Mechanisms of Myocardial Infarction-induced insulin resistance

心肌梗死引起的胰岛素抵抗的机制

基本信息

批准号：
10116453
负责人：
Partha Dutta
金额：
$ 51.63万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116453
关键词：
ANXA5 gene Acute myocardial infarction Address Adipose tissue Anti-Inflammatory Agents Apoptosis Apoptotic Applications Grants Arterial Fatty Streak Bone Marrow Cause of Death Cells Colony-Stimulating Factor Receptors Coronary Data Developed Countries Diabetes Mellitus Diet Event Exhibits Flow Cytometry Genetic Glucose Glucose Clamp Glucose Intolerance High Fat Diet Human Hyperglycemia Immunofluorescence Immunologic Inflammatory Insulin Resistance Interleukin-1 Interleukin-1 beta Interleukin-13 Interleukin-4 Interleukin-6 Knowledge Ligation Macrophage Colony-Stimulating Factor Macrophage Colony-Stimulating Factor Receptor Mouse Strains Mus Myelogenous Myeloid Cells Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Organ Parabiosis Patients Phenotype Play Production Propidium Diiodide Recording of previous events Reporting Role Series Source Supplementation TNF gene Tamoxifen Testing Tissue Differentiation Tissues Visceral cytokine drug development experimental study fasting blood glucose level improved inflammatory milieu insulin sensitivity intravital microscopy macrophage monocyte mortality mouse model neutralizing antibody novel therapeutics prevent recruit

项目摘要

Myocardial infarction (MI) is the leading cause of mortality in the USA. Patients develop insulin resistance after acute MI. In a mouse model of MI, we found coronary ligation significantly increased insulin resistance in mice fed with either a chow diet or high fat diet. Recent studies have shown that MI-induced insulin resistance has direct proatherogenic effects at the level of atherosclerotic plaques leading to a series of cellular atherogenic events and plaque progression. But the mechanistic underpinnings of insulin resistance after MI are not explored. We have recently shown that MI increases production of inflammatory monocytes, which can infiltrate visceral adipose tissue (VAT) and differentiate into macrophages. Consistently, our preliminary data revealed that MI-induced insulin resistance was associated with accumulation of CX3CR1+ CCR2+ monocyte-derived macrophages in VAT. We hypothesize that the influx of monocyte-derived macrophages into VAT after MI creates an inflammatory milieu, resulting in insulin resistance. We will test the hypothesis in three specific aims. 1.We will investigate the dynamics of macrophage subsets in VAT after MI. We will use flow cytometry and intravital microscopy to investigate monocyte accumulation in VAT after MI. 2.To test the mechanisms of MI-induced insulin resistance, we will investigate if loss of M-CSF after MI leads to insulin resistance. Our preliminary experiments showed that coronary ligation in mice reduced systemic levels of M-CSF, a cytokine responsible for tissue resident macrophage survival. 3. We will investigate if the accumulation of monocyte-derived macrophages induces insulin resistance after MI using a mouse strain of tamoxifen-inducible CX3CR1. Furthermore, since monocyte-derived VAT macrophages express high levels of IL-1β, we will use IL-1β neutralizing antibody to explore whether it can improve insulin sensitivity. The proposed grant application will further our understanding of mechanisms behind MI-induced insulin resistance and explore new therapeutic avenues.

心肌梗塞 (MI) 是美国患者出现胰岛素抵抗的主要原因。在急性心肌梗死小鼠模型中，我们发现冠状动脉结扎显着增加了胰岛素抵抗。最近的研究表明，在用食物饮食或高脂肪饮食喂养的小鼠中，心肌梗塞会诱导胰岛素的产生。抵抗力在动脉粥样硬化斑块水平上具有直接促动脉粥样硬化作用，导致一系列但胰岛素抵抗的机制基础。我们最近发现 MI 会增加炎症单核细胞的产生，它可以渗透内脏脂肪组织（VAT）并分化为巨噬细胞。初步数据显示，MI 诱导的胰岛素抵抗与 CX3CR1+ 的积累有关我们捕获了 VAT 中 CCR2+ 单核细胞来源的巨噬细胞的流入。 MI 后巨噬细胞进入 VAT，产生炎症环境，导致胰岛素抵抗。三个具体目标的假设 1.我们将研究 VAT 中巨噬细胞亚群的动态。 MI 后，我们将使用流式细胞术和活体显微镜来研究 VAT 中的单核细胞积累。 2.为了测试 MI 诱导的胰岛素抵抗的机制，我们将研究 M-CSF 是否丢失。我们的初步实验表明，小鼠冠状动脉结扎后会导致胰岛素抵抗。降低 M-CSF 的全身水平，M-CSF 是一种负责组织驻留巨噬细胞存活的细胞因子 3。将研究单核细胞来源的巨噬细胞的积累是否会在 MI 后诱导胰岛素抵抗使用他莫昔芬诱导的 CX3CR1 小鼠品系此外，由于单核细胞衍生的 VAT。巨噬细胞表达高水平的IL-1β，我们将使用IL-1β中和抗体来探讨是否可以提高胰岛素敏感性。拟议的拨款申请将进一步加深我们对机制的理解。探究 MI 引起的胰岛素抵抗的背后并探索新的治疗途径。