keeping me alive so they can sell me more drugs, I say, more power to them. (It’s when they have an interest in keeping me sick that I worry.)
Great article! As a non diabetic, I have been looking for data on optimal dosage of metformin. In the 2014 paper in Diabetes, Obesity and Metabolism they don’t seem to take dosage into account. How have others been approaching this?
As a non diabetic I would like to know more about dosage as well. What brought me to Metformin is the required use of a very small dose of anti-depressant med (Mirtzapedine) for hypothyroid issues. Some docs using Metformin to counteract the increase in weight with the use of AD. I’m going to speak to my Dr about prescribing me Metformin but wanted to know more about dosage other non-diabetics are taking AND is anyone having side effects. I read about lactic acidosis… So does lower dosage of Metformin = less side effects?
Anyone considering taking metformin for a longer time must keep a careful eye on his serum B12 levels. The metformin seems according to some researchers have a negative effect:
Many people, especially vegetarians, are at risk for B12 deficiency anyway. Don’t mess with B12. The possible connection between metformin and Alzheimer’s might run via B12 deficiency.
Josh, what do you think of the accusations of survivorship bias / “immortal time bias” in observational studies of metformin’s effect on cancer rates in humans?
This 2014 article reviews various studies and makes the claim that correctly designed studies have all shown no cancer benefit:
Specifically they cite this large 2014 study, which post-dates the Oncologist article you referenced:
If I understand correctly, the bias is as follows: say you have a group of patients diagnosed with diabetes, and some are prescribed metformin an average of a year into treatment. If you naively compare cancer rates for people who took metformin or not, you are going to see higher cancer rates for non-users, since many patients who got cancer shortly after entering treatment for diabetes won’t end up taking metformin (either because they died, or because they were too unwell to be on metformin).
Of course, even if the evidence in humans isn’t significant per se, there are still the animal studies and suggestive in vitro results.
I haven’t done the calculation, but intuition tells me that this effect is too small to account for the major benefit in cancer mortality that we see from metformin.
From Expat in SE Asia I’ve been using Metformin 500 mg x 2 for 8 years now
I’m almost 72 my lovely Chinese female partner is 23!
I look 20 yrs younger n I’m never sick
Only side effect is that some days my energy is lower than I overcome with extra B12 and every morning on my treadmill and two cups of coffee with ginger powder n 1/2 tsp of Tumeric
I don’t look old or feel old I credit Metformin
Hope info I provided was helpful
A University of Pennsylvania study (http://meetinglibrary.asco.org/content/166913-176) has shown that for people taking Metformin prior to being diagnosed for breast cancer, the
outcomes were worse. On the other hands, for patients given it after diagnosis, outcomes were better. Quoting from the paper ‘On multivariate analysis, a history of metformin use before BC diagnosis was associated with significantly worse OS (HR 2.19; 95%CI 1.24-3.87) while metformin use after BC diagnosis was comparable to non-users (HR 0.47; 95%CI 0.18-1.23)’ It seems that for patients taking Metformin prior to diagnosis, the BC may have been a more aggressive subtype. However other evidence supports use of Metformin for cancer prevention.As Josh says, more robust clinical trials are needed, ‘but who will fund them?’
I wouldn’t put too much stock in this result. Multivariate analysis is hypersensitive to the list of variables chosen as corrections. My guess is that the first result means nothing more than that the women who were on metformin before diagnosis had diabetes, and of course they had worse odds for survival than women who had been diagnosed with the same cancers but who were not diabetic at the time.
Thanks so much for this clarification. Fantastic to have a scientist explain what this means. I think I will start taking Metformin but wanted to do some research of my own first and was a bit worried by this.
Has anyone noticed an increase in homocysteine from taking Metformin? i took it for 6 months and my Homocysteine jumped from 8 to 12. I’m not sure if the Metformin is 100% responsible, i added a lot of supplements and cut out all grain and most sugar from my diet during that period as well. I stopped the Metformin any way and am due blood work in two months so we will see.