Exercise, Exosomes, and Metabolic Health in Type-2 Diabetes

项目概要/摘要 夏威夷原住民和其他太平洋岛民（NHOPI）不成比例地受到2型糖尿病的影响 （2型糖尿病），患病率是夏威夷白人的两倍。T2 DM的特征是高血糖， 在代谢组织中，包括肝脏、骨骼肌和脂肪组织中，胰岛素作用缺陷。锻炼是 改善血糖控制和降低发生T2 DM风险的有效干预措施，但即使这种风险 NHOPI的减少低于白人。解决老年人健康差距的一个重要组成部分是 T2 DM是为了更好地了解运动增加胰岛素敏感性的分子机制。 几乎所有的细胞都会释放一类纳米级的细胞外囊泡，称为外泌体，它们广泛地循环 在整个身体。这些外来体携带来自其来源细胞的细胞蛋白、RNA和脂质， 通过释放它们的货物给受体细胞发信号。最近的证据表明，许多运动引起的 从骨骼肌（SkM）释放的信号分子在外泌体中转运， 增加了这些循环外泌体的数量在临床前研究中，久坐的小鼠注射了 从运动训练小鼠的SkM中分离的外泌体显示出改善的葡萄糖耐量和胰岛素分泌。 灵敏度然而，目前还没有关于运动如何刺激SkM外泌体释放或影响运动的研究报道。 它们的货物内容物，运动诱导的SkM外泌体如何增加胰岛素还知之甚少。 灵敏度该项目的目的是阐明运动诱导的 SkM外泌体调节主要代谢组织的胰岛素敏感性和葡萄糖代谢。我们 初步研究已经确定外囊蛋白复合物是SkM代谢之间的潜在联系， 和外泌体的产生。我们已经发现，SkM细胞中的外囊活性对胰岛素高度敏感， 在其他组织中，外囊调节外泌体的产生。我们的核心假设 运动刺激SkM中依赖于外泌体的外泌体释放， 主要代谢组织中增加胰岛素敏感性的因素。 为了验证这一假设，我们提出以下目的：（1）确定运动如何刺激外泌体 （2）鉴定运动诱导的SkM外泌体的分子货物和受体组织; (3)确定SkM衍生的外泌体增加运动后胰岛素的信号传导机制 胰岛素抵抗模型的敏感性。该项目汇集了最先进的体外和体内 SkM衍生的外泌体及其如何调节的首次全面分子研究的方法 胰岛素敏感性和主要代谢组织的葡萄糖代谢。这些研究奠定了临床前 SkM外泌体治疗方法的基础，并可能导致改进的 运动干预指南，这将有利于NHOPI和其他不成比例的T2 DM患者。

PROJECT SUMMARY/ABSTRACT Native Hawaiians and other Pacific Islanders (NHOPI) are disproportionately affected by type 2 diabetes (T2DM), with a two-fold higher prevalence than Whites in Hawaii. T2DM is characterized by hyperglycemia due to defective insulin action in metabolic tissues, including liver, skeletal muscle, and adipose tissue. Exercise is an effective intervention to improve glycemic control and reduce the risk of developing T2DM, yet even this risk reduction is lower in NHOPI than Whites. One important component of addressing the health disparities of T2DM is to better understand the molecular mechanisms by which exercise increases insulin sensitivity. Almost all cells release a class of nano-sized extracellular vesicles, called exosomes, which circulate widely throughout the body. These exosomes carry cellular proteins, RNAs, and lipids from their cell of origin and signal recipient cells through the release of their cargo. Recent evidence suggests that many exercise-induced signaling molecules released from skeletal muscle (SkM) are transported in exosomes, and acute exercise increases the number of these circulating exosomes. In pre-clinical studies, sedentary mice injected with exosomes isolated from the SkM of exercise-trained mice show improved glucose tolerance and insulin sensitivity. However, there are no reported studies on how exercise stimulates SkM exosome release or affects their cargo contents, and it is poorly understood how exercise-induced SkM exosomes increase insulin sensitivity. The objective of the proposed project is to elucidate the mechanism by which exercise-induced SkM exosomes modulate insulin sensitivity and glucose metabolism of major metabolic tissues. Our preliminary studies have identified the exocyst protein complex as a potential link between SkM metabolism and exosome production. We have found that exocyst activity in SkM cells is highly responsive to insulin and contraction signaling, and in other tissues, the exocyst regulates exosome production. Our central hypothesis is that exercise stimulates the exocyst-dependent release of exosomes in SkM, which deliver muscle-derived factors increasing insulin sensitivity in major metabolic tissues. To test this hypothesis, we propose the following Aims: (1) Determine how exercise stimulates exosome release in SkM cells; (2) Identify the molecular cargo and recipient tissues of exercise-induced SkM exosomes; (3) Determine the signaling mechanism by which SkM-derived exosomes increase post-exercise insulin sensitivity in models of insulin resistance. This project brings together state-of-the-art in vitro and in vivo approaches for the first comprehensive molecular study of SkM-derived exosomes and how they regulate insulin sensitivity and glucose metabolism of major metabolic tissues. These investigations lay the pre-clinical foundation for therapeutic approaches with SkM exosomes, and may lead to the development of improved exercise intervention guidelines, which will benefit NHOPI and others disproportionately afflicted by T2DM.