Medicine is a pragmatic discipline. This means that sometimes a treatment can evolve from experience, well before it is understood scientifically. This is true for the drug metformin, for the treatment of type 2 diabetes (T2D). It is the most widely-prescribed oral medication for T2D, it is often the first-line treatment, and it is increasingly being trialled for other conditions, including cancer. However, metformin is not the latest designer-drug – it came about because of folklore.
A bit of history
Since the middle ages, the herbaceous plant Galega officinalis (French lilac or Goat’s rue) was prescribed to relieve symptoms of thirst and excessive urination associated with the condition we now call T2D. It was also used to treat plague, worms, snake bites, miasma (smelliness), dysuria (difficult urination) and epilepsy, and the plant was fed to goats to increase milk-yield. However, the herb is toxic in excess, particularly for goats (hence the name Goat’s rue), and it is now classified as a noxious weed in most of the US.
Work on identifying the active ingredients in G. officinalis started in earnest at the beginning of the 20th century. Curiously, for a drug now so closely associated with T2D, this work was driven by the need for an alternative to quinine for the prevention or treatment of malaria. Quinine was (and still is) extracted from the bark of the Cinchona tree, originating in South America but mostly cultivated in Indonesia. Supplies were becoming unreliable due to political unrest, and the parasites were becoming resistant. The malaria parasite depends on glucose for its energy needs, so a blood-glucose lowering agent was being sought. Malaria was more of a health concern that T2D, which at that time was a rare condition.
It was long known (since the mid-late 1800s) that G. officinalis was rich in a molecule named guanidine. This was shown to be hypoglycaemic (glucose-lowering) in animal studies, but it had dangerous side-effects in humans. Less toxic guanidine derivatives that could be taken by humans were subsequently synthesised, but they still carried some risks. A safe version, containing two linked guanidine rings (known as a biguanide), was synthesised in 1922 and shown to be hypoglycaemic in 1929. However, it’s clinical use was not reported until 1949 when Eusebio Garcia, working in the Philippines, used it as a treatment for influenza and malaria (he called it flumamine – how he got hold of it remains a mystery). His success brought flumamine to the attention of Jean Sterne (working in Paris) who, in 1957, reported that it could lower blood-glucose in T2D. He renamed the drug glucophage (glucose-eater). It’s effectiveness for T2D was independently confirmed in a larger study in 1962, after which the drug underwent another name-change, becoming known as it is currently – metformin. More effective forms of metformin (phenformin and buformin) were developed, but they carried unacceptable risks (partly because they were too effective), and metformin became established as the first-line oral drug for T2D in Europe. It was not approved in the US until as late as 1995. It’s widespread use since then established its efficacy and safety profile, but without an understanding its mechanisms of action. Indeed, what we know about metformin only started to be uncovered this century.
Metformin in the body
Metformin is absorbed by the small intestine and preferentially transported to the liver via the portal vein. Some metformin also enters the circulation (or is released by the liver), where it can be taken up by other systems, however this is not thought to have a significant clinical effect. We infer this because, if metformin is injected directly into the circulation at the same concentration as would arise from an oral dose, it does not have a significant glucose-lowering effect. Thus, taking metformin orally is crucial for its effectiveness. Only about half of the metformin ingested is absorbed, with the remainder traversing the gut and eliminated in faeces. The metformin that is absorbed is not chemically altered or broken down in the body. Ultimately, it is eliminated, intact, through the kidneys (with a half-life of about 6 hours).
The liver and metformin
Metformin inhibits production of glucose in the liver (known as gluconeogenesis), and this seems to be one of its primary glucose-lowering effects. However, it was not until 2000 that the first of the mechanisms for this was identified – metformin was shown to partly reduce the energy available to liver cells by inhibiting complex I of the mitochondrial respiratory chain. By way of explanation, the mitochondria are cellular power generators, respiratory refers to burning fuel with oxygen, this occurs in steps along a chain and complex I is the first step. The significance of this is that gluconeogenesis is an energy-intensive process, and so, with a reduction in energy-availability, the liver shuts it down (by down-regulating the activity of certain enzymes). It seems a rather clumsy approach though.
Since then, multiple other mechanisms have been identified. For example, metformin has an effect on a master-regulator of cellular energy balance (abbreviated AMP-kinase), which in turn suppresses gene-expression for gluconeogenesis (it’s an epigenetic model). By another mechanism, metformin reduces the bio-availability of some of the molecules that the liver uses to make glucose (e.g. glycerol and lactate). And, by yet another mechanism, it increases fat burning in the liver and suppresses liver lipogenesis (fat generation – the liver can produce fat as well as glucose). This can have a flow-on effect that improves insulin sensitivity, although there is some dispute as to how significant this effect is in T2D. Likewise, metformin can increase insulin sensitivity and glucose uptake in skeletal muscle, but this is not thought to significantly reduce circulating glucose.
Metformin and the gut
So, it’s complex. Furthermore, that’s just the liver (and muscle). Recently, it has been argued that there is another major player involved – the gut. The gut is implicated because we know metformin has to be taken orally to be effective, and that only about half the available metformin is absorbed and sent to the liver or elsewhere. That leaves half in the intestines. There, as for the liver, it can have multiple effects.
