Insulin as a Regulator of Microvascular Exchange

胰岛素作为微血管交换的调节剂

基本信息

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
项目类别：
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

项目摘要

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 (InsR) 状态。虽然 InsR 的特点是血浆胰岛素和葡萄糖水平较高，但在观察到的微血管功能障碍变化的病因学中最常研究的是高血糖。独立于其在葡萄糖代谢中的作用，胰岛素可以改变主要的内皮细胞（EC）功能：交换。交换如何变化也取决于性别。具体而言，仅在男性中，急性高胰岛素（10-7 M，Ins+）会增加微血管对蛋白质的通透性（Ps）。此外，在没有振荡生殖激素的情况下，来自男性和女性的 EC 在培养物中保留了性别差异，并且急性（分钟）和慢性（周）暴露于胰岛素会引起 EC 信号传导的性别依赖性和独立性变化。这些数据导致了新假设的形成，该假设将在 3 个目标中进行测试，即胰岛素在一种基因组、性别依赖性方式，通过调节微血管对蛋白质的通透性（Ps）来促进液体平衡。因此，当 Ins+ 预计会急剧改变（分钟-hrs) 男性而非女性的蛋白质通量。在目标 2 中，胰岛素作用的性别差异是否对将测定慢性高胰岛素血症期间白蛋白的加剧（Ins+，在 InsR 和 DM2 中不存在混杂因素的情况下）。预计慢性胰岛素会导致间质环境发生潜在的变化，表现为蛋白酶活性的变化、组织蛋白和炎症介质的升高，以及相对于 NO 和内皮素-1 (ET-1) 水平的 EC 表型的变化。最后，在目标 3 中，为了完善垂直整合，将分别使用男性和女性培养的微血管 EC 来确定哪些 EC 胰岛素受体介导的信号传导机制具有性别特异性。 EC表型对胰岛素的反应被认为反映了EC-胰岛素信号通路分别导致内皮素(ET-1)和一氧化氮(NO)产生的贡献中的M/F差异。 DM2 是一种慢性进行性疾病，尽管发病率与性别无关，但女性的发病率和死亡率高于男性。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，以及 c) 介导这些反应的细胞 Ins 信号传导将有助于制定早期疾病识别策略调整患者治疗以改善（如果不能逆转）或阻止疾病进展。