Control of glucose homeostasis through the insulin-independent Isthmin pathway

通过不依赖胰岛素的 Isthmin 通路控制葡萄糖稳态

基本信息

批准号：
10201593
负责人：
Katrin Jennifer Svensson
金额：
$ 47.96万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10201593
关键词：
Address Adipocytes Adipose tissue Animals Biochemical Biochemical Genetics Biological Blood Glucose Cardiovascular Diseases Cell Surface Receptors Chronic Complement Data Diabetes Mellitus Effector Cell Endocrine Energy Metabolism Engineering Fatty acid glycerol esters Genetic Glucose Glucose tolerance test Goals High Fat Diet Homeostasis Hormonal Hormones Human In Vitro Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Knockout Mice Lead Liver Maintenance Mammals Mediating Mediator of activation protein Medical Metabolic Metabolic dysfunction Methods Molecular Monitor Mus Muscle Muscle Fibers Non-Insulin-Dependent Diabetes Mellitus Outcome PI3K/AKT Pathway interactions Pharmacological Treatment Pharmacology Physical activity Physiological Physiology Play Polypeptide Hormones Proteins Proteomics Public Health Receptor Protein-Tyrosine Kinases Receptor Signaling Recombinant Proteins Recombinants Reproducibility Role Signal Pathway Signal Transduction Skeletal Muscle Structure Surface Therapeutic Therapeutic Agents Tissues Weight Gain adipokines blood glucose regulation clinical application combat diabetic euglycemia feeding glucose metabolism glucose uptake hormonal signals improved in vivo innovation insight insulin sensitivity metabolic phenotype multidisciplinary mutant novel novel therapeutic intervention novel therapeutics obesity treatment overexpression therapeutic target tool translation to humans vector

项目摘要

PROJECT SUMMARY Chronic metabolic dysfunction has emerged as one of the most severe medical problems worldwide, leading to increases in type 2 diabetes, insulin resistance, and cardiovascular disease. The discovery of alternative pathways to regulate whole-body glucose and energy metabolism is urgently needed to address this great medical need. Such pathways could be exploited for new therapeutic strategies to combat diabetes and insulin resistance. Using a multidisciplinary strategy combining computational, cellular, and in vivo approaches, we have recently uncovered a new adipokine from thermogenic adipose, Isthmin-1 (Ism1), that acts to promote glucose uptake in mouse and human adipocytes. The action of Ism1 requires PI3K/AKT signaling but is entirely independent of the insulin receptor. In animals rendered diabetic by high-fat diet feeding, administration of recombinant Ism1 protein or genetic elevation of circulating Ism1 improves glucose homeostasis. However, more studies are needed in order to understand the contribution of Ism1 to glucose metabolism, and to leverage this understanding for therapeutic purposes. The overall objectives in this proposal are to establish how Ism1 can control blood glucose by determining the signaling effectors and cell surface receptor that mediate the action, determine the endogenous physiological function for Ism1, and evaluate the pharmacological potential of Ism1 as a therapeutic target. In Aim 1, we will utilize biochemical, genetic, and proteomic methods to identify the signaling pathways and cell surface receptor responsible for the signaling action and glucoregulatory mechanisms of Ism1. These studies will identify Ism1’s mechanism of action and will be critical for our understanding of Ism1 signaling as an insulin-independent pathway to regulate glucose uptake. In Aim 2, we will determine the physiological function for Ism1 using our generated whole-body and adipocyte-specific Ism1 knockout mice. These studies are essential in determining the endogenous role of Ism1 in glucose metabolism. In Aim 3, we will determine the minimal requirements for Ism1 bioactivity by generating fragments, mutants, and engineered forms of Ism1. This aim will pave the way for further optimization of a polypeptide hormone as a therapeutic agent, and will be essential in understanding the effects of augmentation of this novel pathway physiology. These contributions are expected to be significant because pathways that can regulate glucose independently of insulin will open entirely new avenues to overcome insulin resistance and diabetes, which could have a significant public health impact.

项目概要慢性代谢功能障碍已成为全球最严重的医学问题之一，导致 2 型糖尿病、胰岛素抵抗和心血管疾病的增加。迫切需要调节全身葡萄糖和能量代谢的途径来解决这一重大问题此类途径可用于对抗糖尿病和糖尿病的新治疗策略。胰岛素抵抗采用结合计算、细胞和体内的多学科策略。最近，我们从产热脂肪中发现了一种新的脂肪因子 Isthmin-1 (Ism1)，促进小鼠和人类脂肪细胞的葡萄糖摄取 Ism1 的作用需要 PI3K/AKT。信号传导，但在因高脂肪饮食而患糖尿病的动物中完全独立于胰岛素受体。喂养、施用重组 Ism1 蛋白或循环 Ism1 基因升高可改善然而，需要更多的研究来了解 Ism1 对葡萄糖稳态的贡献。葡萄糖代谢，并将这种理解用于治疗目的。该提案旨在确定 Ism1 如何通过确定信号效应器来控制血糖介导作用的细胞表面受体，确定 Ism1 的内源性生理功能，以及评估 Ism1 作为治疗靶点的药理学潜力在目标 1 中，我们将利用生化、遗传和蛋白质组学方法来识别负责的信号传导途径和细胞表面受体 Ism1 的信号传导作用和葡萄糖调节机制。这些研究将确定 Ism1 的机制。的作用，对于我们理解 Ism1 信号传导作为一种独立于胰岛素的途径至关重要在目标 2 中，我们将使用我们生成的结果确定 Ism1 的生理功能。这些研究对于确定全身和脂肪细胞特异性 Ism1 敲除小鼠至关重要。在目标 3 中，我们将确定 Ism1 在葡萄糖代谢中的内源性作用。通过生成 Ism1 的片段、突变体和工程形式来提高 Ism1 的生物活性。进一步优化多肽激素作为治疗剂的方法，并且对于了解这种新途径生理学增强的影响。预计将成为重要的途径，因为它可以独立于胰岛素调节血糖克服胰岛素抵抗和糖尿病的全新途径，可能会吸引大量公众健康影响。