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Metformin: Medical Marvel or Magical Medicine?

Published on January 23, 2024

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I am not a big fan of metformin (Glucophage). My disdain for metformin stems not from its efficacy. Metformin is quite adept at lowering blood sugar. In that sense, it is a medical marvel. Consider a pill that will ensure that no matter the individual’s intake of sugar, blood glucose measurements will magically fall within a normal range. What a wonderful invention – to have one’s cake, eat it too, and all the while, maintain normal blood sugar – who wouldn’t want that?

Alas, however, like all magic tricks, when the sleight of hand is revealed, the luster is lost. In the case of metformin, the underlying prestidigitation is not so magical after all. Metformin, like other wonder drugs, treats a symptom of a much greater problem; a symptom that in reality is just a visible sign of a necessary and protective innate process designed for cellular survival. The symptom is insulin resistance, the problem is too much dietary sugar and too few nutrients – an insidious form of high-calorie malnutrition that at once overloads cellular and mitochondrial processing capacities and starves the cells of critical nutrients.

Nutrients – They’re Necessary

A little-appreciated fact in modern medicine, vitamins and minerals power all of the machinery involved in cell function and in mitochondrial energy production. No nutrients, no energy, cellular starvation (even in the face of weight gain), inflammation, dysfunction, and ultimately, death. In the face of too much sugar and not enough nutrition, insulin resistance seems perfectly logical. If cellular fuel is waning, why not keep a little extra floating around, but since the apparatus to process said sugars is crippled, we have to turn down the intake valves. I would argue that it’s not obesity causing insulin resistance, after all not all overweight folks have type 2 diabetes, and not all insulin-resistant diabetics are overweight. It’s the damned sugar and lack of other nutrients initiating insulin resistance. Both the insulin resistance and fat storage are survival mechanisms; ones that ultimately have pathological consequences, but survival mechanisms nevertheless. In fact, folks who are diabetic and overweight have a lower all-cause mortality rate than those who are diabetic and thin.

If the problem is high-calorie malnutrition, which manifests as elevated blood sugar and in many cases, increased fat storage, wouldn’t the more prudent solution be to rectify the problem, to cease sugar intake, and address the nutrient deficiency? Wouldn’t that unwind the damage and heal the body? I think so, but alas, that’s not what we do in modern medicine. No, we don’t correct the problem, we treat the symptom(s) and then we revel in all the cool mechanisms we can interrupt, never considering the bigger picture.

Metformin Usurps Cell Signaling

Metformin bypasses our cells’ innate response to too much of anything – downregulation or desensitization – by overriding the communication systems that control these functions. In this case, metformin becomes the signaling molecule that tells the liver if and when to release glucose into the bloodstream. From an engineering standpoint, it’s a fantastic workaround. No need to address the core problem, just rewire the communication and continue on as if nothing is wrong. The added bonus is that for all intents and purposes, it works. Blood sugar declines, as does some of the pathology associated with elevated blood sugar. A medical marvel, right?

Well, not so fast. It just so happens that we need those pesky nutrients to function and to survive. When we give metformin to individuals who are already in a state of malnutrition, we are effectively ignoring and extending the underlying deficiencies that initiated the insulin resistance in the first place. More importantly, and this is something that is missed almost entirely in western medicine, we are adding to the metabolic mess a chemical that directly leaches a whole bunch of nutrients on its own (which further disables cell function, increases insulin resistance, increases fat storage in the long term and all of the associated pathologies we have come to know and love). Furthermore, we’re disrupting energy metabolism – energy that all cells need to function – and while that may quell some pathologies in the short term, in the long term, we’re all but guaranteeing a progressive decline into ill-health, despite the cheerleading that suggests otherwise.

We Get It. Metformin Treats a Symptom Not the Root Cause. So What?

Why am I blustering on about metformin now, when I have done so on several occasions previously (here, here, and here)? Well, an emerging body of research is showing yet another set of mechanisms by which metformin derails health. It turns out, that in addition to depleting vitamins B12 and B9, which are responsible for 100s of enzymatic reactions and particularly important in central nervous system function including myelination (how many cases of diabetic neuropathy or multiple sclerosis are really vitamin b12 deficiency?) and tanking CoEnzyme Q10 which effectively cripples mitochondrial ATP production in muscles (and likely exercise capabilities) with the resultant loss inducing a whole host of pathological processes (muscle weakness, cognitive decline among a few), metformin also blocks vitamin B1 – thiamine – uptake by multiple mechanisms. And for kicks and giggles, it appears to interfere with the body’s innate toxicant metabolism pathways, the P450 enzymes, rendering those who use this drug less capable of effectively metabolizing a whole host of other medications and environmental toxicants.

