Metformin: Is it a drug for all reasons and diseases?

Triggle, Chris R.; Mohammed, Ibrahim; Bshesh, Khalifa; Marei, Isra; Ye, Kevin; Ding, Hong; MacDonald, Ross; Hollenberg, Morley D.; Hill, Michael A.

doi:10.1016/j.metabol.2022.155223

Cited by 102 publications

(52 citation statements)

References 463 publications

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“…Simultaneously, we evaluated the utility of several insulin-sensitizing oral agents with anti-cancer activity that returns MDR cells to treatment-sensitive states [ 7 , 8 , 10 ]. Metformin, a drug used to treat type 2 diabetes globally, as well as a number of other diseases [ 11 ], can slow the growth of multiple human cancer cells in vitro [ 12 ]. Molecular events impacted by metformin include AMPK activation and TOR inhibition [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple Drug Resistant Lymphoma

Arnason

MacDonald-Dickinson²,

Gaunt³

et al. 2022

Cancers

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Like humans, canine lymphomas are treated by chemotherapy cocktails and frequently develop multiple drug resistance (MDR). Their shortened clinical timelines and tumor accessibility make canines excellent models to study MDR mechanisms. Insulin-sensitizers have been shown to reduce the incidence of cancer in humans prescribed them, and we previously demonstrated that they also reverse and delay MDR development in vitro. Here, we treated canines with MDR lymphoma with metformin to assess clinical and tumoral responses, including changes in MDR biomarkers, and used mRNA microarrays to determine differential gene expression. Metformin reduced MDR protein markers in all canines in the study. Microarrays performed on mRNAs gathered through longitudinal tumor sampling identified a 290 gene set that was enriched in Anaphase Promoting Complex (APC) substrates and additional mRNAs associated with slowed mitotic progression in MDR samples compared to skin controls. mRNAs from a canine that went into remission showed that APC substrate mRNAs were decreased, indicating that the APC was activated during remission. In vitro validation using canine lymphoma cells selected for resistance to chemotherapeutic drugs confirmed that APC activation restored MDR chemosensitivity, and that APC activity was reduced in MDR cells. This supports the idea that rapidly pushing MDR cells that harbor high loads of chromosome instability through mitosis, by activating the APC, contributes to improved survival and disease-free duration.

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Section: Introductionmentioning

confidence: 99%

Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple Drug Resistant Lymphoma

Arnason

MacDonald-Dickinson²,

Gaunt³

et al. 2022

Cancers

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“…This expression pattern could be used for the identification and differentiation between subpopulations of EPCs. We refer the reader to these reviews on the detailed differences between these subtypes and their therapeutic potential in many settings including diabetes ( Medina et al, 2010b ; Yoder, 2012 ; Pelliccia et al, 2022a ; Triggle et al, 2022a ).…”

Section: Introductionmentioning

confidence: 99%

Biofunctionalization of cardiovascular stents to induce endothelialization: Implications for in- stent thrombosis in diabetes

2022

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Stent thrombosis remains one of the main causes that lead to vascular stent failure in patients undergoing percutaneous coronary intervention (PCI). Type 2 diabetes mellitus is accompanied by endothelial dysfunction and platelet hyperactivity and is associated with suboptimal outcomes following PCI, and an increase in the incidence of late stent thrombosis. Evidence suggests that late stent thrombosis is caused by the delayed and impaired endothelialization of the lumen of the stent. The endothelium has a key role in modulating inflammation and thrombosis and maintaining homeostasis, thus restoring a functional endothelial cell layer is an important target for the prevention of stent thrombosis. Modifications using specific molecules to induce endothelial cell adhesion, proliferation and function can improve stents endothelialization and prevent thrombosis. Blood endothelial progenitor cells (EPCs) represent a potential cell source for the in situ-endothelialization of vascular conduits and stents. We aim in this review to summarize the main biofunctionalization strategies to induce the in-situ endothelialization of coronary artery stents using circulating endothelial stem cells.

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“…The therapeutic indications for metformin prescription may therefore be expanding, resulting in even more widespread use. However, as stated in a recent review by Triggle et al (10) metformin may act as an endocrine disrupter through multiple sites of actions and signaling pathways, and this uncertainty may offset the expansion use of metformin.…”

Section: Introductionmentioning

confidence: 99%

“…However, metformin is used in pregnant women with T2DM, and benefits on the maternal glycaemic level and neonatal adiposity are demonstrated ( 9 ). In addition, there is an increase in experimental studies investigating whether metformin can be used in different diseases and conditions including endometriosis ( 10 ). The therapeutic indications for metformin prescription may therefore be expanding, resulting in even more widespread use.…”

Section: Introductionmentioning

confidence: 99%

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Hypothesis: Metformin is a potential reproductive toxicant

et al. 2022

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Metformin is the first-line oral treatment for type 2 diabetes mellitus and is prescribed to more than 150 million people worldwide. Metformin’s effect as a glucose-lowering drug is well documented but the precise mechanism of action is unknown. A recent finding of an association between paternal metformin treatment and increased numbers of genital birth defects in sons and a tendency towards a skewed secondary sex ratio with less male offspring prompted us to focus on other evidence of reproductive side effects of this drug. Metformin in humans is documented to reduce the circulating level of testosterone in both men and women. In experimental animal models, metformin exposure in utero induced sex-specific reproductive changes in adult rat male offspring with reduced fertility manifested as a 30% decrease in litter size and metformin exposure to fish, induced intersex documented in testicular tissue. Metformin is excreted unchanged into urine and feces and is present in wastewater and even in the effluent of wastewater treatment plants from where it spreads to rivers, lakes, and drinking water. It is documented to be present in numerous freshwater samples throughout the world – and even in drinking water. We here present the hypothesis that metformin needs to be considered a potential reproductive toxicant for humans, and probably also for wildlife. There is an urgent need for studies exploring the association between metformin exposure and reproductive outcomes in humans, experimental animals, and aquatic wildlife.

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Metformin: Is it a drug for all reasons and diseases?

Cited by 102 publications

References 463 publications

Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple Drug Resistant Lymphoma

Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple Drug Resistant Lymphoma

Biofunctionalization of cardiovascular stents to induce endothelialization: Implications for in- stent thrombosis in diabetes

Hypothesis: Metformin is a potential reproductive toxicant

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