For centuries, humanity has relied on science to address some of the most pressing medical, clinical, and biological conditions that eventually become widespread public health concerns. Among the many tools developed to combat these diseases, organic synthesis stands out as one of the most important. Various synthetic methods—ranging from metal-catalyzed processes to metal-free approaches, as well as naturally occurring compounds—have been employed to treat a wide array of conditions, including cancer, mycoses, pain, and inflammation. In the context of this review, we focus on diabetes, specifically metformin. This widely used antihyperglycemic drug has become one of the most essential treatments for type II diabetes, and we will explore its synthesis, medical uses, and significance.

History of Metformin:

Metformin has been used in traditional medicine for centuries, with its origins dating back to around 1500 BCE in ancient Egyptian medicine(Witters, 2001). In Europe, a herbal remedy made from Galega officinalis (also known as French lilac) was historically used to treat symptoms like excessive urination and thirst(Thomas and Gregg, 2017). It wasn’t until the early 20th century, however, that the active compound, guanidine, was isolated and identified as the key therapeutic element.

The prevalence of diabetes mellitus (DM) has been steadily rising worldwide, making it one of the most common non-communicable diseases. It is also one of the leading causes of premature death globally, affecting both developed and developing countries. Given this growing health crisis, it’s no surprise that metformin, the most commonly prescribed treatment for diabetes, has been the subject of extensive research. However, much of the focus has been on its role in managing diabetes, with fewer studies exploring its other potential benefits.

Fig2: Galega officinalis

Metformin has indeed been appertained to as “ the aspirin of the twenty-first century. ” Historically, it was primarily  honored for its effectiveness in lowering blood sugar  situations, but recent  exploration has uncovered  fresh health benefits( Romero et al., 2017a). These include its implicit to promote life( Onken and Driscoll, 2010),  help certain types of cancer( Wu et al., 2015), and  give  remedial support for conditions like  habitual  order  complaint, congestive heart failure, and  habitual liver  complaint( Crowley et al., 2017).

 Current  substantiation suggests that metformin’s broad- diapason  goods may operate through at least two  crucial  natural mechanisms one involves inhibiting mitochondrial metabolic  exertion, while the other affects the cellular nutrient-  seeing system, particularly the mTOR pathway( Romero et al., 2017b). mTOR( the mammalian target of rapamycin) is a  pivotal kinase that regulates metabolism, cell growth, and responses to  colorful factors like nutrients, stress, and growth signals.

Fig3: Chemical structure of biguanide- Metformin

Types of diabetes

There are three types of diabetes: type I, type II and gestational Diabetes which differ from each other in various aspects. 

Type I diabetes commonly called “neonatal diabetes” is associated to a low or null insulin production, with an autoimmune background. Here T-lymphocytes attack the β-pancreatic cells, impairing insulin production. Recently, it has been demonstrated that this autoimmune character could have environmental, genetic and other components that might be triggering the disease apparition, thus their molecular action mechanisms are still unknown(Shield and Temple, 2002).

Gestational diabetes is diagnosed in pregnant woman with blood glucose levels higher than normal, but below levels considered for the diagnosis of type II diabetes (>126 mg/dL). The high glucose levels could be attributed to obesity and overeating during pregnancy. These comorbidities and bad habits might increase the probability of further development of type II diabetes in the mother and the child(Seshiah et al., 2011).

Type II diabetes is the most common public health problem which can be explained through three main mechanisms occurring in the following sites:

• Skeletal muscle: A high fatty acids concentration inhibits PI3K activity, subsequently PIP3, leading to the failure on glucose absorption(Chang et al., 2004a).
• Liver: With a similar mechanism, the reduction of PIP3 followed by less stimulation of glycogen synthetase, leads to an increase on the expression of the protein “forkhead” type O (FOXO) which results in a higher activation of gluconeogenesis, rising the blood glucose levels(Ashcroft and Rorsman, 2004; Rorsman and Ashcroft, 2018).
• Fat tissue: Inflammation of fat tissue promotes cytosines liberation, diminishing adiponectin secretion. This contributes to fatty acids liberation(Burhans et al., 2018).

