Control of glucose homeostasis through the insulin-independent Isthmin pathway

项目总结 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 导致2型糖尿病、胰岛素抵抗和心血管疾病的增加。另类选择的发现 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 医疗需要。这些途径可以被用来开发新的治疗策略，以对抗糖尿病和 胰岛素抵抗。使用计算、细胞和体内相结合的多学科策略 方法，我们最近从热源性脂肪中发现了一种新的脂肪因子，Isthmin-1(ISM1)，它 促进小鼠和人类脂肪细胞的葡萄糖摄取。ISM1的操作需要PI3K/AKT 信号传递，但完全独立于胰岛素受体。高脂饮食导致糖尿病的动物 喂食、注射重组ISM1蛋白或提高循环中ISM1的遗传水平均可改善 葡萄糖动态平衡。然而，还需要更多的研究来了解ISM1对 葡萄糖代谢，并利用这一认识用于治疗目的。年的总体目标 这项建议是为了确定ISM1如何通过确定信号效应器和 介导这一作用的细胞表面受体，决定ISM1的内源性生理功能，以及 评价ISM1作为治疗靶点的药理潜力。在目标1中，我们将利用生物化学， 遗传学和蛋白质组学方法确定信号通路和细胞表面受体负责 Ism1的信号作用和糖调节机制。这些研究将确定ISM1的S机制 对于我们理解Ism1信号作为胰岛素非依赖性途径将是至关重要的 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Ism1基因敲除小鼠。这些研究对于确定 Ism1在糖代谢中的内源性作用。在目标3中，我们将确定以下各项的最低要求 通过产生ISM1的片段、突变体和工程形式的ISM1的生物活性。这一目标将为 进一步优化多肽激素作为治疗剂的方法，并将在 了解这一新的生理学途径增强的效果。这些贡献是 预计意义重大，因为可以独立于胰岛素调节血糖的通路将打开 克服胰岛素抵抗和糖尿病的全新途径，这可能会有相当大的公众 对健康的影响。

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.