Leptin regulation of delta cell function

项目摘要 δ细胞在胰岛中的位置独特，可以整合局部信号和循环营养线索， α和β细胞功能。δ细胞通过生长抑素对α和β细胞发挥抑制作用 分泌物SST的旁分泌作用形成负反馈回路，抑制激素分泌，维持 葡萄糖稳态在2型糖尿病（T2D）中，δ细胞对环境葡萄糖的反应不成比例 并因此改变胰岛素和胰高血糖素分泌，导致功能障碍。然而，我们对 关于影响健康和疾病中的δ细胞的机制。因此，了解调节 δ细胞SST分泌可能揭示导致糖尿病的致病机制并指导新的治疗方法 以达到葡萄糖稳态。瘦素是一种循环激素，可降低α和β细胞功能， 具体的胰岛细胞靶点和作用机制尚不清楚。虽然瘦素有效地抑制胰岛素， 虽然瘦素对胰高血糖素分泌的影响，但当代实验表明瘦素对α和β细胞的影响是通过以下途径发生的： 间接机制。值得注意的是，瘦素受体（LepR）仅在人胰岛的δ细胞上表达。 我们的初步数据表明瘦素刺激人和小鼠胰岛SST分泌， 胰岛素和胰高血糖素分泌减少。我们的初步研究还表明，瘦素诱导的SST需要δ 细胞LepR表达，并给予SST抑制α和β细胞功能，表明间接机制 由此瘦素通过SST调节α和β细胞。因此，我们的总体假设是，瘦素刺激 δ细胞SST分泌以抑制α和β细胞功能。我们的项目目标是通过以下方式定义机制： 瘦素调节δ细胞分泌SST。在目标1中，我们将暂时降低循环瘦素水平， 明确瘦素对胰岛功能和形态的急性影响，与明显的高血糖无关。目的2 将使用遗传工具和SST受体拮抗剂来建立瘦素对δ细胞的特异性作用，以及如何 瘦素在胰岛中发挥旁分泌作用。最后，目标3将采用药理学和遗传学干预， 活的功能成像和公正的方法，以揭示分子和转录机制， δ细胞中的瘦素作用。这些研究首次描述了瘦素对胰腺δ细胞和SST的影响， 分泌物鉴于我们对δ细胞知之甚少，我们的项目在胰岛生物学方面取得了重大进展。 我们将定义瘦素调节δ细胞的机制，并揭示一个统一的机制， 瘦素通过旁分泌SST信号传导间接作用于α和β细胞。重要的是，δ细胞发挥着 维持胰岛素和胰高血糖素分泌平衡的关键作用。因此，我们的研究结果预计将 对该领域的影响很大，并将揭示新的信号机制，控制胰岛功能， 治疗糖尿病的好处。

PROJECT SUMMARY The delta cell is uniquely positioned in the islet to integrate local signals and circulating nutrient cues to regulate alpha and beta cell function. Delta cells exert inhibitory effects on alpha and beta cells through somatostatin secretion. Paracrine actions of SST form a negative feedback loop to restrain hormone secretion and maintain glucose homeostasis. In type 2 diabetes (T2D), delta cell responses to ambient glucose are disproportionate and consequently alter insulin and glucagon secretion leading to dysglycemia. However, we know relatively little about the mechanisms influencing delta cells in health and disease. Thus, understanding factors that regulate delta cell SST secretion may reveal pathogenic mechanisms contributing to diabetes and direct new therapies to achieve glucose homeostasis. Leptin is a circulating hormone that reduces alpha and beta cell function, but the specific islet cell target and mechanism of action are unclear. While leptin potently inhibits insulin and glucagon secretion, contemporary experiments suggest leptin effects on alpha and beta cells occurs through indirect mechanisms. Of note, the leptin receptor (LepR) is exclusively expressed on delta cells of human islets. Our preliminary data demonstrate leptin stimulates SST secretion from human and mouse islets, corresponding with decreased insulin and glucagon secretion. Our initial studies also show leptin-induced SST requires delta cell LepR expression, and given SST inhibits alpha and beta cell function, suggests an indirect mechanism whereby leptin regulates alpha and beta cells via SST. Thus, our overarching hypothesis is that leptin stimulates delta cell SST secretion to inhibit alpha and beta cell function. Our project goal is to define the mechanism(s) by which leptin regulates delta cell secretion of SST. In Aim 1, we will temporally reduce circulating leptin levels to define the acute impact of leptin on islet function and morphology independent of overt hyperglycemia. Aim 2 will use genetic tools and SST receptor antagonists to establish the leptin specific effects on delta cells and how leptin exerts paracrine effects in islets. Lastly, Aim 3 will employ pharmacologic and genetic interventions with live functional imaging and unbiased approaches to reveal the molecular and transcriptional mechanisms of leptin action in delta cells. These studies are the first to describe leptin effects on pancreatic delta cells and SST secretion. Our project offers a significant advancement in islet biology given how little we know about delta cells. We will define the mechanisms of leptin regulation of delta cells and uncover a unifying mechanism whereby leptin acts indirectly on alpha and beta cells through paracrine SST signaling. Importantly, delta cells play a critical role to maintain balance of insulin and glucagon secretion. As such, our findings are expected to have high impact on the field and will reveal new signaling mechanisms governing islet function that potentially exert therapeutic benefits for diabetes.