Non-Modulation Phenotype and Vascular Dysfunction in Diabetes Mellitus

描述(申请人提供)：长期以来，血糖控制一直是减少糖尿病心血管并发症(CV)治疗的基石。然而，其他因素也导致了这些复杂的情况：领先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。基因背景又一次脱颖而出，成为主要的贡献者。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害的主要危险因素的概念。我们已经确定了一种特殊的中间表型，包括25%的高血压(HBPive)人群，我们称之为非调节剂。非调节剂具有胰岛素抵抗、肾功能异常、与心血管损害相关的标志物水平升高以及心血管损害风险增加等特点。这种非调节表型与肾素-血管紧张素-醛固酮系统(RAAS)基因的特定多态有关。非调节剂的基本病理生理学是组织血管生成的失调导致组织水平不适当的增加，特别是在存在平均或更高的钠摄入量的情况下。我们在II型糖尿病患者中的初步结果表明，非调节性表型在糖尿病患者中的出现人数可能是HBPive患者的两倍。因此，糖尿病患者心血管疾病的较高频率可能部分是由于与肾脏和心血管异常增加相关的中间表型的较高频率所致。因此，这项建议的总体目标是检验这样一种假设，即介导糖尿病心血管风险的激素因素的遗传基础类似于先前在高血压中发现的那些因素，并且非调制是该心血管风险的重要贡献者。我们的方法将类似于HBP使用的方法。我们将定义糖尿病患者的中间表型，确定与它们相关的基因多态是否与先前在高血压受试者中发现的基因多态相似，确定RAAS的活性与炎症和纤溶系统标志物的关联，并使用药物干预来确定RAAS的阻断是否逆转与特定中间表型相关的异常。支持这一提议的是来自1000多名正常人和HBPive的数据，他们已经进行了相同的方案研究。我们预计在II型糖尿病患者中会出现以下结果：与HBPive相比，非调节型糖尿病患者的表型频率增加，肾素降低的频率降低；糖尿病患者和HBPive非调节型患者的基因多态性相似；与RAAS活性相关的炎症标志物水平上升；使用ACE抑制的非调节型糖尿病患者的异常改变得到纠正。

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.