Non-Modulation Phenotype and Vascular Dysfunction in Diabetes Mellitus

糖尿病的非调节表型和血管功能障碍

• 批准号: 7624594
• 负责人: GORDON H WILLIAMS
• 金额: $ 88.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624594
• 关键词: Accounting; Adipocytes; Adrenergic beta-Antagonists; Adult; Affect; Aldosterone; Aldosterone Synthase; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Arachidonate 12-Lipoxygenase; Area; Argentina; Blindness; Blood Pressure; Blood Vessels; Brain; Calcium Channel Blockers; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular system; Characteristics; Clinical; Combined Modality Therapy; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Dietary Sodium; Diuretics; Environmental Risk Factor; Enzyme Gene; Enzyme Inhibition; Enzymes; France; Frequencies; Functional disorder; Gene Proteins; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Goals; Heart; Hormonal; Hormones; Hydroxyeicosatetraenoic Acids; Hypertension; In Vitro; Individual; Inflammation; Inflammatory; Insulin Resistance; Intake; Interleukin-6; Interruption; Intervention; Italy; Kidney; Kidney Failure; Lead; Leucine Aminopeptidase; Mediating; Metabolic; Mineralocorticoid Receptor; Netherlands; Obesity; Pathway interactions; Peptides; Peptidyl-Dipeptidase A; Pharmacogenetics; Phenotype; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Play; Population; Predisposing Factor; Production; Proteins; Protocols documentation; Qualifying; Relative (related person); Renal function; Renin; Renin-Angiotensin-Aldosterone System; Research Personnel; Retina; Risk; Risk Factors; Role; Secondary to; Sodium; Study Subject; Switzerland; System; Testing; Thinking; Tissues; Triglycerides; United States; Variant; blood pressure regulation; cardiovascular risk factor; cationic antimicrobial protein CAP 37; diabetic; diabetic patient; enzyme activity; glycemic control; human ARTS-1 protein; improved; in vivo; inflammatory marker; mortality; novel strategies; programs; response; salt intake; theories

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.

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）并发症的治疗基石。然而，其他因素也会导致这些并发症：最主要的因素是遗传背景。同样，对于高血压 (HBP)，控制血压很重要，但不足以最大限度地减少心血管并发症。遗传背景再次成为主要因素。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 损伤的主要危险因素的概念。我们已经确定了一种特定的中间表型，其中包括 25% 的高血压 (HBPive) 人群，我们将其称为非调节者。非调节剂具有胰岛素抵抗性、肾功能异常、与心血管损伤相关的标志物水平升高以及心血管损伤的风险增加。非调节表型与肾素-血管紧张素醛固酮系统（RAAS）基因的特定多态性相关。非调节剂的基本病理生理学是组织 ANGII 产生失调，导致组织水平不适当地增加，特别是在钠摄入量平均或较高的情况下。我们对 II 型糖尿病患者的初步结果表明，存在非调节表型的糖尿病患者数量可能是 HBPives 患者的两倍。因此，糖尿病中心血管疾病发生率较高的部分原因可能是与肾脏和心血管异常增加相关的中间表型发生率较高。因此，该提案的总体目标是检验以下假设：介导糖尿病心血管风险的激素因素的遗传基础与之前在 HBP 中发现的相似，并且非调节是导致心血管风险的重要因素。我们的方法与 HBP 中使用的方法类似。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之前在 HBP 受试者中发现的相似，确定 RAAS 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如果 RAAS 中断可以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 HBPives 的数据，他们已经按照相同的方案进行了研究。我们预计 II 型糖尿病患者会出现以下结果：与 HBPives 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 非调节剂中存在相似的多态性；与 RAAS 活性相关的炎症标志物水平升高；并通过 ACE 抑制纠正非调节性糖尿病患者的异常，而不是其他糖尿病患者的异常。