Targeting Insulin Resistance by Estrogen Receptor in Control of Type 2 Diabetes Mellitus

通过雌激素受体靶向胰岛素抵抗来控制 2 型糖尿病

基本信息

批准号：
10407999
负责人：
Shaodong Guo
金额：
$ 35.78万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-12 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407999
关键词：
AKT Signaling Pathway AKT inhibition Address Affect Biogenesis Biological Assay Blood Glucose Cells Chemicals Complex Coupled Cyclic AMP-Dependent Protein Kinases DNA Binding Domain Data Development Diabetes Mellitus Electron Transport Enzymes Estradiol Estrogen Receptor 2 Estrogen Receptor alpha Estrogen Receptors Estrogens Exhibits FOXO1A gene Female Functional disorder Gene Expression Genes Genetically Engineered Mouse Glucose Gonadal Steroid Hormones Grant HIV Hepatic Hepatocyte High Fat Diet Homeostasis Human Hyperglycemia IRS1 gene IRS2 gene Impairment In Vitro Incidence Inflammation Insulin Insulin Receptor Insulin Resistance Knockout Mice Light Liver Liver Mitochondria Maps Mediating Mediator of activation protein Metabolic Metabolism Mitochondria Molecular Mus N-terminal Non-Insulin-Dependent Diabetes Mellitus Nuclear PIK3CA gene Pathway interactions Peptides Phosphoric Monoester Hydrolases Phosphorylation Physiological Play Postmenopause Prevalence Prevention Protein Kinase Proteins Proto-Oncogene Proteins c-akt Protoporphyrins Role Serine Signal Transduction System Testing Woman adenoviral-mediated base blood glucose regulation forkhead protein gender difference glucose metabolism glucose production glucose-6-phosphatase heme a heme oxygenase-1 improved in vivo inhibitor insulin receptor substrate 1 protein insulin sensitivity insulin sensitizing drugs insulin signaling knockout gene liver metabolism male men mitochondrial dysfunction nanoparticle novel overexpression prevent protein protein interaction receptor therapeutic development

项目摘要

Project Summary This proposal “Targeting Insulin Resistance by Estrogen Receptor in Control of Type 2 Diabetes Mellitus” addresses a fundamental mechanism based on the gender difference in control of type 2 diabetes. The gender difference exists for the incidence of T2D, with improved insulin sensitivity and survival in females, but the mechanism is unclear. Sex hormone estrogen and its receptor system have shown benefit to metabolic function. This proposal will address the molecular and physiological mechanism by which estrogen and insulin signaling crosstalk at the level of IRS1 and IRS2 proteins and downstream protein kinase Akt and forkhead transcription factor Foxo1 that controls mitochondrial biogenesis and function through the heme oxygenase 1 (HO1) gene. The O-class of the forkhead transcription factor Foxo1 is a key downstream target of the insulin→PI3K→protein kinase B (Akt) signaling pathway, governing multiple physiological functions. Our previous studies have demonstrated Foxo1 is a key substrate of Akt downstream from both insulin and estrogen signaling that controls glucose homeostasis via glucose-6-phosphatase gene expression. Foxo1 also stimulates expression of heme-oxygenase-1 (HO1) that catalyzes degradation of heme, a key component of mitochondrial electron transport chains, then reducing mitochondrial biogenesis and function. In this proposal, we hypothesize that insulin and 17-beta-estradiol (E2) play important roles in activation of PI3K-Akt and suppressing Foxo1-HO1 in control of mitochondrial function, while loss of IRS1/2 and estrogen receptor-alpha (ERα) signaling and resultant HO1 overexpression are fundamental and unifying mechanisms for mitochondrial dysfunction that promotes meta-inflammation. In Aim 1, we use the liver-specific ER-alpha gene knockout mice in insulin resistant mice and examine whether ERα gene is required for IRS1, 2 and associated PI3K-AKT activation and suppression of Foxo1 and HO1 in the liver. In Aim2, we will use protein- protein interaction assays to map out the key domain of ERα for interaction with IRS1 and IRS2, activating PI3K-Akt and inhibiting Foxo1-HO1 in cells. We test the hypothesis that either N-terminal ERα without DNA binding domain (DBD) interacts with IRS1/2, preventing IRS1/2 serine phosphorylation coupled degradation, suppressing Foxo1 and HO1 in cells. In Aim 3, we will use adenovirus-mediated gene expression of N-terminal domain ERα in HFD-fed mice to examine whether there is achievable hepatic protection by activation of IRS- associated PI3K and suppression of Foxo1 and HO1. Moreover, we will target HO1 with nanoparticle-mediated HO1 inhibitor (Zn2+-protoporphyrin) in the liver of mice lacking IRS1/2 and ERα or high fat-diet (HFD)-induced insulin resistance. We will examine whether HO1 inhibition sufficiently protects hepatic mitochondrial dysfunction and inflammation in insulin resistant mice. Therefore, this proposal will provide novel mechanisms of ERα and HO1 in insulin sensitizing and approaches of therapeutic development for insulin sensitizers in the treatment of type 2 diabetes.