1. Anti- Aging Properties:-

Metformin, a widely used treatment for Type 2 diabetes (T2DM), has been shown to offer a range of health benefits beyond blood sugar control. This has led to growing interest in its potential as an anti-aging therapy. Early research in animals, including studies with the nematode(Chang et al., 2004b) and mice, has suggested that metformin might help extend lifespan. As a result, clinical trials such as the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin) have been launched to explore whether metformin can delay aging and improve longevity in humans.Initial findings from the MILES trial suggest that metformin may induce changes in gene expression that are associated with anti-aging effects. However, the question of whether metformin can offer protective benefits for healthy individuals, free from chronic disease, remains debated. Despite being used as a treatment for over 60 years, the exact cellular mechanisms through which metformin works are still not fully understood.While the evidence supporting metformin’s role as an anti-aging drug is still inconclusive, there is strong support for its ability to improve healthspan—the period of life spent in good health. Metformin seems to reduce early mortality linked to conditions like diabetes, cardiovascular disease, cognitive decline, and cancer. Its beneficial effects on aging are likely indirect, stemming from its ability to improve cellular metabolism. These benefits are thought to arise from metformin’s ability to lower blood sugar, enhance insulin sensitivity, reduce oxidative stress, and protect vascular function. In conclusion, while metformin's direct role in extending lifespan remains uncertain, it clearly plays a valuable role in promoting a healthier, longer life by reducing the burden of chronic diseases(Mohammed et al., 2021).

Fig4(a): Metformin extends median lifespan via an AMPK and LKB1-dependent mechanism.

( https://doi.org/10.1371/journal.pone.0008758.g003 )

The primary mechanism through which metformin exerts its effects is through the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK is a key regulator of cellular energy balance and is activated when the ratio of AMP to ATP increases during metabolic stress, such as under conditions of low oxygen (hypoxia) or glucose deprivation. While AMPK activation remains a well-established pathway through which metformin works, recent research has uncovered additional pathways that may contribute to its diverse beneficial effects. These findings could provide new insights into potential treatment targets for conditions like diabetes and metabolic syndrome.Beyond its use in diabetes management, metformin is increasingly attracting attention from researchers in other fields due to its potential anti-cancer, immunomodulatory, and anti-aging effects(Hsu et al., 2021).

Fig4(b): The Antiaging Effect of Metformin

1. Anti- Cancer Properties:

Metformin is a widely recognized medication for treating Type 2 diabetes, but it is increasingly being explored for other potential uses, including as an anti-cancer agent. One of its major advantages is its excellent safety profile, good tolerability, and affordability—costing less than one US dollar per day. Epidemiological studies have shown that metformin can reduce the risk of developing cancer and lower cancer-related mortality in people with diabetes. However, the accurate mechanisms behind these effects remain unclear. Metformin’s impact on energy metabolism is thought to play a central role in its potential anti-cancer properties. The drug’s modes of action can be broadly categorized into two types: direct effects and indirect effects. The direct effects occur when metformin acts directly on cancer cells, independent of its effects on blood glucose or insulin levels. On the other hand, indirect effects arise from systemic metabolic changes, particularly through improved blood glucose control and enhanced insulin sensitivity(Hua et al., 2023).

Hua et al. Journal of Translational Medicine (2023) 21:403

Fig5: Mechanism of Anti Cancer activity of Metformin

1. Anti- Diabetic Effect:

Metformin is one of the most widely prescribed and safest medications for managing T2D, typically used as a first-line treatment. In addition to its well-known effects on blood sugar control, metformin offers a range of other health benefits, including weight loss and positive effects on various conditions such as cancer, cardiovascular diseases, and metabolic disorders like thyroid disease.Despite decades of clinical use, the exact mechanisms through which metformin exerts its effects are not fully understood. This review explores the current understanding of how metformin benefits mitochondrial and vascular health. We focus on how metformin reduces oxidative stress and limits harmful interactions between leukocytes and the endothelium (the lining of blood vessels). We also delve into the molecular mechanisms by which metformin influences key metabolic processes, such as gluconeogenesis, and its effects on major cellular pathways like AMPK and mTORC1(Apostolova et al., 2020).

