Metformin is an Endocrine Disruptor and Threat to Humankind

Metformin is an Endocrine Disruptor and Threat to Humankind

Metformin is one of the most widely prescribed medications in the world. It is endorsed by Endo Consensus (American Association of Clinical Endocrinologists and American College of Endocrinology) as the first line treatment for T2D. Metformin's MOA was not known at the time of its FDA approval in the United States, and it has still not been fully elucidated. Metformin is also often prescribed off-label. However, Metformin causes many health consequences to humans and is an endocrine disruptor. Metformin has officially infiltrated the ecosystem—particularly causing enormous harm within the aquatic life (IMO any living organism that consumes it). Metformin is irreversibly altering fish reproductive systems by inducing intersex and fecundity.
Metformin is highly prevalent in wastewater treatment plants, sewage sludge, natural water systems, soil, and also drinking water. I am fully aware that Metformin is not the only pharmaceutical and/or substance that is prevalent in water sources. But since Metformin is a neurotoxin, among many other things, coupled with the fact that it is not metabolized within the human body, it becomes reintroduced into the environment unchanged. Metformin has already caused alarming consequences—and this will result in irreversible damages on a global scale if something is not done, IMO.

The occurrence of intersex fish, where male reproductive tissues show evidence of feminization, have been found in freshwater systems around the world, indicating the potential for significant endocrine disruption across species in the ecosystem. Estrogens from birth control medications in wastewater treatment plant effluent have been cited as the likely cause, but research has shown that endocrine disruption is not solely predictable based on hormone receptor interactions. Many other non-hormone pharmaceuticals are found in effluent at concentrations orders of magnitude higher than estrogens, yet there is little data indicating the impacts of these other medications. The widely prescribed anti-diabetic metformin is among the most abundant of pharmaceuticals found in effluent and is structurally dissimilar from hormones. However, we show here that exposing fathead minnows (Pimephales promelas) to a concentration of metformin found in wastewater effluent causes the development of intersex gonads in males, reduced size of treated male fish, and reduction in fecundity for treated pairs. Our results demonstrate that metformin acts as an endocrine disruptor at environmentally relevant concentrations.

Emerging wastewater contaminant metformin causes intersex and reduced fecundity in fish

The anti-diabetic drug metformin is thought to be the pharmaceutical most deposited into the aquatic environment by mass at up to 6 tons per year from individual WWTPs in urban areas. Recent studies have shown that exposure to 40 ug/L of metformin increased the relative expression of the egg yolk precursor protein vitellogenin in adult male fathead minnows (Pimephales promelas) (FHM). For this study, the expression of several other genes involved in estrogen biosynthesis, clearance and downstream effects were assessed in FHM after treatment to three concentrations of metformin, to better understand the estrogenic effects of metformin on FHM. In contrast to the previous study, although upward trends were observed, metformin failed to significantly alter the expression of VTG, ERα, GnRH3, and CYP3A126 in adult male FHM. However, a concentration-dependent response to metformin was observed in younger 80-90 day juvenile FHM. A 17.7-, 22-, and 22-fold increase in the relative expression of VTG mRNA in juvenile FHM exposed to 1, 10, and 100 μg/L as compared to the control was observed. There was also a 3.3-, 4.7-, and 5.5-fold increase in GnRH3 in juvenile FHM exposed to 1, 10, and 100 μg/L as compared to the control. Similarly, a 14-, 16-, and 24-fold increase in the relative expression of CYP3A126 mRNA was measured in juvenile FHM exposed to 1, 10 and 100 μg/L metformin as compared to the control. These results indicate that juvenile FHM were more susceptible to the estrogenic effects of metformin during a 7-d exposure than older, sexually mature male FHM.