项目概要该提案“通过雌激素受体控制胰岛素抵抗来控制 2 型糖尿病” 探讨了基于性别差异控制 2 型糖尿病的基本机制。随着女性胰岛素敏感性和生存率的提高，T2D 的发病率存在差异，但性激素雌激素及其受体系统已显示出对代谢的益处，其机制尚不清楚。该提案将解决雌激素和胰岛素发挥作用的分子和生理机制。 IRS1 和 IRS2 蛋白以及下游蛋白激酶 Akt 和 forkhead 水平的信号串扰通过血红素加氧酶 1 控制线粒体生物发生和功能的转录因子 Foxo1 (HO1) 基因。叉头转录因子 Foxo1 的 O 类是胰岛素→PI3K→蛋白激酶B（Akt）信号通路，调控多种生理功能。先前的研究表明 Foxo1 是胰岛素和 Akt 下游的关键底物雌激素信号还通过葡萄糖 6 磷酸酶基因表达控制葡萄糖稳态。刺激血红素加氧酶-1 (HO1) 的表达，催化血红素的降解，血红素是细胞的关键成分线粒体电子传递链，然后减少线粒体的生物发生和功能。在此提案中，我们研究了胰岛素和 17-β-雌二醇 (E2) 在激活 PI3K-Akt 和抑制 Foxo1-HO1 控制线粒体功能，同时 IRS1/2 和雌激素丧失受体-α (ERα) 信号传导和由此产生的 HO1 过度表达是基本且统一的机制对于促进元炎症的线粒体功能障碍，我们使用肝脏特异性 ER-α。在胰岛素抵抗小鼠中进行基因敲除小鼠，并检查IRS1、2和IRS1是否需要ERα基因在 Aim2 中，我们将使用蛋白质-相关的 PI3K-AKT 激活和肝脏中 Foxo1 和 HO1 的抑制。蛋白质相互作用分析，绘制 ERα 与 IRS1 和 IRS2 相互作用的关键结构域，激活我们测试了 N 端 ERα 没有 DNA 的假设。结合域 (DBD) 与 IRS1/2 相互作用，防止 IRS1/2 丝氨酸磷酸化偶联降解，抑制细胞中的 Foxo1 和 HO1 在目标 3 中，我们将使用腺病毒介导的 N 末端基因表达。在 HFD 喂养的小鼠中研究 ERα 结构域，以检查是否可以通过激活 IRS- 来实现肝脏保护。此外，我们将通过纳米颗粒介导的靶向 HO1。缺乏 IRS1/2 和 ERα 或高脂饮食 (HFD) 诱导的小鼠肝脏中的 HO1 抑制剂（Zn2+-原卟啉）我们将检查 HO1 抑制是否足以保护肝线粒体。因此，该提议将提供新的机制。 ERα和HO1在胰岛素增敏中的作用以及胰岛素增敏剂的治疗开发方法治疗2型糖尿病。