Metformin is a widely used and effective treatment for type 2 diabetes (T2D), a condition in which mitochondrial dysfunction plays a significant role in disease progression. The goal of our study was to explore how metformin affects mitochondrial function in people with T2D, focusing on an outpatient population. To investigate this, we conducted a preliminary cross-sectional study following STROBE guidelines. We analyzed leukocytes from three groups: 139 healthy controls,  T2D patients not taking metformin, and T2D patients who had been on metformin for at least one year.Our findings showed that leukocytes from T2D patients had elevated levels of reactive oxygen species (ROS), both total and mitochondrial, along with a lower mitochondrial membrane potential and reduced oxygen consumption. In addition, these patients had decreased levels of mRNA and proteins associated with mitochondrial fusion, such as mitofusin-1 (MFN1), mitofusin-2 (MFN2), and optic atrophy 1 (OPA1), and increased expression of proteins linked to mitochondrial fission, including FIS1 and DRP-1. We also observed heightened interactions between leukocytes and endothelial cells, which can be an early indicator of atherosclerosis. Interestingly, metformin treatment reversed many of these abnormalities. It improved mitochondrial function and dynamics, reducing the markers of mitochondrial stress and normalizing leukocyte-endothelial interactions. These findings suggest that metformin may help manage T2D not only by improving blood sugar control but also by addressing mitochondrial dysfunction and regulating the balance between mitochondrial fusion and fission. Furthermore, the drug’s ability to reduce leukocyte/endothelial interactions hints at its potential to influence early stages of atherosclerosis, a common complication in T2D(De Marañón et al., 2021).

Redox Biology 34 (2020) 101517 N. Apostolova, et al.

Fig6: Molecular mechanism of metformin in mitochondria

1. Chronic Kidney Disease:

Metformin is a widely used oral medication for treating type 2 diabetes mellitus (T2DM), primarily working through the indirect activation of 5' AMP-activated protein kinase (AMPK). In addition to its well-known anti-diabetic effects, increasing evidence suggests that metformin also offers potential benefits in various kidney diseases. In animal models of acute kidney injury (AKI), metformin has been shown to protect renal tubular cells by reducing inflammation, preventing cell death (apoptosis), decreasing oxidative stress (ROS), and alleviating endoplasmic reticulum (ER) stress. It also helps prevent the transition of epithelial cells to a more fibrotic state (epithelial-mesenchymal transition, or EMT), all through AMPK activation. In diabetic kidney disease (DKD), metformin has been found to reduce podocyte loss, prevent mesangial cell apoptosis, and delay the aging of tubular cells, again via AMPK-dependent pathways. Metformin also has effects in conditions like autosomal dominant polycystic kidney disease (ADPKD), where it inhibits cyst formation by blocking the mammalian target of rapamycin (mTOR) pathway, which is negatively regulated by AMPK. In addition to these effects, metformin has shown promise in conditions like urolithiasis (kidney stones) and renal cell carcinoma (RCC), further highlighting its potential role in kidney health. Renal fibrosis, a common pathway leading to end-stage renal disease (ESRD), can be significantly improved by metformin, with this benefit largely attributed to its activation of AMPK. However, clinical findings on metformin's effectiveness in kidney disease are not always consistent with preclinical data. Some clinical studies have shown minimal or even negative effects, particularly in T2DM patients with existing kidney conditions. Additionally, metformin-associated lactic acidosis (MALA) remains a major safety concern, limiting its use in certain populations, especially those with compromised kidney function(Song et al., 2021).

Diabetic nephropathy is one of the most significant complications of diabetes mellitus, often leading to progressive kidney damage. Key factors involved in the development of diabetic nephropathy include disruptions in cellular signaling pathways, particularly those regulated by AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). Additionally, conditions of high blood sugar (hyperglycemia) trigger oxidative stress and endoplasmic reticulum (ER) stress, which contribute to kidney cell damage. This damage includes the loss of podocytes, specialized cells that are crucial for maintaining the integrity of the kidney’s filtration system. As a result, these processes lead to impaired kidney function, affecting structural integrity and glomerular filtration.Metformin, a commonly prescribed medication for managing type 2 diabetes, has long been known for its blood sugar-lowering effects. However, recent research has uncovered additional benefits of metformin in protecting the kidneys. In both laboratory studies and animal models, metformin has been shown to reduce apoptosis (cell death) in various kidney conditions. Furthermore, metformin has been found to decrease albuminuria—an early sign of kidney damage—in diabetic rats and in humans with type 2 diabetes. These nephroprotective effects appear to be mediated through the AMPK/mTOR signaling pathway, which is involved in regulating cellular metabolism and stress responses(Eisenreich and Leppert, 2017).

