Leptin regulation of delta cell function

项目总结 三角洲细胞位于胰岛的独特位置，以整合局部信号和循环营养信号进行调节 α细胞和β细胞的功能。Delta细胞通过生长抑素对α细胞和β细胞的抑制作用 分泌物。SST旁分泌作用形成负反馈环抑制激素分泌维持 葡萄糖动态平衡。在2型糖尿病(T2D)中，三角洲细胞对环境葡萄糖的反应不成比例 从而改变胰岛素和胰升糖素的分泌，导致血糖紊乱。然而，我们知道的相对较少 关于影响三角洲细胞在健康和疾病中的机制。因此，理解调节因素 Delta细胞SST分泌可能揭示糖尿病的发病机制并指导新的治疗方法 以达到血糖的稳态。瘦素是一种循环荷尔蒙，会降低α细胞和β细胞的功能，但 具体的胰岛细胞靶点和作用机制尚不清楚。而瘦素有效地抑制胰岛素和 同时的实验表明，瘦素对α细胞和β细胞的影响是通过 间接机制。值得注意的是，瘦素受体(Lepr)仅在人胰岛的三角洲细胞上表达。 我们的初步数据显示，瘦素刺激人和小鼠胰岛分泌SST，相应地 胰岛素和胰升糖素分泌减少。我们的初步研究还表明，瘦素诱导的体表温度需要增量 细胞Lepr的表达，以及给定的SST抑制α和β细胞功能，表明了一种间接机制 瘦素通过SST调节α细胞和β细胞。因此，我们的首要假设是瘦素能刺激 三角洲细胞分泌SST抑制α细胞和β细胞的功能。我们的项目目标是通过以下方式定义机制(S) 瘦素调节SST的三角洲细胞分泌。在目标1中，我们将暂时将循环瘦素水平降低到 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。目标2 将使用遗传工具和SST受体拮抗剂来确定瘦素对三角洲细胞的特异性作用以及如何 瘦素在胰岛发挥旁分泌作用。最后，目标3将采用药物和遗传干预措施 用实时功能成像和无偏倚方法揭示血管紧张素转换酶的分子和转录机制 瘦素在三角洲细胞中的作用。这些研究首次描述了瘦素对胰腺三角洲细胞和SST的影响。 分泌物。考虑到我们对三角洲细胞知之甚少，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三角洲细胞的机制，并揭示一个统一的机制， 瘦素通过旁分泌SST信号间接作用于α细胞和β细胞。重要的是，德尔塔细胞扮演着 对维持胰岛素和胰升糖素分泌的平衡起着至关重要的作用。因此，我们的发现预计会有 对该领域的高度影响，并将揭示管理胰岛功能的新信号机制，这些机制可能会 对糖尿病的治疗益处。

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.