Thiamine is Critically Important to Health

For those of you who don’t read our blog and/or are not familiar with thiamine and thiamine deficiency, let’s just say, thiamine is the granddaddy of nutrients, an essential cofactor at the top of the fuel processing pyramid. Without thiamine, food fuel from carbs and, to a lesser extent, fats cannot be converted into ATP. With declining fuel sources, mitochondrial functioning degrades as well and all sorts of diseases processes ensue.

Sit with that for a moment. We’re giving folks who already have an issue with converting foods to energy and who are already very likely nutrient deficient, a medication that blocks the very first step in that conversion process. Since metformin also blocks the lactate pathway and acetyl-coenzyme A carboxylase (an enzyme necessary to process fatty acids into fuels), blocking thiamine effectively shunts the mitochondrial input pathways. Mind you, this is in addition to blocking the critical electron transport functions – via CoQ10 – found at the back of ATP processing. Talk about an induction of energetic stress.

So What If a Few Vitamins Are Depleted?

I bet you’re thinking if these nutrients are so important and metformin is so dangerous, why isn’t metformin more toxic? After all, metformin has been on the market for over 50 years, is considered the first line of treatment for type 2 diabetes, and just about every research article published on this drug begins with a blanket statement that metformin has an excellent safety record.

Why, indeed? Let us consider what constitutes a safe drug?

In modern medicine, the notion of drug safety and toxicology are equated with acute reactions. For decades, we have been operating under the false assumption in medical and environmental toxicology that if something doesn’t kill us immediately it must be safe (and the equally false assumption that toxicological responses are necessarily linear). Many drugs (and environmental toxicants) are much more subtle in their damage. They disrupt systems that, in many cases, have the capacity to compensate, at least for a period of time and until a critical threshold is met. Mitochondrial energetics is one of those systems that is remarkably resilient in the face of a myriad of stressors, sometimes taking years for the damage to be recognized. With nutrient deficiencies, in particular, compensation is aided by continuously changing environmental and lifestyle considerations. Sometimes we eat very well and other times we don’t; sometimes life is good, other times, it is not. Stressors vary.

Nutrient Deficiencies Wax and Wane

With nutrients deficiencies, especially essential nutrients that require dietary intake, there can be waxing and waning of the symptoms that these deficits evoke as diet and other variables change. It’s not until one reaches a critical threshold that the deficiency is recognized if it is recognized at all. With thiamine deficiency, in particular, animal research suggests the threshold for severe symptoms may be as high as 80% depletion. Imagine a system that can maintain life in the face of up to an 80% deficiency. That is remarkable.

Symptoms of severe thiamine deficiency include those associated with a condition called Wernicke’s Encephalopathy, a serious and potentially fatal medical emergency with neurological and cognitive impairments, oculomotor and gait disturbances, and cardiac instability. With milder deficiencies, however, we see things like fatigue, muscle pain, mental fuzziness, GI disturbances, autonomic dysregulation, and a host of symptoms that can easily and incorrectly be attributed to other conditions and/or modern life in general.

Interestingly, once thiamine depletion reaches that critical threshold, it doesn’t take much thiamine to begin seeing improvement in the symptoms. In those same animal studies mentioned above, it took an increase of only 6% of the total thiamine concentration to begin the improvement. So with a change from 20 to 26% of recommended thiamine concentration, symptoms begin to dissipate, at least temporarily. Sit with than one for a moment – what a remarkable bit of resilience. It takes a full 80% reduction in thiamine stores before serious symptoms are recognized but improvement begins with only an additional 6% – when the system is still depleted by 74%.

Given the metabolic capacity to maintain survival in the face of all but critical deficiencies, it is easy to see how and why blocking these nutrients would not be considered dangerous or at least obviously so. The decline is so gradual in most cases, and likely waxes and wanes, that it becomes near impossible to attribute symptoms and underlying nutrient deficiencies to the offending medication(s). Unfortunately, just because we don’t recognize those patterns, doesn’t mean that they do not exist.