Biomedicine & Pharmacotherapy 138 (2021) 111454

1. Song et al.

Fig7: The molecular mechanisms underlying the effect of metformin on DKD

1. Congestive Heart Failure:

Type 2 diabetes mellitus is a significant risk factor for cardiovascular disease, and many individuals with diabetes experience cardiovascular complications. Recent clinical trials focused on cardiovascular outcomes have highlighted that certain new glucose-lowering medications also provide additional heart-protective benefits. For example, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits by reducing the incidence of ischemic events, while sodium-glucose co-transporter-2 inhibitors (SGLT2 inhibitors) offer substantial protection, particularly in relation to heart failure and kidney health.These findings have influenced recent treatment guidelines, which now recommend GLP-1 RAs or SGLT2 inhibitors for patients with type 2 diabetes who have not achieved adequate control on metformin alone, especially if they have a history of atherosclerotic cardiovascular disease. SGLT2 inhibitors are specifically recommended for patients with heart failure or early-stage chronic kidney disease. Additionally, the 2019 European Society of Cardiology (ESC) guidelines, in collaboration with the European Association for the Study of Diabetes (EASD), suggest that these medications should be considered for treatment-naive patients with type 2 diabetes who have pre-existing cardiovascular disease or are at high cardiovascular risk.While these advances in treatment are promising, future research is needed to better understand the mechanisms behind the cardiovascular benefits of these drugs and to determine how widely these results can be applied across the entire population of people with diabetes. In the meantime, current evidence supports the expanded use of GLP-1 RAs and SGLT2 inhibitors in patients with diabetes and cardiovascular disease, with the potential to improve both heart and kidney health(Prattichizzo et al., 2019).

Metformin, a widely recognized AMPK agonist, is commonly prescribed as a first-line treatment for type 2 diabetes. In the past, there were concerns about using metformin in patients with cardiovascular diseases (CVDs) due to the risk of lactic acidosis. However, accumulating clinical and preclinical evidence now suggests that metformin not only helps control blood sugar but may also reduce the risk of cardiovascular events in both diabetic and non-diabetic individuals. The cardiovascular benefits of metformin are thought to stem from its activation of AMPK, a key regulator of cellular energy. By stimulating AMPK, metformin helps correct endothelial dysfunction, reduce oxidative stress, and improve the body's inflammatory response—all of which contribute to better cardiovascular health(Bu et al., 2022).

Fig8: AMPK- dependent actions of protective effects of metformin on atherosclerosis.

Metformin stands out as a cornerstone in the management of type 2 diabetes, with evidence showing it is also beneficial in addressing metabolic and chronic diseases beyond diabetes. Its low cost, extensive safety profile, and diverse health benefits position it as an important therapeutic agent in modern medicine. While its role in glucose control remains central, emerging studies suggest that metformin’s impact on mitochondrial function, cellular aging, and inflammatory pathways opens new avenues for its use in treating conditions like cancer, cardiovascular disease, and kidney disease. As research advances, further studies will be essential to fully elucidate the underlying mechanisms and broader applications of metformin. This knowledge could pave the way for expanding its use, enhancing both healthspan and potentially even lifespan in diverse populations.