Age-dependent effects in fathead minnows from the anti-diabetic drug metformin

In 2030, the World Health Organization estimates that more than 350 million people will be diagnosed with diabetes. Consequently, Metformin – the biguanide drug of choice orally administered for diabetes type II – is anticipated to see a spike in production.
Unlike many pharmaceutical drugs, Metformin (Met) is not metabolized by humans but passes through the body unchanged. Entering aquatic compartments, such as in sewage, it can be bacterially transformed to the ultimate transformation product Guanylurea (Gua).
Sampling over one week (n = 5) from a Southern German sewage treatment plant revealed very high average (AV) concentrations in influent (AVMet = 111,800 ng/L, AVGua = 1300 ng/L) and effluent samples (AVMet = 4800 ng/L, AVGua = 44,000 ng/L).
To provide a more complete picture of the distribution and potential persistence of these compounds in the German water cycle, a new, efficient and highly sensitive liquid chromatography mass spectrometric method with direct injection was used for the measurement of Metformin and Guanylurea in drinking, surface, sewage and seawater. Limits of quantification (LOQ) ranging from 2–10 ng/L allowed the detection of Metformin and Guanylurea in different locations such as: Lake Constance (n = 11: AVMet = 102 ng/L, AVGua = 16 ng/L), river Elbe (n = 12: AVMet = 472 ng/L, AVGua = 9 ng/L), river Weser (n = 6: AVMet = 349 ng/L, AVGua = 137 ng/L) and for the first time in marine North Sea water (n = 14: AVMet = 13 ng/L, AVGua = 11 ng/L). Based on daily water discharges, Metformin loads of 15.2 kg/d (Elbe) and 6.4 kg/d (Weser) into the North Sea were calculated. Lake Constance is used to abstract potable water which is further purified to be used as drinking water. A first screening of two tap water samples contained 2 ng/L and 61 ng/L of Metformin, respectively. The results of this study suggest that Metformin and Guanylurea could be distributed over a large fraction of the world's potable water sources and oceans. With no natural degradation processes, these compounds can be easily reintroduced to humans as they enter the food chain.

Occurrence of the antidiabetic drug Metformin and its ultimate transformation product Guanylurea in several compartments of the aquatic cycle


Continued...

Metformin is the most commonly used anti-diabetic drug in the world. When consumed, this unmetabolised pharmaceutical compound is excreted by the body and eventually enters the environment through a variety of pathways. Based on its high consumption and excretion rates, high concentrations of metformin have been detected in influents of wastewater treatment plants. Metformin and its transformation product, guanylurea, are also expected to be present in other aquatic environments based on their physico-chemical properties. Not surprisingly, guanylurea has also been detected in surface water, groundwater, and drinking water. Available information on ecotoxicological effects of metformin suggests that metformin is a potential endocrine disruptor and thus further emphasising the threat this drug could pose to our environment. This review provides a comprehensive overview of metformin and critically discusses available literature data with respect to its global use/demand, occurrence, fate and ecotoxicity in treatment facilities equipped with conventional and advanced treatment technologies, and its degradation/removal mechanisms. Final section highlights the existing knowledge gaps regarding its ultimate fate under the natural and engineered ecosystems and identifies some important research areas requiring urgent attention from regulatory makers and scientific community.

A global perspective on the use, occurrence, fate and effects of anti-diabetic drug metformin in natural and engineered ecosystems

Pharmaceutical contaminants are growing aquatic-health concerns and largely attributed to wastewater treatment facility (WWTF) discharges. Five biweekly water samples from 59 small Piedmont (United States) streams were analyzed for 108 pharmaceuticals and degradates using high-performance liquid chromatography and tandem mass spectrometry. The antidiabetic metformin was detected in 89% of samples and at 97% of sites. At least one pharmaceutical was detected at every site (median of 6, maximum of 45), and several were detected at ≥10% of sites at
concentrations reported to affect multiple aquatic end points. Maximal cumulative (all detected compounds) concentrations per site ranged from 17 to 16000 ng L−1. Watershed urbanization, water table depth, soil thickness, and WWTF metrics correlated significantly with in-stream pharmaceutical contamination. Comparable pharmaceutical concentrations and detections at sites with and without permitted wastewater discharges demonstrate the importance of non-WWTF sources and the need for broad-scale mitigation. The results highlight a fundamental biochemical link between global human-health crises like diabetes and aquatic ecosystem health.

Metformin and Other Pharmaceuticals Widespread in Wadeable Streams of the Southeastern United States

The occurrence of emerging contaminants in our water resources poses potential threats to the livings. Due to the poor treatment in wastewater management, treatment technologies are needed to effectively remove these products for living organism safety. In this study, Graphene oxide (GO) was tested for the first time for its capacity to remove a kind of emerging wastewater contaminants, metformin. The research was conducted by using a series of systematic adsorption and kinetic experiments. The results indicated that GO could rapidly and efficiently reduce the concentration of metformin, which could provide a solution in handling this problem. The uptake of metformin on the graphene oxide was strongly dependent on temperature, pH, ionic strength, and background electrolyte. The adsorption kinetic experiments revealed that almost 80% removal of metformin was achieved within 20 min for all the doses studied, corresponding to the relatively high k1 (0.232 min 1) and k2 (0.007 g mg 1 min 1) values in the kinetic models. It indicated that the highest adsorption capacity in the investigated range (qm) of GO for metformin was at pH 6.0 and 288 K. Thermodynamic study indicated that the adsorption was a spontaneous (DG0 < 0) and exothermic (DH0 < 0) process. The adsorption of metformin increased when the pH values changed from 4.0 to 6.0, and decreased adsorption were observed at pH 6.0e11.0. GO still exhibited excellent adsorption capacity after several desorption/adsorption cycles. Besides, both so-called pep interactions and hydrogen bonds might be mainly responsible for the adsorption of metformin onto GO.

