With more than 60 years of clinical use, Metformin (1, 1-dimethylbiguanide hydrochloride) is the most widely prescribed drug for the treatment of diabetes, which was named Glucophage, or “glucose-eater,” by French scientist Jean Stearne in the 1950s. Metformin was first synthesized in 1922, and the first report of it being used to lower blood levels of glucose (in rabbits) was published in 1929. In 1949, metformin (called flumamine at that time) was used for the treatment of an epidemic influenza outbreak in the Philippines and was noted to lower blood levels of glucose in some of the patients with influenza. Metformin was approved by the U.S. Food and Drug Administration in 1995 and has since become the most prescribed drug for diabetes in the United States. Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Metformin is increasingly being used during pregnancy for the management of gestational diabetes mellitus and in those with polycystic ovary syndrome or T2DM.

Although, the exact molecular mechanism of action of metformin remains partly unknown despite its use for over 60 years and more than 27,000 articles in PubMed, its main mechanism of action involves the activation of an enzyme called AMP-activated protein kinase (AMPK). Metformin carries a positive charge, which makes it relatively easy to cross the negatively charged cell membrane. Further, metformin is aided by the OCT1 receptor in the cell membrane. Once inside the cell, metformin makes it way to mitochondria. The matrix side of the inner mitochondrial membrane is also negatively charged, and this allows metformin to accumulate inside mitochondria in quantities 1000 times greater than outside the cell. Within mitochondria, metformin directly inhibits the function of complex 1, a cluster of proteins vital to the function of the electron transport chain.

Inhibition of mitochondrial complex I → inhibits oxidative phosphorylation→ low ATP → high AMP/ADP (energetic stress) → activation of AMPK (an enzyme that senses low energy levels and activates numerous pathways to restore the intracellular ATP)→ increased glucose transport into cells and glucose metabolism (increased insulin sensitivity).

This results in a reduction of the production of ATP using oxygen (aerobic respiration) in the cell. The cell, in this instance, must depend on anaerobic glycolysis (making energy from glucose without oxygen). Not only does this use up a lot of glucose inefficiently, it also produces a lot of lactic acid as a byproduct. Excessive lactic acid can lead to metabolic acidosis, which can be a serious side effect of metformin use in certain contexts.

Contrary to this hypothesis, Yale researchers published a paper in PNAS on 1 March 2022, in which they showed that inhibition of complex I activity in vitro and in vivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis. They showed that metformin, and the related guanides/biguanides, phenformin and galegine, inhibit complex IV activity at clinically relevant concentrations, which, in turn, results in inhibition of glycerol-3-phosphate dehydrogenase activity, increased cytosolic redox, and selective inhibition of glycerol-derived hepatic gluconeogenesis both in vitro and in vivo. By the way, the blocklock of complex IV by cyanide depletes ATP culminating in cell death.

So, inhibition of complex I or IV poisons the mitochondrial electron transport chain within cells and renders the body unable to derive energy (adenosine triphosphate—ATP) from oxygen and activates AMPK.

Recent studies have also suggested that metformin may inhibit mitochondrial glycerophosphate dehydrogenase (mGPDH), an enzyme involved in the production of ATP in the mitochondria. By inhibiting mGPDH, metformin may decrease the production of ATP, which triggers a signaling cascade that ultimately increases energy expenditure and stimulates the activation of AMP-activated protein kinase (AMPK), a master regulator of cellular energy metabolism. Recently, using clinically relevant doses of metformin, Ma et al. demonstrated that activation of AMPK by metformin occurs via inhibiting lysosomal proton pump v-ATPase. Ma et al. further identified PEN2, a subunit of γ-secretase7, as a binding partner of metformin. They showed that metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase, leading to the inhibition of v-ATPase and the activation of AMPK. So, Metformin activates AMPK through multiple mechanisms.

As perhaps the most important cellular energy sensor, AMP-activated protein kinase (AMPK) is activated in response to a variety of conditions that deplete cellular energy levels, such as nutrient starvation, hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex. In response, AMPK alters the activity of many other genes and proteins, helping keep cells alive and functioning even when they’re running low on fuel.

The net effect of AMPK activation is inhibition of gluconeogenesis in the liver, stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic beta-cells. Activation of AMPK signifies low energy within the cell, so all of the energy consuming pathways like protein synthesis are inhibited, and pathways that generate energy are activated to restore appropriate energy levels in the cell.

