Selective Insulin Resistance- Diabetic Cardiovascular Diseases

选择性胰岛素抵抗-糖尿病心血管疾病

基本信息

批准号：
8997076
负责人：
GEORGE L KING
金额：
$ 36.82万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-15 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997076
关键词：
Acceleration Address Affect Angiotensins Antiatherogenic Apolipoprotein E Arterial Fatty Streak Atherosclerosis Biochemical Biological Blood Vessels Calories Cardiovascular Diseases Cells Chronic Data Development Diabetes Mellitus Diet Endothelial Cells Endothelin B Receptor Endothelin-1 Endothelium Exhibits Fatty acid glycerol esters Genes Goals Grant Health High Fat Diet Hyperglycemia Hyperinsulinism Hyperlipidemia Hyperplasia IRS1 gene IRS2 gene Inflammatory Insulin Insulin Receptor Insulin Resistance Intervention Intervention Studies Kidney Diseases Knock-in Knock-out MAP Kinase Gene Metabolic Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Pathology Pathway interactions Phosphorylation Plasminogen Activator Inhibitor 1 Prediabetes syndrome Protein Isoforms Regulation Reporting Retinal Diseases Risk Factors Role Serine Severities Signal Transduction Signaling Molecule Site Smooth Muscle Myocytes Threonine Vascular Cell Adhesion Molecule-1 Vascular Endothelial Growth Factors Vascular Smooth Muscle cardiovascular disorder risk cardiovascular risk factor cytokine diabetic diabetic cardiomyopathy diabetic patient endothelial dysfunction feeding glucose metabolism heme oxygenase-1 hypercholesterolemia improved in vivo inhibitor/antagonist insulin sensitivity insulin signaling macrophage migration mortality mouse model mutant novel overexpression platelet-derived growth factor BB receptor receptor expression ruboxistaurin vascular smooth muscle cell proliferation western diet

项目摘要

DESCRIPTION (provided by applicant): Insulin resistance (IR) and hyperinsulinemia are important cardiovascular risk factors in diabetic patients. Insulin actions have been identified on endothelial cells (EC), vascular smooth muscle cells (VSMC) and macrophages. Yet, the question of whether insulin has pro- or anti-atherogenic actions has been hotly debated for many years. We propose that the acceleration of atherosclerosis in diabetes is due to selective insulin resistance in the vascular wall where hyperglycemia and elevated free fatty acids (FFA) can inhibit insulin signaling through the IRS/PI3K/Akt pathway. This may decrease insulin's anti-atherogenic actions in EC such as activation of eNOS, increased expression of heme oxygenase-1 and decreased expression of VCAM-1. Also, insulin and PKC activation may enhance the MAPK pathway leading to increased expression of pro- atherogenic activities such as ET-1, PAI-1 expression, migration and proliferation of VSMC, creating "selective" insulin resistance in the vessel wall. In this grant period, we showed that deletion of insulin receptors, specifically in EC, accelerated atherosclerosis due to the loss of novel insulin actions to decrease VCAM-1 expression. We also showed that hyperinsulinemia alone, without vascular or systemic IR, did not accelerate atherosclerosis in ApoE-/- mice. We have shown that one cause of selective insulin resistance in the endothelium is due to the activation of PKC, especially of the a and b isoforms, induced by hyperglycemia and elevated FFA. We also identified the targets of PKCb activation induced by angiotensin on insulin signaling molecules including p-Ser303 in IRS2 and p-Thr86 of p85a/PI3K. The overexpression of PKCb isoform, specifically in EC, selectively inhibited insulin signaling through the IRS/Akt pathway and exacerbated atherosclerosis. Thus, we propose to: 1. Characterize the effect of exogenous insulin treatment and PKCb inhibition on the development of atherosclerosis in a new model of ApoE-/- mice, which exhibit hyperinsulinemia, hyperglycemia, hypercholesterolemia and IR at the vessel wall, and systemically by feeding a high fat diet (HFD, 60% fat) instead of a western diet (WD, 42% fat), providing a simple diet induced model with atherosclerosis that mimics all of the metabolic abnormalities of type 2 diabetes. 2a. Evaluate ApoE-/- mice overexpressing IRS1 specifically in the endothelium, EIRS1/ApoE-/- mice, which showed dramatic decreases in atherosclerosis, and possibly identified a novel pathway by which insulin activates eNOS via increases in endothelin B receptor (ETB) expression by a pathway independent of p-S(1176)eNOS. 2b. Determine whether intimal hyperplasia and atherosclerosis will decrease in mice which are expressing S-A(1176)eNOS and overexpressing IRS1 in EC on ApoE-/- background while on HFD. 3. We will address the question of insulin's potential atherogenic effects on VSMC by determining the role of insulin and its receptor on aortic SMC regarding their impact on atherosclerotic lesions in ApoE-/- mice with deletion of insulin receptor on HFD.

