Non-Modulation Phenotype and Vascular Dysfunction in Diabetes Mellitus

描述（由申请人提供）：血糖控制长期以来一直是减少糖尿病心血管（CV）并发症治疗的基石。然而，其他因素也会导致这些并发症：主要的候选因素是遗传背景。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心血管并发症。基因背景再次成为主要的影响因素。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心血管损伤的主要危险因素的概念。我们已经确定了一种特定的中间表型，包括25%的高血压（HBPive）人群，我们称之为非调节性。非调节剂是胰岛素抵抗，肾功能异常，与CV损伤相关的标志物水平升高，CV损伤的风险增加。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有关。非调节剂的基本病理生理是组织ANGII产生的失调，导致组织水平不适当地增加，特别是在钠摄入量平均或更高的情况下。我们在II型糖尿病患者中的初步结果表明，非调节性表型可能存在于hbpiv患者的两倍。因此，糖尿病中CV疾病的较高频率可能部分归因于与肾脏和CV异常增加相关的中间表型的较高频率。因此，本研究的总体目标是验证这样一种假设，即糖尿病中介导心血管风险的激素因素的遗传基础与先前在HBP中发现的相似，而非调节是心血管风险的重要因素。我们的方法将与HBP中使用的方法相似。我们将定义糖尿病患者的中间表型，确定与其相关的遗传多态性是否与先前在HBP受试者中发现的相似，确定RAAS活性与炎症标志物和纤溶系统的关联，并使用药理学干预来确定中断RAAS是否逆转与特定中间表型相关的异常。支持这一建议的数据来自1000多名正常人和HBPives，他们在相同的协议上进行了研究。我们预计在II型糖尿病患者中会出现以下结果：与HBPives相比，非调节性表型的频率增加，低肾素的频率降低；糖尿病和HBPive非调节型基因中相似的多态性；与RAAS活性相关的炎症标志物水平升高；纠正非调节性而非其他有ACE抑制的糖尿病患者的异常。

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.