{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T03:41:00Z","timestamp":1783654860255,"version":"3.55.0"},"reference-count":40,"publisher":"American Diabetes Association","issue":"8","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":3331,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:sec>\n                  <jats:title\/>\n                  <jats:p>Diabetic bladder dysfunction (DBD) is common and affects 80% of diabetic patients. However, the molecular mechanisms underlying DBD remain elusive because of a lack of appropriate animal models. We demonstrate DBD in a mouse model that harbors hepatic-specific insulin receptor substrate 1 and 2 deletions (double knockout [DKO]), which develops type 2 diabetes. Bladders of DKO animals exhibited detrusor overactivity at an early stage: increased frequency of nonvoiding contractions during bladder filling, decreased voided volume, and dispersed urine spot patterns. In contrast, older animals with diabetes exhibited detrusor hypoactivity, findings consistent with clinical features of diabetes in humans. The tumor necrosis factor (TNF) superfamily genes were upregulated in DKO bladders. In particular, TNF-\u03b1 was upregulated in serum and in bladder smooth muscle tissue. TNF-\u03b1 augmented the contraction of primary cultured bladder smooth muscle cells through upregulating Rho kinase activity and phosphorylating myosin light chain. Systemic treatment of DKO animals with soluble TNF receptor 1 (TNFRI) prevented upregulation of Rho A signaling and reversed the bladder dysfunction, without affecting hyperglycemia. TNFRI combined with the antidiabetic agent, metformin, improved DBD beyond that achieved with metformin alone, suggesting that therapies targeting TNF-\u03b1 may have utility in reversing the secondary urologic complications of type 2 diabetes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db11-1763","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T05:59:02Z","timestamp":1339480742000},"page":"2134-2145","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":66,"title":["Inhibition of TNF-\u03b1 Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes"],"prefix":"10.2337","volume":"61","author":[{"given":"Zongwei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Howard Hughes Medical Institute, Children\u2019s Hospital Boston, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Cristofaro","sequence":"additional","affiliation":[{"name":"Urology Research, Veterans Administration Boston Healthcare System, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jijun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts"},{"name":"Department of Integrative Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyuan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts"},{"name":"Department of Urology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Gomez","sequence":"additional","affiliation":[{"name":"Urology Research Center, Children\u2019s Hospital Boston, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongbin","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Gong","sequence":"additional","affiliation":[{"name":"Urology Research Center, Children\u2019s Hospital Boston, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klemen","family":"Strle","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Allergy\/Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryrose P.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Urology Research, Veterans Administration Boston Healthcare System, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalyn M.","family":"Adam","sequence":"additional","affiliation":[{"name":"Urology Research Center, Children\u2019s Hospital Boston, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morris F.","family":"White","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Howard Hughes Medical Institute, Children\u2019s Hospital Boston, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aria F.","family":"Olumi","sequence":"additional","affiliation":[{"name":"Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2012,7,17]]},"reference":[{"key":"2022031223075446100_B1","unstructured":"Centers for Disease Control and Prevention. 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