Pleiotropic effects of metformin: Shaping the microbiome to manage type 2 diabetes and postpone ageing

Prattichizzo, Francesco; Giuliani, Angelica; Mensà, Emanuela; Sabbatinelli, Jacopo; Nigris, Valeria De; Rippo, Maria Rita; Sala, Lucia La; Procopio, Antonio Domenico; Olivieri, Fabiola; Ceriello, Antonio

doi:10.1016/j.arr.2018.10.003

Cited by 90 publications

(78 citation statements)

References 187 publications

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confidence: 99%

“…Depending on patient prolife and various disease conditions or stages, metformin treatment-associated beneficial effects in the treatment of hepatic diseases [22][23][24][25], renal damage and disorders [26], neurodegenerative diseases [27][28][29], and bone disorders [30] were reported. In addition, metformin treatment-related antiaging effects, delay in the onset of age-related disorders, and improvement in longevity (lifespan) were reported in C. elegans, insects, and rodents [31][32][33][34].Interest has grown in studying the possible use of metformin as an anti-cancer/anti-tumor agent individually or in combination with frequently used chemotherapeutic agents and/or radiation. Epidemiological studies and meta-analysis data suggest that diabetic individuals on a metformin treatment regimen, to control their blood glucose levels, have a lower risk of developing cancers of all types and additionally individuals who are both diabetic and suffering from cancer and on metformin treatment have an improved response to chemotherapy and radiation therapy, better prognosis, and higher survival rates when compared to those who do not take metformin [5,[35][36][37][38][39][40][41][42].…”

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Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

et al. 2019

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Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer.

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Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

et al. 2019

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“…Here we find metformin, a drug that has been reported to be useful in modulating some of the age-related features. In fact, in cellular and animal models, metformin has been shown to influence and to hold beneficial effects on the following age related hallmarks [91]: (1) genomic instability [92,93], (2) telomere attrition [94], (3) epigenetic changes [95], (4) proteostasis [96,97], (5) nutrient-sensing pathways [98,99], (6) mitochondrial function [100], (7) cellular senescence [101,102], (8) stem cell function [103], and (9) low-grade inflammation [104].…”

Section: Mechanisms Involved In Ageingmentioning

confidence: 99%

“…Metformin holds an insulin-sensitising action and insulin-induced suppression of endogenous glucose production [119]. Although other organs have been discussed as a target for metformin, such as the gut [120], liver remains the main ground of action, as reduced hepatic uptake of metformin prevents the lowering blood glucose effect [91]. There are several mechanisms by which metformin downregulates gluconeogenesis.…”

Section: Mechanisms Of Metformin Action: a Focus On Molecular Pathwaymentioning

confidence: 99%

“…by decreasing cellular respiration through inhibition of the complex I mitochondrial respiratory chain [121,122]. The result of this inhibition is the increase of the ADP:ATP and AMP:ATP ratios, which subsequently activate the cellular energy state sensor AMP-activated protein kinase (AMPK) [91,110,123], the key player of metformin. Once activated, AMPK leads to an increase in ATP production and a decrease in ATP consumption [42].…”

Section: Mechanisms Of Metformin Action: a Focus On Molecular Pathwaymentioning

confidence: 99%

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Metformin Modulates the Mechanisms of Ageing

Cătoi¹,

Andreicuț²,

Vodnar³

et al. 2019

Metformin [Working Title]

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Living in a time when population is continuously ageing, the challenge and demand for assessing the age-related pathways, potential diseases and longevity have become of major interest. The pharmaceutical industry possesses huge resources in this field, mainly due to the recent discoveries of novel mechanisms of action of oldestablished, classical drugs. Here we find metformin, a well-established antidiabetic medicine but with new potential benefits, as the most recent reports quote. We present the main pathways of the possible implications of metformin in the modulation of ageing processes, evolution and diseases, focussing on its ageing counteraction, based on the latest scientifically based biochemical reports.

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Association of Metformin Use With Age-Related Macular Degeneration

et al. 2021

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IMPORTANCE Age-related macular degeneration (AMD), the leading cause of irreversible blindness in older adults, appears to have no effective preventive measures. The common antidiabetic drug metformin has been shown to have protective outcomes in multiple age-associated diseases and may have the potential to protect against the development of AMD.OBJECTIVE To determine whether metformin use is associated with reduced odds of developing AMD. DESIGN, SETTING, AND PARTICIPANTSThis case-control study of patients from a nationwide health insurance claims database included a population-based sample of patients. Those aged 55 years and older with newly diagnosed AMD from January 2008 to December 2017 were defined as cases and matched with control participants. Data analyses were completed from June 2019 to February 2020.EXPOSURES Dosage of metformin and exposure to other prescribed medications, as identified from outpatient drug claims. MAIN OUTCOMES AND MEASURES Risk of developing AMD.RESULTS A total of 312 404 affected individuals were included (181 817 women [58.2%]). After matching, 312 376 control participants were included (172 459 women [55.2%]; age range, 55 to 107 years). The case group had a slightly higher percentage of participants with diabetes (81 262 participants [26.0%]) compared with the control group (79 497 participants [25.5%]). Metformin use was associated with reduced odds of developing AMD (odds ratio [OR], 0.94 [95% CI, 0.92-0.96]). This association was dose dependent, with low to moderate doses of metformin showing the greatest potential benefit (dosages over 2 years: 1-270 g, OR, 0.91 [95% CI, 0.88-0.94]; 271-600 g, OR, 0.90 [95% CI, 0.87-0.93]; 601-1080 g, OR, 0.95 [95% CI, 0.92-0.98]). Doses of more than 1080 g of metformin over 2 years did not have reduced odds of developing AMD. Both the reduction in odds ratio and the dose-dependent response were preserved in a cohort consisting only of patients with diabetes. Metformin use was associated with a decreased OR of AMD in patients with diabetes without coexisting diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]) but was a risk factor in patients with diabetic retinopathy (OR, 1.07 [95% CI,).CONCLUSION AND RELEVANCE In this study, metformin use was associated with reduced odds of developing AMD. This association was dose dependent, with the greatest benefit at low to moderate doses. When looking only at patients with diabetes, we saw a preservation of the dose-dependent decrease in the odds of patients developing AMD. Metformin does not appear to be protective in patients with diabetes and coexisting diabetic retinopathy. This study suggests that metformin may be useful as a preventive therapy for AMD and provides the basis for potential prospective clinical trials.

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Pleiotropic effects of metformin: Shaping the microbiome to manage type 2 diabetes and postpone ageing

Cited by 90 publications

References 187 publications

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

Metformin Modulates the Mechanisms of Ageing

Association of Metformin Use With Age-Related Macular Degeneration

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