Diabetic bladder dysfunction (DBD) is the most common complication in diabetes mellitus (DM). Myogenic abnormalities are common in DBD, however, the underlying mechanisms leading to these remains unclear. To understand the importance of smooth muscle insulin receptor (IR)-mediated signaling in the pathogenesis of DBD, we conditionally deleted it to achieve either heterozygous (SMIR+/−) or homozygous (SMIR−/−) deletion in smooth muscle cells. Despite impaired glucose and insulin tolerance seen with SMIR−/− mice, both SMIR+/− and SMIR−/− mice exhibited normal blood glucose and plasma insulin levels. Interestingly, these mice had abnormal voiding phenotypes, that included urinary frequency and small voids, and bladder smooth muscle (BSM) had significantly diminished contraction force. Morphology revealed a dilated bladder with thinner BSM layer, and BSM bundles were disorganized with penetrating interstitial tissue. Deletion of IR elevated FoxO and decreased mTOR protein expression, which further decreased the expression of Chrm3, P2x1, Sm22, and Cav1.2, crucial functional proteins for BSM contraction. Furthermore, we determined the expression of adiponectin in BSM, and deletion of IR in BSM inhibited adiponectin-mediated signaling. In summary, disruption of IR-mediated signaling in BSM caused abnormalities in proliferation and differentiation, leading to diminished BSM contractility and a voiding dysfunction phenotype that recapitulates human DBD.

中文翻译：

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平滑肌胰岛素受体缺失导致排尿功能障碍：糖尿病膀胱功能障碍的机制

糖尿病膀胱功能障碍（DBD）是糖尿病（DM）最常见的并发症。肌源性异常在 DBD 中很常见，然而，导致这些异常的潜在机制仍不清楚。为了了解平滑肌胰岛素受体 (IR) 介导的信号在 DBD 发病机制中的重要性，我们有条件地删除它，以在平滑肌细胞中实现杂合 (SMIR+/-) 或纯合 (SMIR−/−) 删除。尽管 SMIR−/− 小鼠的葡萄糖和胰岛素耐受性受损，但 SMIR+/- 和 SMIR−/− 小鼠均表现出正常的血糖和血浆胰岛素水平。有趣的是，这些小鼠具有异常的排尿表型，包括尿频和小排尿，并且膀胱平滑肌（BSM）的收缩力显着减弱。形态学显示膀胱扩张，BSM 层较薄，BSM 束杂乱，有穿透性间质组织。IR 的缺失会升高 FoxO 并降低 mTOR 蛋白的表达，从而进一步降低 Chrm3、P2x1、Sm22 和 Cav1.2（BSM 收缩的关键功能蛋白）的表达。此外，我们确定了 BSM 中脂联素的表达，BSM 中 IR 的缺失抑制了脂联素介导的信号传导。总之，BSM 中 IR 介导的信号传导的破坏导致增殖和分化异常，导致 BSM 收缩性减弱和排尿功能障碍表型，再现了人类 DBD。