How Metformin Blocks Thiamine: The Technicals

Backing up just a bit, it is important to understand the mechanisms by which metformin reduces thiamine. When metformin is present, a set of transporters that normally bring thiamine into the cell to perform its task as a cofactor in the machinery that converts carbs to ATP, brings metformin into the cell instead, replacing thiamine altogether. The transporters involved are the SLC22A1, also called the organic cation transporter 1, [OAT1], and the SLC19A3. Conversely, when metformin is not present or at least not overwhelming all of the transporters as it is during the initial phases of absorption post intake, thiamine becomes available for transport. Since these transporters are not completely and continuously blocked (and there are other thiamine transporters), thiamine uptake occurs, just not continuously and just not at full capacity. This may be one reason why metformin is not as acutely damaging as some of the other drugs in its class, but make no mistake, it is still dangerous. Thiamine deficiency is deadly. With the right combination of thiamine blocking variables (other medications/vaccines block thiamine as well), thiamine concentrations can tank and even if the thiamine concentrations hover at a subclinical deficit, the likelihood of chronic illness is high.

Thiamine and Diabetes: Connecting a Few More Dots

A little over a year ago, I stumbled upon some research showing a high rate of thiamine deficiency in individuals with both type 1 and type 2 diabetes (75% and 64%, respectively). I wrote about that research in Diabetes and Thiamine: A Novel Treatment Opportunity. According to several studies, diabetics appear to excrete higher amounts of thiamine than non-diabetics. The research attributes this to either poor kidney reabsorption and/or mutations in the thiamine transporter genes that prevent absorption. None of the research detailed the medication usage of the participants, but one might expect a good percentage of the type 2 diabetics were using metformin. It seems reasonable that if metformin supplants thiamine uptake via the thiamine transporters mentioned above, then the body would excrete the unused thiamine, leading to a higher rate of thiamine excretion than observed in non-diabetics and a higher rate of thiamine deficiency in diabetics versus non-diabetics. Based upon this, additional clinical research has shown that thiamine supplementation normalizes, the aberrant processes activated by sustained hyperglycemia including:

High dose thiamine (300mg/day) reduces the biochemical stress of hyperglycemia in human subjects.
Thiamine can prevent and/or offset incipient vascular damage in diabetic patients.
In rodent models of Type 1 diabetes, thiamine transporters have been identified and emerging research shows that thiamine moderates pancreatic insulin secretion significantly.

Metformin, in treating a symptom rather than a root cause, is likely exacerbating, and perhaps even initiating, some of the very disease processes that it is intended to prevent. 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. From my perspective, that makes metformin a very dangerous drug.

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This article was published originally on Hormones Matter on February 16, 2016.

Image by kalhh from Pixabay.

Stop the Metformin Madness

by Chandler Marrs, PhD

Published on June 18, 2015

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I have never been a fan of Metformin. It seemed too good to be true. Many years ago I had a conversation with a researcher about all of its possible therapeutic indications. His lab was actively pursuing the anti-cancer angle. That should have been a clue that Metformin might be causing more damage than we recognized, but it wasn’t. At that point, I was still enamored with the wonders of pharmacology and hadn’t yet begun my path toward understanding medication adverse reactions. Indeed, it wasn’t until very recently, when a family member began suffering from one of these reactions, that I began my investigation in full. This is what I learned.

Type 2 Diabetes is Big Business

The global profits from Type 2 diabetes medications rested at a paltry 23 billion dollars in 2011 but are expected to grow to over $45 billion annually by 2020. The market growth is bolstered in large part by the ever-expanding demand for therapeutics like Metformin or Glucophage. Metformin is the first line of treatment and standard of care for insulin resistance across all populations of Type 2 diabetics with over 49 million Americans on Metformin in 2011-2012. It is particularly popular in women’s health with an increasing reliance on Metformin for the metabolic dysfunction observed in women with PCOS, PCOS-related infertility, and even gestational diabetes. Metformin is prescribed so frequently and considered so innocuous that it is sometimes euphemistically referred to as vitamin M.

If we quickly scan the safety research for metformin, there is little immediate evidence suggesting any side effects whatsoever. In fact, in addition to controlling blood sugar by blocking the hepatic glucose dump, this drug is suggested to promote weight loss, increase ovulation in women, (thereby helping achieve pregnancy), and prevent an array of pregnancy complications (everything from miscarriage to gestational diabetes, pre-eclampsia and preterm birth). Metformin is argued to prevent cancer and the neurocognitive declines associated with aging, even aging itself. By all accounts, Metformin is a wonder drug. Why isn’t everyone on Metformin prophylactically? Increasingly, we are.

