Insulin as a Regulator of Microvascular Exchange

胰岛素作为微血管交换的调节剂

• 批准号: 8665418
• 负责人: VIRGINIA H HUXLEY
• 金额: $ 40.01万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665418
• 关键词: Accounting; Acute; Address; Adolescent; Adult; Albumins; Beryllium; Caliber; Cell physiology; Cells; Characteristics; Chronic; Clinical; Data; Dependence; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Drug Formulations; Endothelial Cells; Endothelin; Endothelin-1; Environment; Etiology; Exercise; Exposure to; Female; Fluid Balance; Functional disorder; Genomics; Glucose; Goals; Gonadal Steroid Hormones; Health; Homeostasis; Hormones; Hyperglycemia; Hyperinsulinism; Hypertension; In Situ; In Vitro; Incidence; Individual; Inflammation Mediators; Inflammatory; Ingestion; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Knowledge; Laboratories; Lead; Life; Liquid substance; MAP Kinase Gene; Matrix Metalloproteinases; Mediating; Metabolic; Metabolic Diseases; Methods; Microvascular Dysfunction; Microvascular Permeability; Morbidity - disease rate; Myocardial Infarction; Nitric Oxide; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Patients; Peptide Hydrolases; Permeability; Pharmaceutical Preparations; Phenotype; Plasma; Plasma Proteins; Play; Production; Progressive Disease; Proteins; Rattus; Regulation; Relative (related person); Role; Sex Characteristics; Shock; Signal Pathway; Signal Transduction; Signaling Molecule; Stroke; Symptoms; Testing; Time; Tissues; Training; Woman; arteriole; blood glucose regulation; glucose metabolism; hepatocyte growth factor-regulated tyrosine kinase substrate; in vivo; interstitial; male; men; mortality; novel; pressure; receptor; receptor-mediated signaling; reproductive hormone; response; sex

DESCRIPTION (provided by applicant): Prior to diagnosis of type 2 diabetes (DM2) the state of insulin resistance (InsR) exists. While InsR is characterized by high plasma levels of insulin and glucose, it is hyperglycemia that is most often studied in the etiology of observed changes in microvascular dysfunction. Independent of its role in glucose metabolism insulin can alter the major endothelial cell (EC) function: exchange. How exchange changes also depends on sex. Specifically, acute high insulin (10-7 M, Ins+) increases microvascular permeability (Ps) to protein only in males. Further, EC from males and females retain sex differences in culture in the absence of oscillating reproductive hormones and acute (min) and chronic (weeks) exposure to insulin elicits both sex-dependent and -independent changes in EC signaling. These data lead to the formulation of the novel hypothesis, to be tested in 3 aims that insulin, in a genomic, sex-dependent manner, contributes to fluid balance via regulation of microvessel permeability (Ps) to proteins. Thus, Psalbumin in adult rats of both sexes will be assessed using quantitative in vivo and in vitro methods to determine the sex-dependence of acute insulin in the regulation of in situ microvascular exchange in Aim 1, when Ins+ is predicted to alter acutely (min-hrs) protein flux in males, not females. In Aim 2 whether sex differences in insulin action on Psalbumin are exacerbated during chronic hyperinsulinemia (Ins+, in the absence of confounding factors present in InsR and DM2) will be determined. Chronic insulin is predicted to lead to insidious changes in interstitial milieu manifested as changes in protease activity, elevated tissue protein and inflammatory mediators, and changes in EC phenotype with respect to levels of NO and endothelin-1 (ET-1). Finally, in Aim 3, to round out the vertical integration, cultured microvessel EC of males and females, respectively, will be used to determine which EC insulin receptor-mediated signaling mechanisms are sex-specific. The EC phenotype in response to insulin is posited to reflect M/F-differences in the contribution of the EC- insulin signaling pathways leading to endothelin (ET-1) and nitric oxide (NO) production, respectively. DM2 is a chronic progressive disease with a greater morbidity and mortality in women than men albeit the incidence is sex-independent. Knowledge of a) the direct role of Ins+ in loss of barrier function, b) the sex-specific, genomic EC responses to acute and chronic insulin, and c) the cellular Ins signaling mediating these responses will facilitate formulation of strategies for earler disease identification and tailoring of patient therapy to ameliorate, if not reverse, or stop disease progression.

描述（由申请人提供）：在诊断2型糖尿病（DM2）之前，存在胰岛素抵抗状态（INSR）。虽然INSR的特征是高血浆胰岛素和葡萄糖水平高，但在观察到的微血管功能障碍变化的病因中，最常研究高血糖。独立于其在葡萄糖代谢胰岛素中的作用可以改变主要的内皮细胞（EC）功能：交换。交换的变化也取决于性。具体而言，急性高胰岛素（10-7 M，INS+）仅在男性中增加微血管通透性（PS）。此外，在没有振荡的生殖激素，急性激素（最小）和慢性（几周）暴露于胰岛素的情况下，男性和女性的EC在培养中保留了性别差异。这些数据导致了新假设的制定，以3个目的进行测试，这些目标是胰岛素，在 一种基因组，性别依赖性的方式，通过调节微血管通透性（PS）对蛋白质有助于流体平衡。因此，将使用体内定量和体外方法评估两性成年大鼠的psalbumin，以确定急性胰岛素在AIM 1中的原位微血管交换调节中的性别依赖性，而INS+预计将改变INS+在急性（min-hrs）急性（min-hrs）蛋白质蛋白质蛋白质中的蛋白质量。在AIM 2中，胰岛素作用的性别差异是否 在慢性高胰岛素血症期间（INS+，在INSR和DM2中没有混杂因素的情况下）将加剧psalbumin。预计慢性胰岛素会导致蛋白酶活性，组织蛋白和炎症介质升高以及EC表型的变化相对于NO和Endophelin-1（ET-1）的水平，EC表型的变化表现为蛋白酶活性，升高的组织蛋白和炎症介体的变化。最后，在AIM 3中，为了完善垂直整合，分别使用培养的男性和女性的微血管EC来确定哪种EC胰岛素受体介导的信号传导机制是性别特异性的。假定对胰岛素的EC表型，以反映导致内皮素（ET-1）和一氧化氮（NO）产生的EC-胰岛素信号传导途径的M/F-差异。 DM2是一种慢性进行性疾病，女性的发病率和死亡率比男性更大，尽管发生率是与性无关的。了解a）INS+在屏障功能丧失中的直接作用，b）性别特异性，基因组EC对急性和慢性胰岛素的反应； c）介导的这些反应的细胞信号传导将促进核心疾病鉴定和量身定制患者疗法的策略，以降低患者的疗法，即使疗法反向或停止疾病进展。