Yes, Metformin activates AMPK, but it mimics energy deprived state by inhibiting the mitochondrial transport chain complex-I, which essentially poisons the mitochondria leading to ATP production mainly via glycolysis which produces only 2 ATP. On contrast, without metformin approximately 36 ATP are produced from the three stages in cellular respiration – glycolysis, the Krebs cycle (citric acid cycle), and the electron transport chain. So, cells treated with metformin become energetically inefficient, and display increased glycolysis and reduced glucose metabolism through the citric acid cycle.

Most studies still concentrate on the liver as the main target of metformin, arguing that the blood glucose-lowering effect of metformin is mediated mainly through the suppression of hepatic glucose production. However, after oral administration, Metformin’s journey in the body begins with gut cells called enterocytes and the highest concentration of metformin is not found in the liver but in the intestinal epithelium [link], [link], [link]. Based on observations in patients with T2DM receiving metformin, PET–CT imaging after intravenous administration of 18F-FDG, which enters enterocytes via basolateral GLUT2, showed that increased glucose uptake from the circulation into the gastrointestinal system contributes to the glucose-lowering effect of the drug and the improvement in glycaemic control.

The area of the small intestine is about the size of a tennis court, where Metformin alters nutrient metabolism in intestinal epithelial cells and microbiome, leading to increased lactate production. Furthermore, enterocytes have a voracious appetite. The intestine and its accessory organs account for about 6% of our total bodyweight but 20-25% of our total energy expenditure. So, up to 300 times higher concentrations of metformin accumulate in the intestine than in the circulation. This suggests that mitochondria in enterocytes are the primary targets of metformin. Therefore, the gut might predominantly act as a glucose sink through the uptake of glucose by enterocytes in response to metformin action.

The lactate produced from intestine is then transported to the liver, where it is subjected to the Cori cycle, which results in a net loss of 4 ATP. The energy required to operate the Cori cycle further reduces available glucose, creating a futile intestine-liver cycle, because it consumes energy but does not generate glucose, meaning that the energy spent in the cycle is wasted.

Metformin causes a futile intestinal-hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state.

In sum, metformin’s entry into intestinal cells causes the intestine and liver to use glucose inefficiently, burn more fat, and increase insulin sensitivity in these areas.

So, it is not rocket science that, preasbsorptive metformin activates AMPK in gastrointestinal cells due to mitochondrial inhibition which leads to significantly increased glucose consumption in the intestine and consequently indirectly lowers blood glucose by reducing the amount of glucose that goes into the bloodstream. So, inhibition of transepithelial glucose transport in the intestine is responsible for lowering blood glucose levels during an early response to oral administration of metformin. By the way, Metformin was more effective in lowering blood glucose levels when it was administrated orally as compared to its intravenous administration. Thus, metformin establishes a crosstalk between the intestine and the liver that contributes to its antidiabetic effects

Furthermore, there is convincing evidence that metformin changes intestinal microbiota in humans and the gut metabolome, but the significance of this finding for whole-body glucose metabolism remains unclear. As stated above, the activation of the glucose-lactate-glucose futile cycle during long-term treatment with metformin, which includes both the intestine and the liver, results in increased energy consumption. Increased conversion of glucose-1-13C to glucose-1,6-13C under metformin strongly supports a futile cycle of lactic acid production in the intestinal wall, and usage of the produced lactate for gluconeogenesis in liver.

Pretty smart, yes?

Metformin also activates AMPK in skeletal muscle which increases insulin-mediated glucose uptake into skeletal muscle cells (increased insulin sensitivity). But, on the other hand, we know that when AMPK is activated by ATP depletion, AMPK switches on catabolic pathways that generate ATP while switching off anabolic pathways and other ATP-consuming processes, which restores the energy balance. So it is not rocket science, that Metformin blunts the benefits of exercise by reducing mitochondrial ATP production in skeletal muscle by as much as 48%. In simple terms, Metformin abolishes the improvement in mitochondrial respiration after exercise training.

Not only that, there are preliminary findings that metformin may inhibit skeletal muscle mass gains in response to resistance training in the elderly. Recently in september 2019, The MASTERS ( Metformin to Augment Strength Training Effective Response in Seniors) trial found that Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults.

Since cardiorespiratory fitness is one of the strongest factors for survival into old age, and since it decreases with age, the effect of metformin on this factor is concerning, because Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Ironically, reporting and findings of randomised trials of metformin have resulted in continuing uncertainty regarding whether it reduces risk of diabetes-related complications, particularly cardiovascular disease. Furthermore, there is a lack of cardiovascular endpoint data directly relevant to a significant proportion of the patients with type 2 diabetes worldwide for whom metformin is the recommended first-line medication.