Adsorption of emerging contaminant metformin using graphene oxide


Continued...

• In the human body, Metformin directly alters the gut microbiota, induces vitamin b12 deficiency, induces oxidative stress, causes neuronal death, and increases amyloid precursor proteins and presenilin which cause aggregation of beta-amyloid. I believe also it induces a cascading web of negative effects through inducing vitamin b12 deficiency via the colon because vitamin b12 is essential for DNA synthesis and RBC production. My personal thinking is (in no particular order) Metformin > impairment and dysfunction of the gut-brain axis via directly altering gut microbiota > liver impairment and dysfunction > impaired glucose homeostasis > vitamin b12 deficiency > decreased production in RBC and impaired DNA synthesis > peripheral neuropathy > CVD, stroke, microvascular disease, decreased blood supply to all bodily tissues and organs > neurodegenerative diseases.

• Metformin Facts:

—Metformin is a fluorescent molecule able to reach the brain

—Chronic metformin use stimulates APP processing in the cortex

—Metformin induces mitochondrial dysfunction by impairing MPT pores and membrane channels

—Metformin induces neuronal apoptosis

—Metformin directly interacts with amyloid-beta peptides influencing its aggregation kinetics in vitro

—Metformin changes the levels of expression of TOM40, VDAC1 and HKI, which are proteins involved in mitochondrial import and export of molecules and metabolites in the cortex where amyloid-beta aggregates are mostly present. Studies on human brain biopsies have demonstrated that TOM40 pore mediates the internalization of Aβ and APP

—Metformin increases Aβ Generation

—Metformin up-regulates BACE1 promoter activity

—Metformin's effect is independent of glucose metabolism and insulin signaling

—Metformin's effect is mediated by activation of the AMP kinase in virto and in vivo.

—Metformin has an antagonizing effect on intracellular amyloid-beta generation

—Metformin induces APP expression and processing via oxidative stress

—Metformin triggers APP and presenilin via NFκB activation

—Insulin plays a protective role against Metformin by inhibiting oxidative stress

• Sources:

Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription

Biological and biophysics aspects of metformin‐induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre‐fibrillar aggregates

Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation

Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-κB activation: Use of insulin to attenuate metformin's effect

[Metformin and the gastrointestinal tract

[Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug

Study of Vitamin B12 deficiency and peripheral neuropathy in metformin-treated early Type 2 diabetes mellitus

I read this all, very well put together. Question I have still is this. What is the half life of such compounds? I would think that in evaporation, they would simply be broken down in the atmosphere, eaten, and destroyed?

a reply to: M4ngo

Just one little teensy weensy problem.

Metform affects minnows at 40 mg/L.

the concentration of metformin found in waste water is in the ng/L range.

Quite a difference there.

Taking 100 aspirin all at once will kill

Nasty stuff, thanks for the info.
Add this to the Dirty Dozen
Now what the hell can we do about it? Who is accountable? Would regulations help? Good luck going against big pharma.

Perhaps each toilet needs a neutralizing agent that drips into water with each flush.....I'm not kidding

a reply to: TiredofControlFreaks

sorry - pressed enter before I finished.

taking 100 aspirin all at once will kill you. Take 1 aspirin for 100 days and you will be fine and maybe experience beneficial effects.

Just because a lot of something causes a problem, does not mean that a little of the same thing will also have an effect.

The poison, as usual is in the dose.

I call this doom porn

I'm not sure that Metformin is a very good drug for Diabetis. I know a dozen people on it, it is used to treat symptoms. Two of the people are experiencing some bad effects from it, initially they felt better but later on they had some complications that were pretty severe. I guess it blocks folate absorbtion because it causes a lot of diarrhea in some people. Both people I know taking it and having problems have the diahrea problem. A simple multimineral and some real folate and a little B12 and they are fine now.

There are a lot of drugs ending up in the sewer, excreted unchanged by the body. Sewer plants can't take a lot of this stuff out of the water they release. They are working on a way to fix this, but it will take a few more years to make the process financially viable.

