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）：长期以来，血糖控制一直是减少糖尿病心血管（CV）并发症的治疗基石。但是，其他因素也导致了这些并发症：主要候选者是遗传背景。同样，在高血压（HBP）中，控制血压很重要，但不足以最大程度地减少CV并发症。遗传背景再次成为主要贡献者。数据还支持这样的概念，即血管紧张素II（Angii）和醛固酮（ALDO）是相关炎症的主要危险因素，以及纤维蛋白水解系统驱动的CV损伤。我们已经确定了一种特定的中间表型，其中占我们称为非调节剂的高血压（HBPIVE）人群的25％。非调节剂具有胰岛素耐药性，肾功能异常，与CV损伤相关的标记水平升高以及CV损伤的风险增加。非调节表型与肾素 - 血管紧张素系统（RAAS）基因中的特定多态性有关。非调节剂中的基本病理生理学是组织ANGII产生的失调，导致组织水平不当，特别是在存在平均或更高钠摄入量的情况下。我们在II型糖尿病患者中的初步结果表明，非调节表型的存在可能是HBPIVE的两倍。因此，糖尿病中CV疾病的频率较高，部分原因是与肾脏和简历异常增加有关的中间表型的较高频率。因此，该提案的总体目标是检验以下假设：介导糖尿病中简历风险的激素因素的遗传基础与先前在HBP中鉴定的遗传因素相似，并且非调节是对该简历风险的重要贡献。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中的中间表型，确定与它们相关的遗传多态性是否与先前在HBP受试者中鉴定的遗传多态性相似，确定RAA的活动和炎症和纤维纤维溶解系统的活动的关联，并使用药理干预来确定与RAAS相关的混合逆转的中断。为了支持该提案，来自1000多个正常的数据和已经研究了相同协议的HBPIVE。我们预计II型糖尿病患者会产生以下结果：与HBPIVE相比，非调节表型的频率增加和低肾素的频率较低；糖尿病和HBPIVE非调节剂中的类似多态性；与RAAS活性相关的炎症标记水平增加；并纠正非调节的异常，但没有其他具有ACE抑制的糖尿病患者。