A study of over 7,000 patients with Alzheimer’s disease showed that, metformin increased the risk of developing Alzheimer’s. In a cohort study that followed about 9300 patients with T2DM in Taiwan for up to 12 years, the risk for Parkinson’s disease (PD) or Alzheimer’s dementia was more than double during a 12-year period for those who took metformin vs those who did not — even after adjusting for multiple confounders. The use of metformin may be associated with an increased risk for dementia in older African Americans with diabetes. This research was presented at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018 in Chicago, Illinois. So, supplementation with B12 is suggested with metformin use.

In simple terms, Metformin Could Be Dangerous To Your Brain.

There have even been a handful of reports of metformin-induced hepatotoxicity (toxicity in the liver). In a case of nonalcoholic liver disease, metformin was pegged as the cause of jaundice, nausea, fatigue, and unintentional weight loss, two weeks after initiating treatment, due to abnormalities in liver enzymes caused by the drug.

The reduction in energy production by inhibiting complex I can lead to an increase in anaerobic metabolism and lactate production in many different types of cells, similar to what happens under hypoxia.

Imagine reductions in ATP production were observed in the brain or the heart or the GI tract which leads to neurocognitive decline, psychiatric instability, neuropathy, heart rate, rhythm and blood pressure abnormalities, along with gastrointestinal distress to name but a few. Underlying all of these symptoms, and indeed, all mitochondrial dysfunction, is an overwhelming sense of fatigue and malaise.

Moreover, when insulin producing beta cells are exposed to metformin without metabolic challenges, beta cell proliferation is known to be suppressed and apoptosis is promoted [link,link,link]. Prolonged exposure results in apoptosis either via c-JNK activation and caspase-3cascade [link] or via increasing AMPK-dependent autophagy [link]. Metformin exposure also impairs insulin secretion in primary human islets, mouse islets and, mouse and rat pancreatic beta cell lines in a normoglycaemic environment [link,link]. Therefore, metformin overdosing or exposure without metabolic challenges might result in potential beta cell toxicity.

Metformin is excreted almost entirely unchanged in urine so reduced kidney function may lead to accumulation of both metformin and lactate and therefore, a metformin-associated lactic acidosis (MALA). So it’s not a secret that, Metformin may have an adverse effect on renal function in patients with T2D and moderate CKD. Mild to moderate renal impairment is common among metformin initiators. Treatment with metformin was associated with an increased risk of major adverse cardiac and cerebrovascular events (MACCE) in patients with diabetes and CKD. Even, FDA recommends against metformin therapy in patients with estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73m2

Metformin alters immune reactivity first by damaging the mitochondrial ATP factory and reducing energy production capacity and then by inhibiting the signaling cascades that would normally respond to the danger signals.

So, what gives? Is metformin healthy and anti-aging, or not?

In a retrospective 2014 analysis of 78,241 adult type 2 diabetics in their 60s, those who took metformin lived longer, on average, than healthy controls of 90,463 without diabetes of the same age. This has led a growing body of doctors beginning to prescribe the drug off-label, so that their patients may benefit from its purported anti-aging effects. Such widespread speculation demands deeper scientific investigation.

One may ask, what about the epidemiological evidence which has linked metformin to decrease the risk of cancer and cancer-related mortality?

Studies published in 2018 and 2015 suggest that people taking metformin may have a lower risk for cancer, with some studies suggesting a reduced risk of 30% to 50%. Data from two large-scale, population-based, case-control studies of breast and colorectal cancers etiology, conducted in Northern Israel since 1998 found that, Metformin use prior to diagnosis of cancer was associated with a decrease in risk of both breast cancer (OR = 0.821, 0.726–0.928, p = 0.002) and colorectal cancer (OR = 0.754, 0.623–0.912, p = 0.004).

But, it’s also hard to tell if metformin itself lowered cancer risk in the supporting studies because other treatments and interventions may have been involved.

But, how Metformin may work to reduce cancer?

As stated above, the main mechanism of action of Metformin is widely recognized as inhibition of mitochondrial complex I → inhibits oxidative phosphorylation → low ATP → high AMP/ADP (energetic stress) → activation of AMPK which inhibits mTOR phosphorylation in the AMPK/mTOR signaling pathway, which may lead to the arrest of tumor cell cycle and the inhibition of cell growth and proliferation, which finally results in cell apoptosis.

