METFORMIN: THE UNSUNG HERO DRUG

By Jack Osborn Marissa McCollum

Metformin is a commonly prescribed drug used to treat high blood sugar most commonly in diabetic patients as an antihyperglycemic biguanide, referring to a class of drugs used to treat type 2 diabetes. These drugs function by decreasing hepatic glucose primarily by inhibiting the body’s metabolic process of producing sugar, known as gluconeogenesis. While the drug has been widely distributed for over two decades as a diabetic drug, having received FDA approval in October of 1998, only recently has evidence provided support for the use and implementation of the drug to both improve insulin sensitivity and limit carcinogenesis in otherwise healthy individuals. Thus, the drug shows new potential in delivering anti-cancer benefits that can be of use to everyone in society. Today, the drug is largely distributed as 1,1-dimethylbiguanide hydrochloride and has recently been shown to function though previously undescribed mechanisms, including pathways that may offer overarching benefits to health.

Beyond its capacity for diabetes treatment, increasing data has come to light surrounding metformin’s implications in regulating and improving gut health. More than one third of all Americans suffer from metabolic syndrome, an overarching disease state used to describe a series of inflammatory conditions such as elevated blood sugar, high blood pressure, and gut dysbiosis; the gut microbiome has been shown to play a crucial role in metabolic syndrome pathogenesis. Due to metformin’s therapeutic capacity to boost gut health, the drug shows promise in improving an otherwise healthy individual’s metabolic state, critical to longevity and a healthy life.

Type 2 diabetes is characterized in its simplest terms as an inability or resistance to release insulin in response to carbohydrates, resulting in elevating blood sugar. Insulin, a hormone normally released by the pancreas, serves to allow glucose to pass from blood into cells for use in metabolism. Since its initial administration, metformin has been shown to chronically improve insulin sensitivity and thereby mitigate a diabetic’s fasting blood sugar levels. Specifically, metformin both directly and indirectly upregulates the AMPK pathway, an essential control system of many cellular processes, including glucose production in the liver (see Figure I). In a cell treated with metformin, cellular respiration is suppressed, and glucose biosynthesis (gluconeogenesis) is inhibited. Metformin also indirectly mediates several other metabolic pathways that increase insulin sensitivity, resulting in lower overall blood sugar and healthier metabolism of consumed sugars. Importantly, metformin does not

actually promote insulin release, which could cause compensatory low blood sugar, making it the preferred treatment for type 2 diabetes.

In addition to its direct role in diabetes treatment, metformin also plays a crucial role in weight loss by inhibiting Insulin-like Growth Factor receptor signaling, a pathway similar to that of insulin. Unlike other diabetic drugs that specifically protect beta islet cells of the pancreas that release insulin in response to sugar, metformin plays a more widespread role in maintaining metabolic health. Additionally, the drug has been shown to decrease fasting insulin levels in patients with cognitive impairment and aberrant glucose metabolism. As both hypoglycemia and hyperglycemia are implicated in cognitive dysfunction, metformin’s potential use therein lies in improving cognition in diabetic individuals. Thus, metformin’s wide-ranging direct impact on a multitude of biochemical pathways, some of which remain undescribed, make therapeutic benefits possible not only for diabetic patients but also for otherwise healthy adults looking to improve their health and potentially lose weight without dangerous consequences.

Today metformin remains somewhat understudied from the viewpoint of its anticancer and profound anti-inflammatory properties— both relevant and salient benefits. One elucidated mechanism surrounding its anti-cancer potential has been discovered through a series of protein phosphorylation cascades. Since the drug activates the AMPK pathway, leading to mTOR signaling inhibition, protein synthesis is altered, thereby hindering aberrant cell proliferation associated with cancer cells. The drug also suppresses oxidative phosphorylation, a process that can inadvertently generate reactive oxygen species (ROS); through inhibition of mitochondrial complex I (see Figure I), ROS production is hindered, further reducing DNA damage and limiting the extent through which cancer can develop. Furthermore, leukemia has been well-characterized by mTOR pathway activation; metformin has been shown to inhibit the AKT/mTOR signaling pathway, creating a potential therapeutic approach for combating blood cancers, in addition to a series of cancers proliferated by the broader biochemical pathways. Regarding its anti-inflammatory properties, which alone have suppressive cancer capabilities, metformin has been shown to increase activity of brown fat, adipose tissue critical to generating body heat, thereby suppressing fat storage and increasing metabolic efficiency. As a result, especially in chronic use of the drug, metformin is capable of reducing fatty acid uptake and increasing cellular thermogenesis (heat generation), increasing resting metabolic rates, and thereby promoting weight loss, especially when coupled with exercise. Lastly, since the gut microbiome has been implicated in regulating metabolic health via production of short chain fatty acids critical to the immune system, metformin’s ability to regulate gut microbiota has been shown to vitally increase

the presence of short-chain fatty acid-producing bacteria, improving gut health. Taken together, by targeting a series of complicated but individually critical pathways often dysregulated through poor health, metformin presents significant hope as a therapeutic drug in not only harnessing but also improving health as a society at large.

While metformin’s numerous benefits largely outweigh its costs, as with any drug, the costs must be considered before an individual is prescribed the drug. Prior to prescription, physicians evaluate the drug’s potential to cause more serious—albeit rare—side effects including lactic acidosis, which can occur if significant amounts of the drug accumulate in the blood, most often due to dehydration and kidney issues. Additionally, the drug can reduce absorption of vitamin B12 through chronic use, requiring metformin patients to supplement their diet with B12 intake. If patients are anemic, metformin must be supplemented with a series of vitamins to ensure that the drug does not exacerbate deficiencies already present in the body. Some concerns stem from distribution rather than the drug itself: the FDA recommended that some metformin distributors producing an extended release version of the drug remove their tablets from the market in May of 2020 due to concerning levels of carcinogens.

Even taking into account the negative associations and dangers of the drug, metformin holds astounding promise in unlocking a multitude of biological targets critical to longevity, including cancer, gut microbiome inflammatory pathways and even lipid metabolism pathways. While the future of the drug is not fully clear, looking back on the drug in years to come, the drug will assuredly continue to reveal benefits beyond its capacity to treat diabetes, akin to a miracle drug.

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