To begin with, metformin inhibits the small intestine from absorbing dietary glucose, although this may not be a strong effect. More significantly, it up-regulates glucose metabolism in the cells of the gut wall, so that more of the glucose that is absorbed is burned for energy by these cells. These processes can work together to restrict glucose availability elsewhere in the body by retaining it in the gut (although it would be simpler not to eat the glucose in the first place). Glucose-imaging techniques (such as positron emission tomography – PET scans) can demonstrate an increased gut concentration. As an aside, this can make early-detection of cancer in the gut more difficult in people on metformin, because this same imaging method is used to detect cancers (they are high-glucose consumers).
Metformin can also increase the secretion of a range of hormones and signalling molecules, the most important of which are the incretins that are strongly involved in glucose regulation. These hormones can also have effects on the liver and the brain, creating one mechanism for a gut-brain-liver axis. The gut-brain axis is currently receiving much attention, beyond that associated with metformin.
Bile helps the small intestine to absorb nutrients, particularly fatty nutrients (by acting as an emulsifier). It is produced by the liver (from cholesterol) and stored in the gall bladder, from where it is released at the top of the small intestine, to aid digestion after a meal. It travels with the food through the intestine and is resorbed at the end of the small intestine to be recycled. Metformin interrupts the resorption of bile, which causes the liver to have to keep making more, thus consuming cholesterol. This is thought to be the main way that metformin can lower cholesterol.
Bile acids are also involved in glucose regulation, and may act as signalling molecules. Furthermore, the lack of resorption means that there is an increase in bile entering the large intestine (colon). This may have an effect on the resident gut microbiota, perhaps beneficially, but this is not known. It may also underlie the diarrhoea experienced by some people on metformin. Newly-developed, delayed-release methods for delivering metformin are seemingly more effective than the older, immediate- or intermediate-release methods, suggesting that it is advantageous to allow time for the metformin to get to the colon before it is released. These considerations suggest that the colon may have a role, however it is early days and its role remains to be understood.
Metformin in other conditions
It seems that metformin has many potential applications, however it is not certain whether these will all result in a clinical benefit. Conditions under investigation include cancer, non-alcoholic fatty liver disease, Alzheimer’s disease, obesity, renal disease, cardiovascular health, dysregulation of the circadian clock and polycystic ovary syndrome (POS). In nearly all of these situations, there are conceptual grounds for considering metformin, and laboratory studies that support it, however studies of the efficacy in humans are still lacking. I will discuss just three of these.
1. Non-alcoholic fatty liver disease (NAFLD)
NAFLD encompasses a spectrum of liver diseases that are not attributable to alcohol consumption, but that can progress to cirrhosis and liver failure or cancer. It’s prevalence is rapidly rising worldwide, and it is on course to overtake alcohol-related liver failure as the primary reason for liver transplants.
NAFLD starts with a build up of fats in liver cells, perhaps due to a disorder in energy utilisation and storage combined with chronic liver inflammation. It coincides with an increased risk of T2D, metabolic syndrome and cardiovascular disease among others, and its prevalence has risen in association with that of these conditions. Metformin increases fat oxidation in the liver and is therefore a logical treatment option. However, most randomised control trials have not been able to show a benefit in the human, and metformin is not part of current clinical guidelines for the treatment of NAFLD (in adults or children).
T2D is associated with an increased risk of cancer. This may arise from chronically-elevated insulin levels as a consequence of insulin resistance, combined with high blood glucose. Many cancer cells are hungry for glucose, and high levels of both insulin and glucose can facilitate transport of glucose into cancer cells for their energy needs and growth. As well, insulin is implicated in cellular growth through insulin-like growth factors (IGFs). The role of metformin in T2D, and the link with cancer, has raised interest in its possibilities as an adjunct cancer therapy. However, while laboratory studies have been promising, studies in the human have not been consistent.
3. The brain
Metformin can cross the blood-brain barrier (BBB) and enter the brain. What it does in the brain is not yet certain. However, laboratory studies have shown that metformin can reduce the plaques and tangles that are the hallmark of later-stage Alzheimer’s disease (AD). This is relevant because T2D is a risk-factor for AD and they have some commonalities linked to glucose metabolism and insulin resistance. Metformin has also been shown to have neuroprotective effects, reduce oxidative stress and promote neurogenesis in various laboratory models. It could also influence the brain via the gut-brain axis. However, again, studies in the human have not been definitive.
We live in a technologically-advanced era of drug discovery and development. So, it is worth reminding ourselves that metformin, the most widely prescribed oral drug for T2D, is based on a herbal remedy dating back to the middle ages. The drug has not been modified since it was synthesised in 1922 (around the same time as insulin was discovered), making two of the most important drugs in modern diabetes management close to a century old. Metformin was prescribed for decades without an understanding of how it worked. We have only begun to uncover its mechanisms in the present century, and a complete grasp of how it acts in the body still eludes us.
After researching this post, I am better informed but none the wiser.
Note: The content of this post is intended to be educational and informative. I am not a medical practitioner, and this content should not be taken as medical advice.
Wu et al. (2017) New insights into the anti-diabetic actions of metformin: from the liver to the gut.
Zheng et al. (2015) Metformin and metabolic diseases: a focus on hepatic aspects.
Viollet et al. (2012) Cellular and molecular mechanisms of metformin: an overview.
Bailey and Day (2004) Metformin: its botanical background
Moreira (2014) Metformin in the diabetic brain: friend or foe?