Also, according to articles ‘metformin and cancer’ as the search terms published within the last 15 years to 15 February 2019 in the available databases including; Medline via PubMed and EMBASE via Elsevier, the potential anticancer activity of metformin was due to activation of AMPK .

On the other hand, cancer cells are known to be generally highly glycolytic (Warburg effect) and are thus not supposed to be very sensitive to mitochondrial poison. But, even if the proportion of mitochondrial ATP production is reduced in cancer cells, some mitochondrial ATP production exists and its reduction could be toxic. So, cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis, highlighting their metabolic vulnerability. So, theoretically Metformin may act as an anti cancer agent.

By the way, Rotenone (a broad-spectrum insecticide, piscicide, and pesticide) is a well-known strong mitochondrial complex I inhibitor, yet associated with toxic effects, has also shown anti-cancer activity.

But, Recent study on 55 629 T2DM patients found no evidence of a protective effect of metformin on individual cancer outcomes. In a recent 2020 cohort, metformin use was associated with increased risk of being diagnosed with prostate cancer. After adjusting for baseline characteristics, metformin use was significantly associated with 76% and 77% increased odds of high-grade PCa and overall PCa, respectively, the investigators reported in Prostate Cancer and Prostatic Diseases.

Metformin 850 mg twice per day for 5 years versus placebo did not improve invasive disease-free survival (IDFS) or overall survival (OS) in patients with early breast cancer, regardless of estrogen or progesterone receptor (PR) status, according to results from the phase 3 CCTG MA.32 trial (NCT01101438) presented at the 2021 San Antonio Breast Cancer Symposium.

A massive 2021, randomized, placebo-controlled trial showed that metformin did not reduce all-cause, cancer, or cardiovascular mortality rates in people at high risk of developing type 2 diabetes.

Cancer patients with type 2 diabetes had worse outcomes on immune checkpoint inhibitor (ICI) therapy, which was only significant in patients who were taking metformin and not in those who were taking insulin or other glucose-lowering medications, according to a study published in Clinical Cancer Research.

In summary, the available evidence suggests that AMPK can act as either a tumor suppressor or a tumor promoter, depending on context. Before tumors have arisen, AMPK appears to act as a tumor suppressor by suppressing cell growth and proliferation, inhibiting mTORC1, and promoting the oxidative metabolism typical of quiescent rather than proliferating cells. After tumors have arisen, AMPK may switch to being a tumor promoter, most likely by enhancing survival of tumor cells during stressful situations. A corollary is that while AMPK activators like metformin may provide protection against the development of cancer, AMPK inhibitors might be indicated to treat cancer after it has arisen.

So, when we contrast the reduction in glucose mediated by Metformin with the damage this medication does to the mitochondria and immune signaling, along with its ability to leach vitamin B12 and reduce aerobic capacity, one cannot help but wonder if we are causing more harm than good. Metformin use is associated with an increase in methylmalonic acid (MMA) and worsening neuropathy score in patients with type 2 diabetes. Diagnosis of vitamin B12 deficiency can, however, be difficult, because functional vitamin B12 deficiency can occur regardless elevated serum B12 levels (normal reference range 140 to 450 pmol/L).

Clinical trials, including MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), were designed for aging research purpose. Early results from MILES suggest that metformin may induce changes in gene expression that likely contribute to increased longevity. However, it is not clear if these benefits extend to non-diabetic individuals.

Researchers and advocates have been trying from 2015 to launch the TAME (Targeting Aging with Metformin) trial in USA nationwide that will engage over 3,000 individuals between the ages of 65-79. These trials will test whether those taking metformin will experience delayed development or progression of age-related chronic diseases—such as heart disease, cancer, and dementia—compared with those who take a placebo. Groundbreaking TAME trial, which directly targets aging as an endpoint, finally should have started in November 2019, but it’s been more than six years since the FDA gave a green light, the project has not started due to lack of funds ($50 million).

Whether metformin itself is a success or a failure, the trial will very likely revolutionise the way that aging research is done. Lets hope for the best, although since 2002, The National Institute on Aging’s Interventions Testing Program (ITP) has been conducting studies on various compounds, including metformin, to assess their effects on lifespan and age-related health. Till date, Metformin failed in all of its tests!

Has the effectiveness of metformin actually been proven?

