Non-Modulation Phenotype and Vascular Dysfunction in Diabetes Mellitus

描述（由申请人提供）：长期以来，血糖控制一直是减少糖尿病心血管（CV）并发症治疗的基石。然而，其他因素也有助于这些并发症：主要候选人是遗传背景。同样，在高血压（HBP）中，控制血压很重要，但不足以最大限度地减少CV并发症。遗传背景再次成为一个主要因素。数据还支持血管紧张素II（ANGII）和醛固酮（ALDO）是炎症相关和纤溶系统驱动的CV损伤的主要风险因素的概念。我们已经确定了一个特定的中间表型，包括25%的高血压（HBPive）的人口，我们称之为非调制器。非调节剂具有胰岛素抵抗、肾功能异常、与CV损伤相关的标志物水平升高以及CV损伤风险增加。非调节表型与肾素-血管紧张素醛固酮系统（RAAS）基因的特异性多态性相关。非调节剂的基本病理生理学是组织ANGII产生的失调，导致组织水平不适当地增加，特别是在平均或更高钠摄入量的存在下。我们在II型糖尿病患者中的初步结果表明，非调节表型可能存在于HBPives的两倍多的糖尿病患者中。因此，糖尿病患者CV疾病的发生率较高可能部分归因于与肾脏和CV异常增加相关的中间表型的发生率较高。因此，本提案的总体目标是检验以下假设：糖尿病中介导CV风险的激素因素的遗传基础与先前在HBP中确定的遗传基础相似，并且非调节是CV风险的重要贡献者。我们的方法将类似于HBP中使用的方法。我们将定义糖尿病患者的中间表型，确定与它们相关的遗传多态性是否与先前在HBP受试者中确定的相似，确定RAAS活性与炎症标志物和纤溶系统的相关性，并使用药物干预来确定RAAS中断是否逆转与特定中间表型相关的异常。支持这一建议的是来自1000多名正常人和HBPives的数据，他们在相同的协议上进行了研究。我们预期在II型糖尿病患者中会出现以下结果：与HBPive相比，非调节表型的频率增加，低肾素的频率降低;糖尿病患者和HBPive非调节剂的多态性相似;与RAAS活性相关的炎症标志物水平增加; ACE抑制可纠正非调节型糖尿病患者的异常，但不能纠正其他糖尿病患者的异常。

DESCRIPTION (provided by applicant): Glycemic control has long been the cornerstone of treatment to reduce diabetic cardiovascular (CV) complications. However, other factors also contribute to these complications: the leading candidate being the genetic background. Likewise, in hypertension (HBP), control of blood pressure is important, but not sufficient to maximally reduce CV complications. Again genetic background has come to the fore as a major contributor. Data also support the concept that angiotensin II (ANGII) and aldosterone (ALDO) are major risk factors for inflammation associated, and fibrinolytic system driven CV damage. We have identified a specific intermediate phenotype comprising 25% of the hypertensive (HBPive) population whom we have termed non-modulators. Non-modulators are insulin resistant, have abnormalities in renal function, elevated levels of markers associated with CV damage and an increased risk of CV damage. The non-modulating phenotype is associated with specific polymorphisms in the genes of the renin-angiotensin aldosterone system (RAAS). The fundamental pathophysiology in non-modulators is dysregulation of tissue ANGII production leading to inappropriately increased tissue levels, particularly in the presence of an average or higher sodium intake. Our preliminary results in type II diabetics suggest that the non-modulating phenotype may be present in twice as many diabetics as in HBPives. Thus, the greater frequency of CV disease in diabetes may in part be accounted for by the higher frequency of an intermediate phenotype associated with increased renal and CV abnormalities. Thus, the overall goal of this proposal is to test the hypothesis that the genetic underpinnings of hormonal factors mediating CV risk in diabetes are similar to those previously identified in HBP and that non-modulation is a substantial contributor to that CV risk. Our approach will be similar to that used in HBP. We will define intermediate phenotypes in diabetic patients, determine whether genetic polymorphisms associated with them are similar to those previously identified in HBP subjects, determine the association of activity of the RAAS and markers of inflammation and the fibrinolytic system, and use a pharmacologic intervention to determine if interruption of the RAAS reverses abnormalities associated with a specific intermediate phenotype. In support of this proposal are data from more than 1000 normals and HBPives who have been studied on identical protocols. We anticipate the following results in type II diabetics: an increased frequency of the non-modulating phenotype and lower frequency of low renin compared to HBPives; similar polymorphisms in diabetic and HBPive non-modulators; increased levels of inflammatory markers that correlate with RAAS activity; and correction of the abnormalities in the non-modulating but not other diabetics with ACE inhibition.