{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T08:43:57Z","timestamp":1778661837270,"version":"3.51.4"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2017,8,23]],"date-time":"2017-08-23T00:00:00Z","timestamp":1503446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:sec><jats:label\/><jats:p>Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10\u2013100\u2010fold higher than the plasmatic concentration measured in patients. Here, we evaluated the biochemical, metabolic, and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines. We found that the response of wild\u2010type cells to MET is concentration dependent. Low concentrations (15 and 150\u2009\u00b5M) increase both oxidative phosphorylation and the oxidative stress response, acting on the AMPK\/Sirt1 pathway, while the high concentration (1.5\u2009mM) inhibits the respiratory chain, alters cell morphology, becoming toxic to the cells. In FA cells, MET was unable to correct the energetic\/respiratory defect and did not improve the response to oxidative stress and DNA damage. By contrast, HL60 cells appear sensitive also at 150\u2009\u03bcM. Our findings underline the importance of the MET concentration in evaluating the effect of this drug on cell metabolism and demonstrate that data obtained from in vitro experiments, that have used high concentrations of MET, cannot be readily translated into improving our understanding of the cellular effects of metformin when used in the clinical setting.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.26085","type":"journal-article","created":{"date-parts":[[2017,7,6]],"date-time":"2017-07-06T11:02:59Z","timestamp":1499338979000},"page":"1736-1751","source":"Crossref","is-referenced-by-count":28,"title":["Concentration\u2010dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells"],"prefix":"10.1002","volume":"233","author":[{"given":"Silvia","family":"Ravera","sequence":"first","affiliation":[{"name":"Department of Pharmacy Biochemistry Laboratory, University of Genova Genova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Cossu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Biochemistry Laboratory, University of Genova Genova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Tappino","sequence":"additional","affiliation":[{"name":"Centro di Diagnostica Genetica e Biochimica Delle Malattie Metaboliche Istituto Giannina Gaslini Genova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Nicchia","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences University of Trieste Trieste Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Dufour","sequence":"additional","affiliation":[{"name":"Hematology Unit Istituto Giannina Gaslini Genova Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Cavani","sequence":"additional","affiliation":[{"name":"Laboratorio di Genetica Umana E.O. 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