500 COMBINATION OF METFORMIN AND INHIBITION OF TNF-A REVERSE THE BLADDER DYSFUNCTION ASSOCIATED WITH TYPE 2 DIABETES

Abstract

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology II1 Apr 2012500 COMBINATION OF METFORMIN AND INHIBITION OF TNF-A REVERSE THE BLADDER DYSFUNCTION ASSOCIATED WITH TYPE 2 DIABETES Zongwei Wang, Zhiyong Cheng, Vivian Cristofaro, Pablo Gomez, Maryrose Sullivan, Rosalyn Adam, Morris White, and Aria Olumi Zongwei WangZongwei Wang Boston, MA More articles by this author , Zhiyong ChengZhiyong Cheng Boston, MA More articles by this author , Vivian CristofaroVivian Cristofaro Boston, MA More articles by this author , Pablo GomezPablo Gomez Boston, MA More articles by this author , Maryrose SullivanMaryrose Sullivan Boston, MA More articles by this author , Rosalyn AdamRosalyn Adam Boston, MA More articles by this author , Morris WhiteMorris White Boston, MA More articles by this author , and Aria OlumiAria Olumi Boston, MA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.570AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Diabetic bladder dysfunction (DBD) in type 2 diabetes mellitus (DM2) affects up to 80% of individuals, but its underlying pathophysiology is poorly understood. Here we demonstrate a genetic mouse model with DM2 with hepatocyte-specific double knockout of Insulin receptor substrates 1 & 2 (DKO), which mimics the diabetic bladder dysfunction in humans. The level of TNF-α is significantly upregulated during the excitatory phase of diabetic cystopathy. METHODS Bladders from 6, 12, 16 and 20 week old DKO/control mice were harvested and functional alterations were evaluated by muscle strip experiment ex vivo, by urodynamic and Voiding Stain on Paper test in vivo. The gene expression was evaluated by microarray. The level of TNF-α in serum was measured by ELISA. Cultured rat Bladder Smooth Muscle Cell (BSMC) contraction in vitro was assayed by collagen gel retraction. The presence of macrophages, the expression of specific proteins was assessed with IHC and western blot respectively. RESULTS Bladders of DKO animals exhibited detrusor overactivity at an early stage but hypo-activity at late stage ̈C findings consistent with clinical features of diabetes in humans. TNF superfamily genes were upregulated in bladder smooth muscle tissue. TNF-α was upregulated in serum and in bladder smooth muscle tissue. TNF-α augmented the contraction of BSMC through upregulating Rho kinase activity and pMLC. Systemic treatment of DKO animals with soluble TNF receptor 1 (TNFRI) prevented upregulation of RhoA signaling and reversed the bladder dysfunction without affecting hyperglycemia. TNFRI combined with the anti-diabetic agent, metformin, improved DBD beyond that achieved with metformin alone. CONCLUSIONS Our findings demonstrate that hyperactive bladder dysfunction occurs in early/middle aged animals whereas the bladder is hypoactive in older animals. Targeted inhibition of the TNF-α pathway may have a role in treating DBD and reducing the burden of the secondary complications of DM2. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e205 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Zongwei Wang Boston, MA More articles by this author Zhiyong Cheng Boston, MA More articles by this author Vivian Cristofaro Boston, MA More articles by this author Pablo Gomez Boston, MA More articles by this author Maryrose Sullivan Boston, MA More articles by this author Rosalyn Adam Boston, MA More articles by this author Morris White Boston, MA More articles by this author Aria Olumi Boston, MA More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...