Blocking folate by this method actually can disrupt the endocrine system.

originally posted by: SR1TX
I read this all, very well put together. Question I have still is this. What is the half life of such compounds? I would think that in evaporation, they would simply be broken down in the atmosphere, eaten, and destroyed?

• From one of the papers:

Elsewhere, Campbell (2013) investigated the fate of nine pharmaceuticals in an anaerobic sludge digester and reported 82% mineralisation of metformin over a test period of 60 days with a calculated half-life of 26.

In a recent study, the behaviour of metformin in soils was compared with other sulfonylurea based anti-diabetic drugs (Mrozik and Stefan ska, 2014). In comparison to the other pharmaceuticals tested (glimepiride, glibencamide, gliclazide), which were much less soluble than metformin (Mrozik and Stefan ska, 2014), calculated sorption coefficient of metformin was at least one order of magnitude lower. Based on the results, it was more apparent that the soil with the highest cation exchange capacity and correspondingly the highest organic matter content had the most sorbed amount of metformin. However, the authors never mentioned if the soils were sterilised or bacterial activity sup- pressed during the sorption experiments. The same study calculated half-lives of 1-5 days for metformin under aerobic biodegradation. Thus, throughout the 24-h duration of the experiments, biodegradation is likely to have occurred and sorption may not be the only mechanism involved in metformin removal. Analysis of literature data on sorption of metformin (Mrozik and Stefan ska, 2014; Scheurer et al., 2012) as a function of organic carbon content revealed that Kd decreased as organic carbon content of soil increased (Fig. 5). In contrast an opposite trend was observed for guanylurea for same set of soils.

originally posted by: TiredofControlFreaks
a reply to: M4ngo

Just one little teensy weensy problem.

Metform affects minnows at 40 mg/L.

the concentration of metformin found in waste water is in the ng/L range.

Quite a difference there.

Taking 100 aspirin all at once will kill

When you do factor in the fact that T2D prevalence is going to sky rocket in the coming years, then factor in the fact that all of them will be put on Metformin first, and then factor in the fact that Metformin I already altering reproductive systems of aquatic life—I think there is problem. I see long-term consequences.

Metformin showed negative impacts on the growth and devel- opment of carrots in soil concentration of 6e10 mg/kg (Eggen et al., 2011). Based on the EC50 value of metformin (64 mg/L) in the Daphnia test conducted by Cleuvers (2003), which determines the acute toxicity of a substance, this pharmaceutical compound can be classified as harmful to aquatic organisms.

Exposure of fish (fathead minnow fry) to 40 mg/L metformin for a full-life cycle beginning in early development showed impacts on repro- duction and the authors have concluded that chronic exposure to this pharmaceutical compound could potentially cause endocrine disrupting effects in fishes (Niemuth and Klaper, 2015).
Continuous high volume consumption of this compound and its release into the environment via various pathways may not show apparent acute effects but may potentially have adverse effects due to chronic exposure (Al-Odaini et al., 2010). Additionally, co- occurrence of drugs was found to have strong and positive corre- lation to wastewater effluent concentrations which may suggest synergistic effects in the environment and could potentially lead to complex ecotoxicity (Ghoshdastidar et al., 2015).

Oxidation products formed during disinfection steps could potentially be harmful to human health. DMA is an ingredient used in the synthesis of metformin hydrochloride (Shalmashi, 2008), and a major precursor of N-nitro- sodimethylamine (NDMA) which is also a probable human carcinogen (USEPA, 1993). Tukkeeree et al. (2012) reported that prepared metformin drug has been found to contain 0.0482% of DMA relative to a 500 mg metformin tablet purchased from a local pharmacy. However, even such trace levels of DMA can produce NDMA after chlorination/ozonation (Padhye et al., 2011).

It has been reported that organic precursors interact with ozone or OH to generate NDMA during water treatment (Padhye et al., 2011). Tertiary and secondary amines are dominant precursors of NDMA formation during the disinfection process (Wu et al., 2015). As such, the presence of tertiary and secondary amine moieties in the oxidation products listed in Table 6 suggests potential for NDMA formation. The active tertiary amine moiety attached to the ring structure of the identified chlorination by-product shown in Fig. 3a may also be attacked by OH or O3 and further react to form NDMA. It has been shown recently that DMA associated with branched alkyl groups or benzyl like structures having only one carbon between the ring and DMA structure consistently give higher NDMA yields (Selbes, 2014).

a reply to: M4ngo

So, what exactly are people that need Metformin to keep their sugar under control supposed to do exactly? I find this concerning because I know diabetics and they can't go without this medication.

a reply to: M4ngo

a ng/l is 1 part per million. a mg/l is 1 part per thousand.

