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

• 批准号: 10025485
• 负责人: Katrin Jennifer Svensson
• 金额: $ 48.34万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10025485
• 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; Obesity; 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; overexpression; therapeutic target; tool; translation to humans; vector

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.

项目摘要 慢性代谢功能障碍已成为全球最严重的医学问题之一， 2型糖尿病、胰岛素抵抗和心血管疾病的增加。替代品的发现 调节全身葡萄糖和能量代谢的途径迫切需要解决这一重大问题。 医疗需求。这些途径可以用于新的治疗策略，以对抗糖尿病， 胰岛素抵抗使用多学科策略结合计算，细胞和体内 最近，我们从产热脂肪中发现了一种新的脂肪因子，Isthmin-1（Ism 1）， 促进小鼠和人脂肪细胞中的葡萄糖摄取。Ism 1的作用需要PI 3 K/AKT 胰岛素依赖于胰岛素信号，但完全不依赖于胰岛素受体。高脂饮食导致糖尿病的动物 喂食、给予重组Ism 1蛋白或循环Ism 1的遗传升高可改善 葡萄糖稳态然而，需要更多的研究来了解Ism 1对 葡萄糖代谢，并利用这种理解用于治疗目的。之整体目标 该建议旨在通过确定信号效应子来确定Ism 1如何控制血糖， 介导该作用的细胞表面受体，决定Ism 1的内源性生理功能，以及 评估Ism 1作为治疗靶点的药理学潜力。在目标1中，我们将利用生物化学， 基因和蛋白质组学方法来确定信号通路和细胞表面受体负责 Ism 1的信号传导作用和糖调节机制。这些研究将确定Ism 1的机制 这对于我们理解Ism 1信号传导作为胰岛素非依赖性途径， 调节葡萄糖摄取。在目标2中，我们将使用我们生成的 全身和脂肪细胞特异性Ism 1敲除小鼠。这些研究对于确定 Ism 1在葡萄糖代谢中的内源性作用。在目标3中，我们将确定以下方面的最低要求： 通过产生Ism 1的片段、突变体和工程化形式的Ism 1生物活性。这一目标将为 作为治疗剂的多肽激素的进一步优化的方法，并且将是必不可少的， 了解增强这种新途径生理学的效果。这些捐款 因为可以独立于胰岛素调节葡萄糖的途径将打开， 克服胰岛素抵抗和糖尿病的全新途径， 健康影响。