Erectile Dysfunction in Type II Diabetes: Role of Adiponectin

描述（由申请人提供）：II型糖尿病患者勃起功能障碍（ED）的发病率估计是非糖尿病患者的3倍。基础科学研究概述与2型糖尿病相关的ED机制非常有限。鉴于II型糖尿病及其并发症的患病率不断上升，以及该人群中药物治疗（主要是磷酸二酯酶V抑制剂）的疗效不足（<50%），该领域进一步研究的必要性是显而易见的。虽然高血糖是糖尿病的共同特征，但与2型糖尿病相关的肥胖和脂质异常相关的其他因素可能有助于本队列中ED的机制。脂联素是一种脂肪产生的细胞因子，对胰岛素致敏很重要，在肥胖和II型糖尿病患者中降低。最近的研究表明，脂联素具有血管保护作用，增加了有效的血管舒张剂一氧化氮（NO）的生物利用度。本研究的一般假设是，2型糖尿病患者脂联素的降低导致海绵体血管反应性和ED的改变，并将进行以下具体目的的测试：1)通过测试以下假设来表征2型糖尿病小鼠模型（db/db）的勃起功能：a.与对照组相比，db/db小鼠在体内对海绵体神经的电刺激有较低的海绵体内压力。b.与对照组相比，db/db小鼠的分离海绵体组织在体外表现出内皮依赖性松弛减弱和激动剂诱导的收缩增强。c. db/db小鼠海绵体组织表现出enos介导的超氧化物生成增加和NO减少。2)通过验证以下假设，确定脂联素的恢复是否能增强II型糖尿病小鼠NO的生物利用度和勃起功能：a.与空载体相比，腺病毒介导的脂联素递送能改善体内勃起功能。b.经脂联素腺病毒转染的db/db小鼠分离海绵体组织在体外表现出增强的内皮依赖性扩张和NO生物利用度。从所提出的实验中获得的知识可能会增加对II型糖尿病ED机制的理解，并有助于开发更有效的治疗方法来预防ED或恢复这一快速增长的人群的勃起功能。

DESCRIPTION (provided by applicant): Erectile dysfunction (ED) in the type II diabetic patients is estimated to be 3 times more prevalent than in non-diabetic subjects. Basic science studies outlining mechanisms involved in ED associated with type II diabetes are very limited. In light of the increasing prevalence of type II diabetes and its complications, and the insufficient efficacy (<50%) of pharmacologic therapeutics (mainly phosphodiesterase V inhibitors) in this population, the need for further research in this field is readily apparent. Although hyperglycemia is a common feature of diabetes, additional factors related to obesity and lipid abnormalities associated with type II diabetes potentially contribute to mechanisms of ED in this cohort. Adiponectin, an adipose-produced cytokine, is important for insulin sensitization, and is decreased in obesity and in type II diabetic patients. Recent studies demonstrate that adiponectin has a vasoprotective role, increasing the bioavailability of the potent vasodilator, nitric oxide (NO). The general hypothesis of this study is that decreased adiponectin in type II diabetes contributes to altered cavernosal vasoreactivity and ED, and will be tested with the following Specific Aims: 1) To characterize erectile function in a mouse model of type II diabetes (db/db) by testing the following hypotheses: a. Db/db mice have lower intracavernosal pressure in response to electrical stimulation of the cavernous nerve in vivo as compared to controls. b. Isolated cavernosal tissue from db/db mice, compared to control, exhibits attenuated endothelium-dependent relaxation and heightened agonist-induced contraction in vitro. c. Cavernosal tissue from db/db mice exhibits increased eNOS-mediated superoxide generation and decreased NO. 2) To determine if restoration of adiponectin enhances NO bioavailability and erectile function in type II diabetic (db/db) mice by testing the following hypotheses: a. Adenoviral-mediated delivery of adiponectin, as compared to empty vector, improves erectile function in vivo. b. Isolated cavernosal tissue from db/db mice transfected with adiponectin adenovirus exhibits enhanced endothelium-dependent dilation and NO bioavailability in vitro. The knowledge gained from the proposed experiments may add to the understanding of mechanisms underlying ED in type II diabetes, and contribute to the development of more efficacious therapies to prevent ED or restore erectile function in this rapidly growing population.