There is a very very big difference between those 2 numbers.

Nobody can predict how many diabetics will exist in the future and nobody can predict that metformin will still be in use by then.

Like I said - doom porn. Keep the people anxious and fearful and they will pay any amount of money to someone who can save them. Especially lucrative when there is no problem in the first place.

originally posted by: Metallicus
a reply to: M4ngo

So, what exactly are people that need Metformin to keep their sugar under control supposed to do exactly? I find this concerning because I know diabetics and they can't go without this medication.

All T2D's can either:

1. Consume Cannabis.
—See my thread here (Cannabis turns on fat burning, among other things, and can prevent T2D and even T1D): The Endocannabinoid System and Diabetes

2. Take insulin. First line treatment for T2D should be insulin, no arguement about it. But, I would take the only insulin that does not cause amyloidosis nor have potential to travel from the periphery into the brain and aggregate into amyloid fibrils. It's an inhaled meal-time insulin that utilizes an inert carrier particle that does not penetrate cell membranes.
—See my there here: Injectable Insulins are Amyloidogenic

originally posted by: TiredofControlFreaks
a reply to: M4ngo

a ng/l is 1 part per million. a mg/l is 1 part per thousand.

There is a very very big difference between those 2 numbers.

Nobody can predict how many diabetics will exist in the future and nobody can predict that metformin will still be in use by then.

Like I said - doom porn. Keep the people anxious and fearful and they will pay any amount of money to someone who can save them. Especially lucrative when there is no problem in the first place.

Metformin is irreversibly altering fish reproductive systems and already causes neurological damage. I see the problem.

originally posted by: TiredofControlFreaks
a reply to: M4ngo

a ng/l is 1 part per million. a mg/l is 1 part per thousand.

There is a very very big difference between those 2 numbers.

Nobody can predict how many diabetics will exist in the future and nobody can predict that metformin will still be in use by then.

Like I said - doom porn. Keep the people anxious and fearful and they will pay any amount of money to someone who can save them. Especially lucrative when there is no problem in the first place.

I'm sorry you don't see the long-term consequences. It is absorbed in the soil, taken up by plants. It runs rampant in all water sources, already altering aquatic life, and it already damages the human body. No doom porn here whatsoever. You are not going to hear about this stuff anywhere else. Hence, not doom porn. All species depend on food sources and health for survival.

Based on daily water discharges, Metformin loads of 15.2 kg/d (Elbe) and 6.4 kg/d (Weser) into the North Sea were calculated. Lake Constance is used to abstract potable water which is further purified to be used as drinking water.

a reply to: M4ngo

With all due respect - No, No you don't

What is the rate at which aquatic creatures change sex without exposure to metformin?? it happens naturally you know.

Did the scientist run a control population?

Are you not aware that hundreds and hundreds of laboratory research simply does not translate into the real world?

metfromins patent ran out decades ago but it is still the cheapest and most effective treatment for T2D. The pharmaceutical companies have spent billions developing new drugs for the same purpose but almost every diabetic still takes metformin.

Now if you were a pharmaceutical company and you wanted people to get away from metformin and onto the more expensive drugs, what research would you fund? Could it be the research that shows there is terrifying environmental effect and if you can instill enough fear in enough people, there will be a ban on metformin.

Hell, you don't even need the regular popluation, you can just hire an environmental group like Greenpeace or WWF to do the lobbying for you.

No I don't think you see the problem at all

a reply to: Metallicus

Not a doctor, but some people claim blueberry extract works as a "natural" alternative to Metformin.

*shrug* I have no personal experience, but I know people who extol its virtues.

a reply to: Kettu

There already exist quite a number of "natural" remedies. Like an extract of cinnamen but by the time you pay for the extracts, the cost far exceed metformin.

There also exists a number of new drugs but the cost is prohibitive and there is no improvement in effectiveness. Some of the new drugs can cause wieght loss but there could be side effects especially on the kidney function.

originally posted by: Kettu
a reply to: Metallicus

Not a doctor, but some people claim blueberry extract works as a "natural" alternative to Metformin.

*shrug* I have no personal experience, but I know people who extol its virtues.

I appreciate your input.

My concern is that someone with type 2 diabetes will read this and then think they can get along without their medication which they can't in most cases. Whatever other effects Metformin may have it is an effective treatment for T2D.

a reply to: Metallicus

I totally agree. In fact, I would not hestitate to say that it is the most effective one. Even when the disease has progressed to insulin, metformin is still prescribed to decrease the amount of insulin that you have to take. Insulin causes weight gain.