Ever since the results of the UKPDS 34 study were published in 1998, metformin has been considered as the first-line pharmacological treatment for type 2 diabetes. Its efficacy was supposedly conclusively demonstrated in the UKPDS 34 study published in 1998 (reduction in mortality: RR=0.64; CI 95% (0.45 to 0.91) and in myocardial infarction: RR=0.61; CI 95% (0.41 to 0.89). However, these rather impressive results regarding total 10 year mortality (ARR=0.07; NNT=14) in a small subgroup of obese type 2 diabetes patients (342 in the metformin group vs. 411 patients in the conventional group) have never been reproduced .

For instance, the home study in 2009 evaluated the efficacy of metformin versus placebo (in addition to insulin). After four years of follow-up, no statistically significant difference was found for total mortality: RR=1.48; CI 95% (0.54 to 4.09) or for IDM: RR=0.99; CI 95% (0.25 to 3.90). Taking into account all the other randomized clinical trials (RCTs) having evaluated the specific effectiveness of metformin in DT2 patients, it becomes evident that although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality.

In 2019, Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that “Metformin remains the preferred option for initiating glucose-lowering medication in type 2 diabetes and should be added to lifestyle measures in newly diagnosed patients” referring to a single result from the UKPDS 34 study in 342 patients!

Even in 2021, American Diabetes Association recommends Metformin as the preferred initial pharmacologic agent for the treatment of type 2 diabetes. ADA urges “Once initiated, metformin should be continued as long as it is tolerated and not contraindicated; other agents, including insulin, should be added to metformin.”

Today more than 20 years after UKPDS 34 study, why no other studies cannot duplicate the positive effects of Metformin as in UKPDS 34 study?

May be, for that reason, is UKPDS study methodologically questionable? The effectiveness of metformin with regard to microvascular and macrovascular complications has never been proven in a randomized double-blind placebo-controlled clinical trial. And upon analysis of published randomized clinical trials taken as a whole, it becomes increasingly apparent that the effectiveness of metformin has not been proven, even when microvascular complications are involved. This observation leads to a more general interrogation on the fact that assessment of the clinical benefits of Metformin in general is presently lacking.

Although metformin is not often acutely toxic, the underlying mechanisms manipulated by this drug suggest that it is likely to induce and not prevent, as is so frequently suggested, chronic illness.

To conclude, if the level of evidence concerning the efficacy of metformin is poor, and given the fact that it is proposed as firstline treatment, what are we to think of the other antidiabetic medicines? In 2019 American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) state “the absolute effectiveness of most oral medications rarely exceeds an 11 mmol/mol (1%) reduction in HbA1C“.

Even in 2021 there are no data to suggest that metformin should not be initiated soon after the diagnosis of diabetes.

Interestingly the results of a meta-analysis of 19 RCTs with >18,000 subjects with T2D that was published in 2022 concluded that compared to other glucose-lowering drugs and placebo there was no evidence that metformin was clinically superior in protecting against the microvascular complications investigated.

So, it is high time to rigorously reassess antidiabetic medication on the basis not of the so-called surrogate HbA1c, but rather according to patient-relevant outcomes.

You might ask, what about the use of Metformin in PCOS?

Metformin is commonly prescribed to women with PCOS to improve the insulin sensitivity. But, Metformin has side effects such as occasional heartburn, indigestion, bloating and gas, diarrhea/constipation, weird taste in the mouth and pancreatitis, which are a common cause of treatment discontinuation.

A meta-analysis included 10 randomized controlled trials (RCTs) with a total of 845 infertile women with PCOS undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment, found that metformin has no clinical effect on the rate of pregnancy or live birth, but reduces the risk for ovarian hyperstimulation syndrome (OHSS). A later meta-analysis, including 12 RCTs and 1,516 patients, has shown the same results: metformin does not improve assisted reproductive technology outcomes among infertile patients with PCOS. The only benefit deriving from the use of metformin was the decrease in the risk for OHSS.

In conclusion, metformin represents the main insulin sensitizing agent in the management of infertile women with PCOS, with no clear benefit in improving live birth rates. Moreover, Metformin has other downfalls.

Metformin May Predispose Your Unborn Child to Neural Tube Defects

30% of people who take metformin for PCOS are vitamin B12 deficient. If you have PCOS and insulin resistance and low levels of B12, you don’t want to take a drug which could lower those levels even more. However, B12 deficiency can also cause an increased risk of neural tube defects in unborn children. This is important for all women, but especially those who are trying to get pregnant. One study found that mothers with a vitamin B12 deficiency were up to nine times more likely to have a baby with neural tube defect, compared to those who did not have a deficiency.

