Metformin modulates the TXNIP-NLRP3-GSDMD pathway to improve diabetic bladder dysfunction

• Published in: Scientific reports Vol. 14; no. 1; pp. 23868 - 10
• Main Authors: Huang, Bincheng, Zhang, Jin, Tian, Haifu, Ren, Shuai, Chen, Keming, Feng, Jiajin, Fan, Shuzhe, Tuo, Yunshang, Wang, Xuehao, Yu, Leyi, Ma, Cunling, Peng, Qingjie, Chen, Xiaojiang, He, Rui, Li, Guangyong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 692/163; 692/4025; 692/420; Animals; Bladder; Carrier Proteins - metabolism; DBD; Diabetes; Diabetes Complications - drug therapy; Diabetes Complications - metabolism; Diabetes mellitus; Diet, High-Fat - adverse effects; Gasdermins; Glucose metabolism; Glucose tolerance; High fat diet; Humanities and Social Sciences; Intracellular Signaling Peptides and Proteins - metabolism; Male; Metformin; Metformin - pharmacology; Mice; Mice, Inbred C57BL; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Phosphate-Binding Proteins - metabolism; Proteins; Pyroptotic; Science; Science (multidisciplinary); Signal Transduction - drug effects; Thioredoxins - metabolism; Urinary Bladder - drug effects; Urinary Bladder - metabolism; Urinary Bladder - pathology; Urinary Bladder Diseases - drug therapy; Urinary Bladder Diseases - etiology; Urinary Bladder Diseases - metabolism; Urination; Zonula occludens-1 protein; NLRP3; Pyroptotic; DBD
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-72129-0

To validate the therapeutic efficacy of metformin on diabetic bladder dysfunction (DBD) and further elucidate whether the TXNIP-NLRP3-GSDMD axis serves as a target for metformin in ameliorating DBD. C57BL/6J mice were induced with diet-induced obesity by being fed a high-fat diet (HFD) for 16 weeks. After establishing the model, the mice were treated with metformin for 4 weeks, and their glucose metabolism-related parameters were assessed. Urine spot assays and urodynamic measurements were conducted to reflect the bladder function and urinary behavior in mice, while histological examination was performed to observe morphological changes. Western blot analysis was employed to measure the expression levels of pyroptotic factors such as TXNIP, NLRP3, GSDMD, and tight junction proteins. Metformin treatment significantly improved glucose tolerance and insulin sensitivity in mice. Moreover, it showed promise in decreasing urinary spot occurrence, reducing urination frequency, alleviating non-voiding contractions, and stabilizing peak urinary pressure. Following metformin therapy, mice displayed restored epithelial fold structure, increased thickness of the muscular layer, substantial decrease in muscle fiber content, notably reduced levels of TXNIP and GSDMD proteins in the metformin-treated group compared to the DBD group, and restored expression of tight junction proteins Zo-1, Claudin-1, and Occludin. Metformin ameliorates urothelial cells damage in DBD mice by inhibiting TXNIP generation and reducing NLRP3 and GSDMD production.