Role of the Renin-Angiotensin System in Glucose Homeostasis

肾素-血管紧张素系统在血糖稳态中的作用

• 批准号: 10665042
• 负责人: Sakeneh Zraika
• 金额: $ 39.05万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-14 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665042
• 关键词: Address; Adolescent; Adult; Anabolism; Angiotensins; Antidiabetic Drugs; Apoptosis; Beta Cell; Binding; CRISPR/Cas technology; Cell Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Clinical Management; Data; Deterioration; Development; Diabetic mouse; Dipeptides; Diphtheria Toxin; Exposure to; Failure; Future; GLP-I receptor; GPRC6A gene; Genetic Transcription; Glucagon; Glucose; Goals; Human; Hydrolysis; In Vitro; Inhibition of Apoptosis; Insulin; Investigation; Islets of Langerhans Transplantation; Knock-out; Mediating; Modeling; Mus; Mutagenesis; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Output; Paracrine Communication; Pharmaceutical Preparations; Prevalence; Production; Proliferating; Property; Proteins; Public Health; Renin-Angiotensin System; Research; Resistance; Role; Signal Pathway; Signal Transduction; Structure of beta Cell of islet; Testing; Therapeutic; Therapeutic Intervention; Time; Withdrawal; Youth; active method; age related; blood glucose regulation; cell regeneration; diabetic; gain of function; glucagon-like peptide 1; glycemic control; improved; in vivo; inhibitor; innovation; insulin secretion; islet; loss of function; new therapeutic target; non-diabetic; novel; paracrine; phosphoproteomics; preservation; prevent; proglucagon; protective effect; targeted treatment; therapeutic development; transplant model

PROJECT SUMMARY/ABSTRACT In treating type 2 diabetes (T2D), there is a paucity of medications simultaneously targeting deficits in both β-cell function and mass. Angiotensin(1-7), a metabolite of the renin-angiotensin system, may fill this gap; however, its underlying mechanisms of action are incompletely understood. Our data reveal that the insulinotropic action of angiotensin(1-7) is dependent on its hydrolysis to the dipeptide, angiotensin(1-2), the latter also conveying pro-survival and proliferative effects in β cells. Angiotensin(1-2) activates G-protein- coupled receptor family C group 6 member A (GPRC6A), which we show is expressed in islet a cells. Further, angiotensin(1-2) increases a cell-derived glucagon-like peptide-1 (GLP-1) release, suggesting it acts via GPRC6A on the a cell to promote insulin secretion in a paracrine fashion. Indeed, in GLP-1 receptor deficient islets, we find that angiotensin(1-2) fails to potentiate insulin secretion; however, its ability to enhance β-cell survival and proliferation is retained. The latter suggests angiotensin(1-2)’s action is, in part, GLP-1 receptor- independent. Based on these novel data, we hypothesize angiotensin(1-2) enhances β-cell function via intra- islet paracrine signaling, and promotes β-cell survival/proliferation via a novel GLP-1-independent mechanism. The following specific aims address this hypothesis, with the goal of improving treatment options in T2D: Specific Aim 1. To determine the mechanism by which angiotensin(1-2) increases islet-derived GLP-1 and insulin secretion. Mice (in vivo) and islets (in vitro) with diphtheria toxin-induced a-cell destruction or a cell-specific GPRC6A knockout will be used to determine whether angiotensin(1-2)-mediated increases in insulin release require a cells or a-cell GPRC6A, respectively. We will probe mechanisms for increased GLP-1 release, and confirm key findings in human islets with and without GLP-1 receptor or GPRC6A blockade. Specific Aim 2. To identify signaling pathways/proteins mediating the β-cell survival and proliferative effects of Ang(1-2) in human islets. The ability of angiotensin(1-2) to inhibit apoptosis, reduce dedifferentiation and enhance proliferation of β cells will be examined in human islets under non-diabetic and diabetic conditions. The contribution of mechanisms independent of GLP-1 or GPRC6A will be determined. Effectors of angiotensin(1-2) action will be identified using non-biased phosphoproteomics, then loss-/gain-of- function studies in islets will serve as a preliminary screen for effectors that could be targeted therapeutically. Specific Aim 3. To determine whether Ang(1-2) improves human islet function/survival in vivo, and whether hydrolysis of Ang(1-7) is required for its anti-diabetic effects. We will utilize a human islet transplant model to determine the ability of angiotensin(1-2) to improve β-cell function/survival and glycemia in diabetic mice. Further, we will test whether the insulinotropic action of angiotensin(1-7) requires its hydrolysis, as is the case in vitro. The latter is highly significant for clinical management of T2D because it will inform on the utility of hydrolysis-resistant angiotensin(1-7)-based medications currently in development.

