Smooth Muscle Insulin Receptor Deletion Causes Voiding Dysfunction: A Mechanism for Diabetic Bladder Dysfunction

Abstract

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.

Time-dependent progress of lower urinary tract dysfunction in streptozotocin-induced diabetic rats with or without low-dose insulin treatment

“…Based on the above findings, the use of sustained-release low-dose insulin injections can create a relatively stable model of DM-induced LUTD. Moreover, low-dose insulin demonstrates a certain protective effect against lower urinary tract dysfunction, potentially mediated through its interaction with insulin receptors in the lower urinary tract 20 . However, it is important to note that low-dose insulin cannot fully reverse the damage caused by diabetes.…”

Deletion of Nrf2 induced severe oxidative stress and apoptosis in mice model of diabetic bladder dysfunction

“…As the most common complication of DM, DBD presents many symptoms such as overactive bladder, bladder emptying disorder and urinary retention, which seriously affects patients' quality of life [13]. In the study, the mechanism of Nrf2 in the pathogenesis of DBD is further explored by establishing T2DM mice model and Nrf2 gene knockout mouse with T2DM.…”

A Spectrum of Age- and Gender-Dependent Lower Urinary Tract Phenotypes in Three Mouse Models of Type 2 Diabetes

“…When methylglyoxal—a reactive by-product of glycolysis found at high levels in diabetic plasma—was administered to healthy mice for four weeks, an overactive bladder phenotype was observed in the complete absence of hyperglycemia [ 51 ]. Furthermore, an intriguing recent study from Chen et al [ 52 ] proposed a novel theory on the etiology of DVD. Using a smooth muscle-specific insulin receptor knockout mouse, they showed that voiding phenotypes resembling DVD could be induced despite the mutation having no effect on blood glucose levels.…”