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。概述与II型糖尿病相关的ED机制的基础科学研究非常有限。鉴于II型糖尿病及其并发症的日益流行，以及药物疗法(主要是磷酸二酯酶V抑制剂)在这一人群中的疗效不足(&lt；50%)，在这一领域进行进一步研究的必要性显而易见。虽然高血糖是糖尿病的共同特征，但与肥胖和与II型糖尿病相关的血脂异常相关的其他因素可能有助于该队列中的ED的机制。脂联素是一种脂肪产生的细胞因子，对胰岛素增敏很重要，在肥胖症和II型糖尿病患者中减少。最近的研究表明，脂联素具有血管保护作用，增加了强大的血管扩张剂一氧化氮(NO)的生物利用度。本研究的总体假设是，II型糖尿病患者脂联素降低有助于改变海绵体血管反应性和勃起功能，并将进行以下特定目标的测试：1)通过测试下列假设来表征II型糖尿病(db/db)小鼠的勃起功能：a.与对照组相比，db/db小鼠对海绵体神经的电刺激具有更低的海绵体内压。从db/db小鼠分离的海绵体组织，与对照组相比，在体外表现出内皮依赖性的松弛减弱和激动剂诱导的收缩增强。C.db/db小鼠的海绵体组织显示eNOS介导的超氧化物歧化酶的生成增加而no.2)通过检验以下假设来确定脂联素的恢复是否增强了II型糖尿病(db/db)小鼠的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改善了体内的勃起功能。B.从db/db小鼠分离的脂联素腺病毒感染的海绵体组织表现出增强的内皮依赖性的扩张，并且在体外没有生物利用度。从拟议的实验中获得的知识可能会增加对II型糖尿病勃起功能障碍的潜在机制的了解，并有助于开发更有效的治疗方法来预防勃起功能障碍或在这一快速增长的人口中恢复勃起功能。

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.