描述（由申请人提供）：胰岛素抵抗（IR）和高胰岛素血症是糖尿病患者的重要心血管危险因素。已经确定了胰岛素作用内皮细胞（EC），血管平滑肌细胞（VSMC）和巨噬细胞。然而，多年来，胰岛素是否具有促疾病或抗动脉植物的作用的问题已经进行了激烈的辩论。我们建议糖尿病中动脉粥样硬化的加速度是由于血管壁中选择性胰岛素抵抗引起的，在该血管壁中高血糖和升高的游离脂肪酸（FFA）可以通过IRS/PI3K/AKT途径抑制胰岛素信号传导。这可能会降低胰岛素在EC中的抗毒素作用，例如eNOS的激活，血红素氧酶-1的表达增加以及VCAM-1的表达降低。同样，胰岛素和PKC激活可以增强MAPK途径，从而导致促进性动脉粥样硬化活性的表达增加，例如ET-1，PAI-1表达，VSMC的迁移和增殖，从而在容器壁上产生“选择性”的胰岛素抵抗。在这一赠款期间，我们表明胰岛素受体的缺失，特别是在EC中，由于失去了新型胰岛素作用而加速了动脉粥样硬化，从而降低了VCAM-1的表达。我们还表明，单独的高胰岛素血症，没有血管或全身性IR，不会在APOE - / - 小鼠中加速动脉粥样硬化。我们已经表明，内皮中选择性胰岛素抵抗的原因是PKC的激活，尤其是由高血糖和FFA升高的A和B同工型的激活。我们还鉴定了血管紧张素引起的PKCB激活的靶标在P85A/PI3K的IRS2和P-THR86中，包括P-SER303在内的胰岛素信号分子。 PKCB同工型的过表达，特别是在EC中，有选择地抑制了IRS/AKT途径的胰岛素信号传导，并加剧了动脉粥样硬化。因此，我们提出：1。表征外源胰岛素治疗和PKCB抑制对动脉粥样硬化发展的影响，在新的APOE - / - 小鼠模型中，这些模型表现出高胰岛素血症，高血糖，高血糖，高血糖，高胆固醇血症和IR在血管壁上，以及通过系统的脂肪饮食（相反）脂肪饮食（相反），而不是脂肪饮食，而不是脂肪饮食（HFD），而不是APOE-/ - 小鼠。提供一个简单的饮食诱导模型，并具有动脉粥样硬化，以模仿2型糖尿病的所有代谢异常。 2a。评估APOE - / - 小鼠在内皮中特别表达IRS1的EIRS1/APOE - / - 小鼠在动脉粥样硬化中显示出急剧下降的降低，并且可能通过Endothelin B受体（ETB）表达胰岛素通过与P-S的表达在PATER中的增加来鉴定胰岛素通过与P-S（1176）ENS（1176）EN（1176）识别ENOS。 2b。确定在HFD上表达S-A（1176）eNOS的小鼠（1176）eNOS和EC中的IRS1过表达IRS1是否会降低内膜增生和动脉粥样硬化。 3。我们将通过确定胰岛素及其受体对主动脉SMC对APOE - / - 小鼠中动脉粥样硬化病变的影响而对胰岛素损伤的影响，并通过胰岛素受体删除HFD对动脉粥样硬化病变的影响来解决胰岛素对VSMC的潜在动脉粥样硬化作用的问题。