Metformin Inhibits Glutaminase Activity and Protects against Hepatic Encephalopathy 英文参考文献.docVIP

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Metformin Inhibits Glutaminase Activity and Protects against Hepatic Encephalopathy 英文参考文献.doc

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Metformin Inhibits Glutaminase Activity and Protects against Hepatic Encephalopathy 英文参考文献

MetforminInhibitsGlutaminaseActivityandProtects againstHepaticEncephalopathy JavierAmpuero1,IsidoraRanchal1,DavidNun?ez1,Mar?′adelMarD?′az-Herrero2,MartaMaraver1,Jose′ AntoniodelCampo1,Angela′ Rojas1,Ine′sCamacho1,BlancaFigueruela1,JuanD.Bautista2, ManuelRomero-Go′mez1* 1Unit for Clinical Management of Digestive Diseases and CIBERehd, Hospital Universitario de Valme, University of Sevilla, Sevilla, Spain, 2Department of Molecular Biology,UniversityofSevilla,Sevilla,Spain Abstract Aim: To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohortofdiabeticcirrhoticpatients.Toanalyzetheimpactofmetforminonglutaminaseactivityandammoniaproduction invitro. Methods: Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were classified as insulin sensitizersexperienced(metformin)and41ascontrols(cirrhoticpatientswithtype2diabetesmellituswithoutmetformin treatment). Baseline analysis included: insulin, glucose, glucagon, leptin, adiponectin, TNFr2, AST, ALT. HOMA-IR was calculated. Baseline HE risk was calculated according to minimal hepatic encephalopathy, oral glutamine challenge and mutationsinglutaminasegene.Weperformedanexperimentalstudyinvitroincludinganenzymaticactivityassaywhere glutaminaseinhibitionwasmeasuredaccordingtodifferentmetforminconcentrations.InCaco2cells,glutaminaseactivity inhibitionwasevaluatedbyammoniaproductionat24,48and72hoursaftermetforminatreatment. Results: Hepatic encephalopathy was diagnosed during follow-up in 23.2% (19/82): 4.9% (2/41) in patients receiving metformin and 41.5% (17/41) in patients without metformin treatment (logRank 9.81; p=0.002). In multivariate analysis, metforminuse[H.R.11.4(95%CI:1.2–108.8);p=0.034],ageatdiagnosis[H.R.1.12(95%CI:1.04–1.2);p=0.002],femalesex [H.R.10.4 (95% CI: 1.5–71.6); p=0.017] and HE risk [H.R.21.3 (95% CI: 2.8–163.4); p=0.003] were found independently associated with hepatic encephalopathy. In the enzymatic