You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology1 Apr 2014MP17-14 CORRECTION OF HYPERGLYCEMIA AND HYPERINSULINEMIA BY GENETIC MODIFICATION RESTORES BLADDER DYSFUNCTION ASSOCIATED WITH TYPE 2 DIABETES Zongwei Wang, Vivian Cristofaro, Zhiyong Cheng, Hongying Cao, Evgeniy Kreydin, Joseph Gabrielsen, Rongbin Ge, Shulin Wu, Chao Cai, Peng Wu, Maryrose Sullivan, Morris White, and Aria Olumi Zongwei WangZongwei Wang More articles by this author , Vivian CristofaroVivian Cristofaro More articles by this author , Zhiyong ChengZhiyong Cheng More articles by this author , Hongying CaoHongying Cao More articles by this author , Evgeniy KreydinEvgeniy Kreydin More articles by this author , Joseph GabrielsenJoseph Gabrielsen More articles by this author , Rongbin GeRongbin Ge More articles by this author , Shulin WuShulin Wu More articles by this author , Chao CaiChao Cai More articles by this author , Peng WuPeng Wu More articles by this author , Maryrose SullivanMaryrose Sullivan More articles by this author , Morris WhiteMorris White More articles by this author , and Aria OlumiAria Olumi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.547AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Diabetes bladder dysfunction (DBD) is a major urologic complication associated with type 2 diabetes (DM2). In a mouse model that develops DM2 using a hepatic-specific insulin receptor substrate 1 and 2 (Irs1/Irs2) deletions (double knockout: DKO), we have shown specific molecular alterations associated with DBD. Previously, we have shown that DBD occurs progressively with hyperactivity in the early stage and hypoactivity in late stage of DBD. Here we demonstrate that correction of hyperglycemia/hyperinsulinemia with a third hepatic-specific deletion of Foxo1 gene (i.e.: IRS1/IRS2/Foxo1 triple knockout: TKO) restores the bladder dysfunction in DKO type 2 diabetic animals. METHODS Insulin and glucose levels were measured and glucose tolerance tests (GTT) were carried out in DKO, TKO and control animals at 4, 8, 12, and 20 weeks of age. Bladder functional alterations were evaluated by in vivo cystometry and voiding stain on paper (VSOP) for 12 and 20 week old mice. Bladders were harvested for ex vivo muscle strip contraction analyses. RESULTS The DKO mice developed significant insulin resistance and glucose tolerance starting from 5 weeks of age, and persisted at the age of 8, 12, and 20 weeks. TKO animals with hepatic-specific deletion of Irs1/Irs2/Foxo1 genes did not develop hyperglycemia or hyperinsulinemia. In the diabetic DKO animals, the post void residual (PVR) urine volume in in-vivo cystometry was elevated and the voiding efficiency was lowered at 12 weeks and 20 weeks in comparison to the controls. The bladder compliance and capacity of 12 week but not 20 week DKO mice was lower than age-matched controls. An abnormal voiding pattern was observed in the DKO mice as determined by VSOP analysis with lower micturition volumes, and higher frequency of small volume voids. In TKO animal, the voiding parameters were restored to normal levels equivalent to age-matched controls. CONCLUSIONS Our findings demonstrate that secondary complication of diabetes, DBD, is corrected in diabetic animals with hepatic-specific genetic modification in the TKO mice, with deletions of IRS1/IRS2 & Foxo1 genes. Our findings suggest that the DKO and TKO reversible diabetic mouse model system is a rational model to evaluate the pathophysiology and molecular alterations associated with diabetic cystopathy. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e140-e141 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Zongwei Wang More articles by this author Vivian Cristofaro More articles by this author Zhiyong Cheng More articles by this author Hongying Cao More articles by this author Evgeniy Kreydin More articles by this author Joseph Gabrielsen More articles by this author Rongbin Ge More articles by this author Shulin Wu More articles by this author Chao Cai More articles by this author Peng Wu More articles by this author Maryrose Sullivan More articles by this author Morris White More articles by this author Aria Olumi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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Dec 30, 2017
Oksana Popadynets + 9
Open Access
