Diabetes：抑制TNF-alpha改善糖尿病膀胱功能障碍

糖尿病膀胱功能障碍（DBD）是常见的糖尿病并发症状之一，8％的糖尿病患者都会出现膀胱功能性障碍。然而， DBD相关的分子发病机制仍然悬而未决，其最主要的原因就是缺乏合适的动物模型来开展相关。

最新研究阐述了肝特异性胰岛素受体底物1和2双敲除小鼠模型中DBD的发病机理，肝特异性胰岛素受体底物1和2敲除的老鼠容易得2型糖尿病。肝特异性胰岛素受体底物1和2敲除的老鼠膀胱逼尿肌早期阶段的表现为：在膀胱充盈时收缩频率增加，排尿量减少。

相比之下，患有糖尿病的老年老鼠逼尿肌活性较低，其症状与临床糖尿病患者特点相一致。在肝特异性胰岛素受体底物1和2敲除的老鼠中，肿瘤坏死因子（TNF）家族的基因被上调。尤其是血清和膀胱平滑肌组织中，肿瘤坏死因子-α的水平明显升高。

体外实验中，肿瘤坏死因子-α通过上调Rho激酶活性和磷酸化肌球蛋白促进原代培养膀胱平滑肌细胞的收缩。给予肝特异性胰岛素受体底物1和2敲除的老鼠可溶性肿瘤坏死因子受体1（TNFRI）全身治疗后可抑制Rho信号的上调，逆转膀胱功能障碍，但同时不会影响血糖升高。

TNFRI与降糖剂二甲双胍联合后可提高二甲双胍单用治疗糖尿病膀胱功能障碍的功效，提示针对肿瘤坏死因子-α可能有逆转2型糖尿病继发的泌尿系统并发症的功效。

编译自：Inhibition of TNF-alpha Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes

doi:10.2337/db11-1763
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Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes.

Wang Z, Cheng Z, Cristofaro V, Li J, Xiao X, Gomez P, Ge R, Gong E, Strle K, Sullivan MP, Adam RM, White MF, Olumi AF.

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-α was upregulated in serum and in bladder smooth muscle tissue. TNF-α 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-α may have utility in reversing the secondary urologic complications of type 2 diabetes.