1. Apostolova, N., Iannantuoni, F., Gruevska, A., Muntane, J., Rocha, M., Victor, V.M., 2020. Mechanisms of action of metformin in type 2 diabetes: Effects on mitochondria and leukocyte-endothelium interactions. Redox Biol. 34, 101517. https://doi.org/10.1016/j.redox.2020.101517
2. Ashcroft, F.M., Rorsman, P., 2004. Molecular Defects in Insulin Secretion in Type-2 Diabetes. Rev. Endocr. Metab. Disord. 5, 135–142. https://doi.org/10.1023/B:REMD.0000021435.87776.a7
3. Bu, Y., Peng, M., Tang, X., Xu, X., Wu, Y., Chen, A.F., Yang, X., 2022. Protective effects of metformin in various cardiovascular diseases: Clinical evidence and AMPK ‐dependent mechanisms. J. Cell. Mol. Med. 26, 4886–4903. https://doi.org/10.1111/jcmm.17519
4. Burhans, M.S., Hagman, D.K., Kuzma, J.N., Schmidt, K.A., Kratz, M., 2018. Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus, in: Prakash, Y.S. (Ed.), Comprehensive Physiology. Wiley, pp. 1–58. https://doi.org/10.1002/cphy.c170040
5. Chang, L., Chiang, S.-H., Saltiel, A.R., 2004a. Insulin Signaling and the Regulation of Glucose Transport. Mol. Med. 10, 65–71. https://doi.org/10.2119/2005-00029.Saltiel
6. Chang, L., Chiang, S.-H., Saltiel, A.R., 2004b. Insulin Signaling and the Regulation of Glucose Transport. Mol. Med. 10, 65–71. https://doi.org/10.2119/2005-00029.Saltiel
7. Crowley, M.J., Diamantidis, C.J., McDuffie, J.R., Cameron, C.B., Stanifer, J.W., Mock, C.K., Wang, X., Tang, S., Nagi, A., Kosinski, A.S., Williams, J.W., 2017. Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease: A Systematic Review. Ann. Intern. Med. 166, 191. https://doi.org/10.7326/M16-1901
8. De Marañón, A.M., Canet, F., Abad-Jiménez, Z., Jover, A., Morillas, C., Rocha, M., Victor, V.M., 2021. Does Metformin Modulate Mitochondrial Dynamics and Function in Type 2 Diabetic Patients? Antioxid. Redox Signal. 35, 377–385. https://doi.org/10.1089/ars.2021.0019
9. Eisenreich, A., Leppert, U., 2017. Update on the Protective Renal Effects of Metformin in Diabetic Nephropathy. Curr. Med. Chem. 24. https://doi.org/10.2174/0929867324666170404143102
10. Hsu, S.-K., Cheng, K.-C., Mgbeahuruike, M.O., Lin, Y.-H., Wu, C.-Y., Wang, H.-M.D., Yen, C.-H., Chiu, C.-C., Sheu, S.-J., 2021. New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway. Int. J. Mol. Sci. 22, 9453. https://doi.org/10.3390/ijms22179453
11. Hua, Y., Zheng, Y., Yao, Y., Jia, R., Ge, S., Zhuang, A., 2023. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J. Transl. Med. 21, 403. https://doi.org/10.1186/s12967-023-04263-8
12. Mohammed, I., Hollenberg, M.D., Ding, H., Triggle, C.R., 2021. A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan. Front. Endocrinol. 12, 718942. https://doi.org/10.3389/fendo.2021.718942
13. Onken, B., Driscoll, M., 2010. Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1. PLoS ONE 5, e8758. https://doi.org/10.1371/journal.pone.0008758
14. Prattichizzo, F., La Sala, L., Rydén, L., Marx, N., Ferrini, M., Valensi, P., Ceriello, A., 2019. Glucose-lowering therapies in patients with type 2 diabetes and cardiovascular diseases. Eur. J. Prev. Cardiol. 26, 73–80. https://doi.org/10.1177/2047487319880040
15. Romero, R., Erez, O., Hüttemann, M., Maymon, E., Panaitescu, B., Conde-Agudelo, A., Pacora, P., Yoon, B.H., Grossman, L.I., 2017a. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am. J. Obstet. Gynecol. 217, 282–302. https://doi.org/10.1016/j.ajog.2017.06.003
16. Romero, R., Erez, O., Hüttemann, M., Maymon, E., Panaitescu, B., Conde-Agudelo, A., Pacora, P., Yoon, B.H., Grossman, L.I., 2017b. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am. J. Obstet. Gynecol. 217, 282–302. https://doi.org/10.1016/j.ajog.2017.06.003
17. Rorsman, P., Ashcroft, F.M., 2018. Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men. Physiol. Rev. 98, 117–214. https://doi.org/10.1152/physrev.00008.2017
18. Seshiah, V., Balaji, V., Madhuri, B., 2011. Gestational Diabetes Mellitus - A Perspective, in: Radenkovic, M. (Ed.), Gestational Diabetes. InTech. https://doi.org/10.5772/20770
19. Shield, J.P.H., Temple, I.K., 2002. Neonatal diabetes mellitus: Neonatal diabetes mellitus. Pediatr. Diabetes 3, 109–112. https://doi.org/10.1034/j.1399-5448.2002.30208.x
20. Song, A., Zhang, C., Meng, X., 2021. Mechanism and application of metformin in kidney diseases: An update. Biomed. Pharmacother. 138, 111454. https://doi.org/10.1016/j.biopha.2021.111454
21. Thomas, I., Gregg, B., 2017. Metformin; a review of its history and future: from lilac to longevity: THOMAS AND GREGG. Pediatr. Diabetes 18, 10–16. https://doi.org/10.1111/pedi.12473
22. Witters, L.A., 2001. The blooming of the French lilac. J. Clin. Invest. 108, 1105–1107. https://doi.org/10.1172/JCI14178
23. Wu, L., Zhu, J., Prokop, L.J., Murad, M.H., 2015. Pharmacologic Therapy of Diabetes and Overall Cancer Risk and Mortality: A Meta-Analysis of 265 Studies. Sci. Rep. 5, 10147. https://doi.org/10.1038/srep10147