Metformin: its uses, mechanism of action,

and side effects

Throughout this essay, I will discuss Metformin in general, including its applications and mechanism of
action, as well as its adverse effects and how they arise.
Metformin is a 17th-century herbal treatment and was mentioned in herbal manuals as having qualities
ideal for the treatment of the type 2 diabetes mellitus.
Metformin is a biguanide-family medicine used to treat type 2 diabetes, this is brought on by the body's
failure to handle insulin effectively, and hence manage blood sugar levels.
Metformin is popular because of its low risk of adverse effects, low cost, convenience of administration,
and weight-loss benefits. Metformin is an oral drug that comes in extended-release formulations and can
be used once a day. The danger of lactic acidosis in specific patient groups is the main source of worry.
(Thomas,2017)
Metformin (dimethyl biguanide), which was showed in 1959 to help people with type 2 diabetes lower
their blood glucose levels, and it has been a tremendous blessing for millions of people who suffer from
this widespread metabolic illness. Metformin is also being investigated as a treatment for other major
illnesses such as fatty liver disease, cardiovascular disease, and cancer. (Spiering,2019)
Despite extensive clinical experience and ongoing research, the specific mechanisms of action of
metformin remain unknown. But to produce a therapeutic impact, metformin is administered at high
dosages compared to other drugs. Most patients get a therapeutic dosage of two gm/day, showing that
the effect is not attributable to a single protein target interaction. (Thomas,2017)
With a half-life of five hours, Metformin is not digested and is excreted unchanged in the urine. The
average renal clearance in the population is 510±120 ml/min. Metformin is primarily excreted in the
kidney by active tubular secretion. The drug is transported throughout the body through organic cation
transporters, which include the stomach, liver, and kidney, also its absorption is assumed to be primarily
regulated via the plasma membrane monoamine transporter, which is expressed on the endothelial
surface of intestinal mucosa. However, there is presently no in-vivo evidence of PMAT's role in
metformin distribution and pharmacological effect. Metformin absorption in the liver is controlled by
OCT1 and maybe OCT3, where both transporters should be produced on the basolateral membrane.
(Gong,2012)
Metformin is an old medicine, but throughout the course of its lengthy existence, its pleiotropic modes
of action have been increasingly understood.
Mechanism of action of metformin include reducing hepatic glucose synthesis and enhancing glucose
utilization to enhance insulin sensitivity and glycemic control. Metformin has been proven to activate
AMPK in the liver, making it one of the most critical cellular regulators of glucose and lipid
metabolism, as a consequence, acetyl-CoA carboxylase will be reduced, fatty acid oxidation will be
enhanced, and lipogenic enzyme synthesis will be repressed. Additionally, metformin-induced AMPK
activation, and inhibits fatty acid production by lowering the expression of sterol regulatory element
binding protein-1c, a major lipogenic transcription factor. Moreover, metformin-mediated AMPK
activation lowers the gluconeogenic enzymes (glucose 6-phosphatase and phosphoenolpyruvate
carboxy-kinase), resulting in gluconeogenesis suppression in the liver. Metformin also increases glucose

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 transporter 4 translocation to the cell membrane and hence glucose absorption by activating AMPK in
skeletal muscle. Finally, these actions help to reduce fatty liver and insulin resistance. Recently,
Metformin has been demonstrated to inhibit mitochondrial respiratory complex I, increasing the ratio of
adenosine monophosphate (AMP) to adenosine triphosphate (ATP) (ATP). Inactivation of AMPK is
expected as a result of such a change. Metformin was also shown to inactivate mitochondrial glycerol-3-
phosphate dehydrogenase, which was thought to be involved in gluconeogenesis suppression in the liver.
(Kaneto,2021)
Metformin is well known for improving glycemic control while also having a favorable safety profile,
weight neutrality or weight reduction, no related hypoglycemia, lower cardiovascular mortality, and a
reasonable cost. However, due to the medication's related adverse effects, a considerable percentage of
patients are unable to tolerate it in sufficient dosages. Up to 25% of individuals experience metformin-
related gastrointestinal adverse effects, with around 5% unable to tolerate the drug at all.
Metformin contains certain molecular similarities with selective 5-HT3 receptor agonists and is
delivered in part by SERT, as previously indicated. Serotonin (5-HT) release from the stomach causes
nausea, vomiting, and diarrhea, which are similar to the symptoms of metformin intolerance. As a result,
altered serotonin transport or a direct serotonergic-like effect of metformin might be one potential
explanation for metformin-related gastrointestinal discomfort. Metformin may also decrease diamine
oxidase, an enzyme that is highly expressed in enterocytes and is involved in histamine metabolism, and
because histamine similar to serotonin, it is linked to a boost in gastrointestinal motility. More study is
needed to figure out what causes metformin gastrointestinal intolerance, in addition to the way to avoid
or manage this serious side effect. (McCreight,2016)
In conclusion, Metformin is a drug belonging to the biguanide group for the treatment of type 2 diabetes,
as a result of the body's inability to properly metabolize insulin, diabetes develops, and therefore cannot
control the level of blood sugar. Also, it is a safe and efficient 1st line therapy for diabetes type 2.
Although the liver is known to be a key location of metformin pharmacodynamics, new research implies
that the gut it is also possible that it will play a part of metformin pharmacodynamics. In addition,
metformin tolerance and response are inextricably connected to the stomach. Because metformin passes
through the stomach, it has an impact on the individual's metformin therapy effectiveness, and
contributes to metformin intolerance adverse effect.

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 References
 Thomas, I., & Gregg, B. (2017). Metformin; a review of its history and future: from lilac to
longevity. Pediatric diabetes, 18(1), 10–16. https://doi.org/10.1111/pedi.12473
 Spiering M. J. (2019). The mystery of metformin. The Journal of biological chemistry, 294(17),
6689–6691. https://doi.org/10.1074/jbc.CL119.008628
 Gong, L., Goswami, S., Giacomini, K. M., Altman, R. B., & Klein, T. E. (2012). Metformin
pathways: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics, 22(11),
820–827. https://doi.org/10.1097/FPC.0b013e3283559b22
 Kaneto, H., Kimura, T., Obata, A., Shimoda, M., & Kaku, K. (2021). Multifaceted Mechanisms
of Action of Metformin Which Have Been Unraveled One after Another in the Long History.
International journal of molecular sciences, 22(5), 2596. https://doi.org/10.3390/ijms22052596
 McCreight, L. J., Bailey, C. J., & Pearson, E. R. (2016). Metformin and the gastrointestinal tract.
Diabetologia, 59(3), 426–435. https://doi.org/10.1007/s00125-015-3844-9

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