{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T14:24:19Z","timestamp":1784816659625,"version":"3.55.0"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,1,9]],"date-time":"2014-01-09T00:00:00Z","timestamp":1389225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Diabetes"],"published-print":{"date-parts":[[2014,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Metformin is a first\u2010line antidiabetic drug for type 2 diabetes (<jats:styled-content style=\"fixed-case\">T2D<\/jats:styled-content>) with a relatively good safety profile. Metformin activates <jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content>\u2010activated protein kinase (<jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>), which is crucial in maintaining renal medullary function, with inappropriate <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> activation facilitating renal medullary interstitial cells (<jats:styled-content style=\"fixed-case\">RMIC<\/jats:styled-content>s) apoptosis under hypertonic challenge. The present study was to determine the effects of metformin on <jats:styled-content style=\"fixed-case\">RMIC<\/jats:styled-content> survival in both normal and <jats:styled-content style=\"fixed-case\">T2D<\/jats:styled-content> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mice (<jats:styled-content style=\"fixed-case\">C57BL<\/jats:styled-content>\/6, <jats:italic>db\/m<\/jats:italic>, and <jats:italic>db\/db<\/jats:italic>) were treated with 450\u2009mg\/kg metformin for 7 days and subjected to 24\u2010h water restriction (=dehydration) before being killed. Cell apoptosis in the renal medulla was determined by the terminal deoxyribonucleotidyl transferase\u2010mediated <jats:styled-content style=\"fixed-case\">dUTP<\/jats:styled-content>\u2013digoxigenin nick end\u2010labeling (<jats:styled-content style=\"fixed-case\">TUNEL<\/jats:styled-content>) assay. Cultured <jats:styled-content style=\"fixed-case\">RMIC<\/jats:styled-content> were treated with 10\u2009mmol\/L metformin in the presence or absence of hypertonic stress. Cell viability was determined and the underlying mechanisms were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Metformin induced significant apoptosis of <jats:styled-content style=\"fixed-case\">RMIC<\/jats:styled-content> in dehydrated normal mice and both hydrated and dehydrated <jats:styled-content style=\"fixed-case\">T2D<\/jats:styled-content> mice. Hypertonicity increased <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content> production and inhibited <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> phosphorylation in <jats:styled-content style=\"fixed-case\">RMIC<\/jats:styled-content>, which was attenuated by metformin. Metformin augmented hypertonicity\u2010induced apoptosis of <jats:styled-content style=\"fixed-case\">RMIC<\/jats:styled-content>, suppressed the nuclear factor\u2010\u03ba<jats:styled-content style=\"fixed-case\">B<\/jats:styled-content>\/cyclo\u2010oxygenase\u20102 pathway, reduced reactive oxygen species production and inhibited transcriptional activation of tonicity\u2010responsive enhancer binding protein (<jats:styled-content style=\"fixed-case\">TonEBP<\/jats:styled-content>) and its downstream osmoprotective gene expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Metformin treatment is associated with increased <jats:styled-content style=\"fixed-case\">RMIC<\/jats:styled-content> apoptosis in both normally hydrated and dehydrated <jats:styled-content style=\"fixed-case\">T2D<\/jats:styled-content> mice. The results confirm <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content> as a critical factor involved in the maintenance of <jats:styled-content style=\"fixed-case\">RMIC<\/jats:styled-content> viability in <jats:styled-content style=\"fixed-case\">T2D<\/jats:styled-content> and raise safety concerns for metformin and other <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\u2010activating antidiabetic drugs in dehydrated diabetic patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1753-0407.12105","type":"journal-article","created":{"date-parts":[[2013,10,31]],"date-time":"2013-10-31T11:11:50Z","timestamp":1383217910000},"page":"132-146","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Metformin induces renal medullary interstitial cell apoptosis in type 2 diabetic mice 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Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizheng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology Key Laboratory of Cardiovascular Science of the Ministry of Education Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology Key Laboratory of Cardiovascular Science of the Ministry of Education Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology Key Laboratory of Cardiovascular Science of the Ministry of Education Peking University Health Science Center  Beijing 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