Diabetes mellitus (DM) causes debilitating and devastating complications, including these of the lower urinary tract (LUT), such as urinary incontinence. Women with DM have a higher prevalence of LUT complications, contributing to the high prevalence of urinary incontinence (30-60%) among adult women in the US. In addition, women are at increased risk of later development of stress urinary incontinence due to pelvic floor injuries sustained during vaginal delivery of children. Vaginal delivery causes ischemic injury to tissues of the pelvic floor, including muscle, fascia, and nerves. The pudendal nerve, which innervates the external urethral sphincter and contributes to urinary continence, is particularly vulnerable to ischemia, crush, and stretch during delivery. Type I DM affects women at or before their childbearing years and increases their risk of incontinence after vaginal delivery. However, the mechanistic relationship between DM and urinary incontinence is poorly understood. ? In pursuit of their common interests, the Principal Investigator, Dr. Damaser, and the co-Investigator, Dr. Daneshgari, have jointly developed a theory that the accumulation of advanced glycosylation end products (AGEs) from prolonged hyperglycemia induces intracellular oxidative stress, limiting the ability of LUT muscles and associated nerves to recover from the injuries sustained during vaginal delivery, particularly pudendal nerve injury. This could provide the mechanism for the relationship between DM and urinary incontinence. Following this dialogue and in response to PA- 03-136, we have designed and proposed this R21 exploratory research grant to develop a unique animal model and obtain feasibility and preliminary data for a future RO1 application. This application is fully responsive to PA-03-136 since it proposes development of an animal model addressing both bladder complications of diabetes and gender differences in development of incontinence, a LUT disorder. In addition, it would promote a productive research collaboration for the study of the LUT between a clinician (Dr. Daneshgari) and a basic scientist (Dr. Damaser). ? The Hypothesis of this project is that the response of diabetics to pudendal nerve injury involves 1) a decreased neuroregenerative response and 2) increased duration and severity of incontinence symptoms, both of which are temporally associated with an accumulation of advanced glycated endproducts. We will test this hypothesis with 2 specific aims: ? SAI. Determine if pudendal nerve crush in diabetic animals results in: a. decreased pudendal nerve regeneration and b. increased duration and severity of urinary incontinence symptoms. ? SAII Determine if these altered responses in diabetic animals are temporally associated with increased acumulation of AGEs. ? Techniques to be utilized include cystometry, leak point pressure testing, morphometry, light and electron microscopy, and in situ hybridization of ?II tubulin mRNA, mass spectrometry, immunohistochemistry and ELISA. ? The data from this R21 exploratory research grant will be used to propose a RO1 research grant to explore the mechanism of the observed effects. Our long term goals for this project include using this novel animal model to study the mechanism of urinary incontinence in women with DM, to develop & test novel mechanism-based pharmacologic agents, and to develop & test techniques and strategies which could be used to prevent and/or treat incontinence in women with DM. ? ?
| Pan, Hui Q; Lin, Dan L; Strauch, Christopher et al. (2010) Pudendal nerve injury reduces urethral outlet resistance in diabetic rats. Am J Physiol Renal Physiol 299:F1443-50 |
| Hijaz, Adonis; Daneshgari, Firouz; Sievert, Karl-Dietrich et al. (2008) Animal models of female stress urinary incontinence. J Urol 179:2103-10 |
| Kim, Ja-Hong; Huang, Xiao; Liu, Guiming et al. (2007) Diabetes slows the recovery from urinary incontinence due to simulated childbirth in female rats. Am J Physiol Regul Integr Comp Physiol 293:R950-5 |
