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: 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
• 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

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疗问题之一，领先 增加2型糖尿病，胰岛素抵抗和心血管疾病。替代的发现 迫切需要调节全身葡萄糖和能量代谢的途径以解决这一伟大 医疗需求。可以探索这种途径，以解决与糖尿病和 胰岛素抵抗。使用组合计算，细胞和体内的多学科策略 方法是，我们最近从热脂肪（ISTHMIN-1（ISM1））中发现了一种新的脂肪因子（ISM1） 作用于促进小鼠和人脂肪细胞中的葡萄糖摄取。 ISM1的动作需要PI3K/AKT 信号传导，但完全独立于胰岛素受体。在动物中，通过高脂饮食糖尿病 进食，重组ISM1蛋白的给药或循环ISM1的遗传升高可改善 葡萄糖稳态。但是，需要更多的研究才能了解ISM1对 葡萄糖代谢，并将这种理解用于治疗目的。总体目标 该建议是建立ISM1如何通过确定信号效应和 介导动作，确定ISM1的内源性生理功能的细胞表面受体，并 评估ISM1作为治疗靶标的药物潜力。在AIM 1中，我们将利用生化， 遗传和蛋白质组学方法，以识别负责的信号通路和细胞表面受体 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 行动，对于我们对ISM1信号传导的理解至关重要 调节葡萄糖摄取。在AIM 2中，我们将使用生成的ISM1确定ISM1的物理功能 全身和脂肪细胞特异性ISM1敲除小鼠。这些研究对于确定 ISM1在葡萄糖代谢中的内源性作用。在AIM 3中，我们将确定最小的要求 ISM1生物活性通过产生碎片，突变体和ISM1的工程形式。这个目标将为 进一步优化多肽马酮作为治疗剂的方法，并且至关重要 了解这种新型途径生理学增强的影响。这些贡献是 预计会很重要，因为可以独立于胰岛素来调节葡萄糖的途径将打开 全新的新途径要克服胰岛素抵抗和糖尿病，这可能会有重要的公众 健康影响。