With the increasing rates of obesity and associated metabolic disturbances, drugs that purportedly reduce those indicators are primed for growth. Like the push to expand statin prescription rates from 1 in 4 Americans to perhaps 1 in 3, millions have been spent increasing the therapeutic indications and reach for this medication. Amid all the excitement over this drug, one has to wonder if it isn’t too good to be true. In our exuberance to get something for nothing, to have cake, if you will, have we overlooked the very real risks and side effects associated with Metformin? I think we have.

Metformin and Vitamin B12 Deficiency

As we’ve reported previously, Metformin leaches vitamin B12 and to a lesser degree B9 (folate) from the body. One study found almost 30% of Metformin users are vitamin B12 deficient. For the US alone, that’s almost 15 million people who could be vitamin B12 deficient and likely do not know that they are deficient. What happens when one is vitamin B12 deficient?

Firstly, inflammation increases, along with homocysteine concentrations, which is a very strong and independent risk factor for heart disease (the very same disease Metformin is promoted to prevent). And that is the tip of the iceberg.

Vitamin B12 is involved with a staggering number of physiological functions including DNA, RNA, hormone, lipid, and protein synthesis. Deplete vitamin B12 and a whole host of problems emerge, mostly neurological.

Vitamin B12 is critical for the synthesis of the myelin sheaths around nerve fibers. There is a growing relationship between multiple sclerosis, which involves the disintegration of myelin and brain white matter, and vitamin B12 deficiency. Often the first signs of B12 deficiency are nervous system-related with cognitive disturbances and peripheral neuropathy among the most common.

Additionally, many women have dysregulated hormones connected to vitamin B12 deficiency. In light of the Metformin-mediated vitamin B12 deficiency, one has to wonder if some of the chronic health issues plaguing modern culture are not simply iatrogenic or medication-induced.

Metformin, Pregnancy and Maternal and Fetal Complications

Considering that half the population is female, many of whom are on Metformin and may become pregnant, we must consider the potential effects of Metformin-induced vitamin B12 deficiency during pregnancy. As troubling as the effects of B12 deficiency are on non-pregnant individuals, during pregnancy they can be devastating. Vitamin B12 deficiency during pregnancy leads to an increased incidence of neural tube defects and anencephaly (the neural tube fails to close during gestation). Once thought to be solely related to folate deficiency (vitamin B9) which Metformin also induces, researchers are now finding that B12 has a role in neural tube defects as well.

Scan the internet for Metformin and infertility and you’ll see long lists of fertility centers boasting the benefits of this drug. During pregnancy, the exuberance for vitamin M is palpable, although entirely misplaced. Early reports suggested Metformin would reduce an array of pregnancy complications including gestational diabetes. The data supporting these practices were mixed at best. At worst, however, they were downright incorrect. Metformin, it appears, may evoke the very conditions it was promoted to prevent during pregnancy and then some. Additionally, recent research suggests Metformin alters fetal development and induces long-term metabolic changes in the offspring, likely predisposing the children to Type 2 Diabetes, an epigenetic effect perhaps.

Metformin Inhibits Exercise-Induced Insulin Sensitivity

As if those side effects were not enough to question mass Metformin prescribing practices, it appears that Metformin reduces any gains in insulin sensitivity that normally would be achieved from exercise. I cannot help but wonder if Metformin impairs insulin signaling in general. Cancer research suggests that it might.

According to one study, physical exercise can increase insulin sensitivity by up to 54% in insulin-resistant individuals, unless of course, they are taking Metformin. Metformin abolishes any increased insulin sensitivity gained by exercise. Metformin also reduces peak aerobic capacity, reducing performance and making exercise more difficult. Moreover, despite claims to the contrary, Metformin does not appear to be an especially effective tool for weight loss, netting a reduction of only 5-10 pounds over 4-8 months. Regular exercise and a healthy diet net on average a loss of 5-10 pounds per month for most people and are significantly more effective at reducing diabetes and associated health complications without the potential side effects.

Metformin and Mitochondrial Damage

Perhaps most troubling amongst the Metformin side effects is its ability to severely impair mitochondrial functioning.

Recall from high school biology, the mitochondria are those bean-shaped organelles inside cells that are responsible for cellular respiration or energy production. Through a variety of pathways, the mitochondria provide fuel for cell survival. In addition to cellular energy production, mitochondria control cell apoptosis (death), calcium, copper, and iron homeostasis, and steroidogenesis. In essence, mitochondria perform the key tasks associated with cell survival, and indeed, human survival. Damage the mitochondria and cellular dysfunction or death will occur. Damage sufficient numbers of mitochondrion and chronic, multi-symptom illness arises.