Metformin During Pregnancy Leads to Heavier Mothers and Babies

It’s been shown that metformin can cross the placental barrier and therefore potentially impact the foetus. So metformin may cause metabolic changes in babies born to mothers who have taken the drug during pregnancy. These metabolic changes could predispose the child to complications later in life. A study found that in women who took metformin during pregnancy, both mother and baby were heavier one year postpartum compared to women who were given a placebo.

Metformin use by men in the three-month period before they conceived a child was linked to a 40% higher risk of birth defects in the offspring, according to a study published on 29 March 2022 in the journal Annals of Internal Medicine. The study observed only children born to women without diabetes and who were under age 35. Only men under 40 who filled prescriptions for metformin during the 90 days before conception – the period when viable sperm are being made – were included.

In men, the use of metformin may affect sperm development in a way that increases birth defects in their sons, a study found. Using health-registry data from Denmark that tracked more than 1 million births, the researchers linked men’s use of metformin during sperm development to higher rates of genital birth defects in their sons. A paper describing the study was published 2022 March 28 in the Annals of Internal Medicine.

Metformin can Reduce Your Energy by up to 48%

As already stated above, Studies have shown that metformin depletes the mitochondria’s ability to produce energy, meaning that you are effectively operating on half the energy that you should have. This means that when you’re taking metformin for PCOS, then the cells in all of your essential organs, including your brain and heart, your GI tract and muscle cells are only working at half capacity. It is no wonder women taking metformin for PCOS feel so fatigued all the time.

Metformin use may lead to kidney damage

Metformin is primarily excreted by the kidneys, so if there is existing kidney dysfunction, it can potentially lead to a buildup of metformin in the body, increasing the risk of lactic acidosis—a rare but serious side effect. Maybe, for that reason, FDA has attached a boxed warning that cautioned against use of the drug in people who had even the slightest bit of abnormal kidney function, that is, men who had serum creatinine at or above 1.5 mg/dL and women who had serum creatinine at or above 1.4 mg/dL.

While metformin is generally considered safe for individuals with normal kidney function, there have been some reports suggesting a potential association between long-term metformin use and an increased risk of kidney disease. However, it is important to note that these reports are based on observational studies and the evidence is limited.

Several theories have been proposed to explain the potential mechanisms by which metformin could contribute to kidney disease:

  • Metformin may interfere with the normal functioning of the kidneys by reducing the levels of the lactate dehydrogenase, which is essential for the normal functioning of the renal tubules, because Cori cycle also involves the renal cortex, particularly the proximal tubules, another site where gluconeogenesis occurs.
  • Hemodynamic effects: Metformin may have effects on renal blood flow and intraglomerular pressure, potentially impacting kidney function. It has been suggested that metformin could cause vasoconstriction in the renal arteries, leading to reduced blood flow to the kidneys and potentially causing kidney damage.
  • Oxidative stress and inflammation: Metformin has been found to have antioxidant and anti-inflammatory properties. However, in certain situations, these properties could potentially contribute to kidney damage by altering the balance of oxidative stress and inflammation in the kidneys.

Metformin Kills Your Gut Bacteria

Gut bacteria is essential for immune function and proper weight regulation. Read any forum about metformin and you’ll find loads of stories from women who are having to base their everyday lives around where the nearest toilet just incase they have an ‘incident’. However, what most people don’t realise is that this side effect of metformin is much worse than suffering from loose stools. The reason that metformin has this effect is because it’s actually an antibiotic which seriously affects the microbiome (community of bacteria) living in the intestine. Several human and animal studies emphasized that metformin alters the gut microbiota composition by enhancing the growth of some bacteria, such as Akkermansia muciniphila, Escherichia spp. or Lactobacillus and by decreasing the levels of some other ones like Intestinibacter.

PPIs, metformin, NSAIDs, opioids and antipsychotics were associated with increases in either members of class Gammaproteobacteria (including Enterobacter, Escherichia, Klebsiella, Citrobacter, Salmonella and Proteus) or members of family Enterococcaceae. All of them are frequently isolated pathogens from blood culture samples of patients with sepsis, especially critically ill and cancer patients.

On the other hand, some suggest that metformin alleviates diabetes symptoms by killing off B. fragilis, which decreases FXR activation and the resulting production of ceramides by boosting levels of FXR-inhibiting GUDCA. However, one newer study from September 2018 does suggest that metformin causes an “increase in abundance of opportunistic pathogens and further triggers the occurrence of side effects associated with the observed dysbiosis”.

Neverthless, many will continue to take metformin. Curbs appetite + better colon health + mTor inhibition + AMPK activator + …