As we have come to learn, many pharmaceuticals, environmental toxicants, and even dietary deficiencies can impair mitochondrial functioning and induce disease processes that are often difficult to diagnose and treat. Metformin is no different. Metformin impairs mitochondrial functioning quite significantly by several mechanisms and, in doing so, sets off a cascading sequence of ill effects.

At the center of metformin’s mitochondrial damage is its effect on the most basic of mitochondrial functions – ATP (cellular energy) production. Metformin reduces mitochondrial ATP production in skeletal muscle by as much as 48%. Sit with that one for a moment, a 48% reduction in cell fuel. Imagine functioning at only half capacity. This would make basic activities difficult at best and exercising to lose weight a very unlikely proposition. Imagine similar reductions in ATP production were observed in the brain or the heart or the GI tract (which, when on Metformin are likely), the types of disturbances we might see become quite clear: 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.

Metformin Alters Immune Reactivity via the Mitochondria

As I wrote in a previous post:

Some researchers argue that the mitochondria are the danger sensors for host organisms; having evolved over two billion years to identify and communicate signs of danger to the cells within which they reside. The signaling is simple and yet highly refined, involving a series of switches that control cellular energy, and thus, cellular life or death. When danger is present, energy resources are conserved and the immune system fighters are unleashed. When danger is resolved, normal functioning can resume.
If the danger is not resolved and the immune battles must rage on, the mitochondria begin the complicated process of reallocating resources until the battle is won or the decision is made to institute what can only be described as suicide – cell death. Cell death is a normal occurrence in the cell cycle of life. Cells are born and die for all manner of reasons. But when cell death occurs from mitochondrial injury, it is messy, and evokes even broader immune responses, setting a cascade in motion that is difficult to arrest.

Metformin alters this process, 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. The double hit fundamentally alters immune function and I would suspect predisposes those who take Metformin to more infections and an array of inflammation-based disease processes. More details on this in a subsequent post.

Metformin and the Statins: Beware

The mechanisms through which Metformin derails mitochondrial functioning are complex but likely related to depletion of coQ10, an enzyme involved in what is called the electron transport chain within the mitochondria. CoQ10 also referred to as ubiquinol and ubiquinone, is critical for mitochondrial functioning. Recall from a previous post, that statins, like Lipitor, Crestor and others also deplete coQ10 and from a pharmacological perspective these mechanisms are implicated in the development of atherosclerosis and heart failure.

“statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and ‘heme A’, and thereby ATP generation.”

CoQ10 depletion is also implicated in the more common statin-induced side effects like muscle pain and weakness and in severe cases, rhabdomyolysis. Since Metformin and statins are regularly co-prescribed, the potential for severely depleted mitochondria and significant side effects is very high. Consider muscle pain and weakness among the first signs of problems.

My Two Cents

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, block insulin sensitivity and reduce aerobic capacity, one cannot help but wonder if we are causing more harm than good. Admittedly, obesity and hyperglycemia are growing problems in Western cultures. As we are coming to learn, however, obesity itself is not linked to the diseases processes for which many drugs like statins and Metformin are promoted to protect against – the obesity paradox. Growing evidence suggests that obesity is indicative of mitochondrial dysfunction and chemical exposures which then may provoke impaired insulin sensitivity and hyperglycemia and continued fat storage versus metabolism. If this is true, simply reducing circulating glucose concentrations, in an effort to reduce obesity and the purported health problems associated with obesity, will do nothing to treat the underlying problem.

Insulin resistance and the associated hyperglycemia are environmental and lifestyle-mediated problems that should be reversible with environmental and lifestyle changes. Having said that, those lifestyle and dietary changes will fail unless we consider the underlying mitochondrial damage initiated by dietary choices, pharmaceuticals, and other environmental exposures. For that, we must dig deeper into mitochondrial functioning and correct what we can.

I believe obesity and hyperglycemia are symptoms of damaged and dysfunctional mitochondria, partly mediated by lifestyle, partly iatrogenic (pharmaceutically induced), and likely epigenetic. If we are to solve the ‘obesity’ problem and prevent the damage mediated by hyperglycemia, we have to address these variables. Failing to do so serves no one except those who profit from our continued ill-health.