项目概要/摘要 在治疗 2 型糖尿病 (T2D) 时，同时针对这两种疾病的缺陷的药物很少 β 细胞功能和质量，肾素-血管紧张素系统的代谢物血管紧张素 (1-7) 可能会填补这一空白。 然而，我们的数据表明，其潜在的作用机制尚不完全清楚。 血管紧张素 (1-7) 的促胰岛素作用取决于其水解为二肽血管紧张素 (1-2)、 后者还在 β 细胞中发挥促存活和增殖作用。血管紧张素 (1-2) 激活 G 蛋白。 偶联受体家族 C 组 6 成员 A (GPRC6A)，我们显示其在胰岛 a 细胞中表达。 血管紧张素 (1-2) 增加细胞源性胰高血糖素样肽-1 (GLP-1) 的释放，表明它通过 事实上，在 GLP-1 受体缺陷的情况下，细胞上的 GPRC6A 以旁分泌方式促进胰岛素分泌。 在胰岛中，我们发现血管紧张素(1-2)不能增强胰岛素分泌，但其增强β细胞的能力； 存活和增殖得以保留，后者表明血管紧张素 (1-2) 的作用部分是由 GLP-1 受体驱动的。 基于这些新数据，我们研究血管紧张素 (1-2) 通过体内增强 β 细胞功能。 胰岛旁分泌信号传导，并通过一种新型的 GLP-1 独立机制促进 β 细胞存活/增殖。 以下具体目标针对这一假设，旨在改善 T2D 的治疗选择： 具体目标 1. 确定血管紧张素(1-2) 增加胰岛来源的 GLP-1 的机制 小鼠（体内）和胰岛（体外）受到白喉毒素诱导的 a 细胞破坏或胰岛素分泌。 细胞特异性 GPRC6A 敲除将用于确定血管紧张素 (1-2) 介导的血管紧张素 (1-2) 是否增加 胰岛素释放分别需要a细胞或a细胞GPRC6A，我们将探讨GLP-1增加的机制。 释放，并确认在有或没有 GLP-1 受体或 GPRC6A 阻断的人胰岛中的关键发现。 具体目标 2. 确定介导 β 细胞存活和增殖的信号通路/蛋白质 Ang(1-2) 对人胰岛的影响 血管紧张素(1-2) 抑制细胞凋亡、降低细胞凋亡的能力。 将在非糖尿病和糖尿病患者胰岛中检查β细胞的去分化和增强增殖。 将确定独立于 GLP-1 或 GPRC6A 的机制的贡献。 将使用无偏磷酸蛋白质组学来鉴定血管紧张素（1-2）作用的效应器，然后损失/增加 胰岛功能研究将作为可作为治疗目标的效应器的初步筛选。 具体目标 3. 确定 Ang(1-2) 是否能改善人体内胰岛功能/存活率，以及 Ang(1-7) 的水解是否是其抗糖尿病作用所必需的 我们将利用人类胰岛。 移植模型以确定血管紧张素 (1-2) 改善 β 细胞功能/存活和血糖的能力 此外，我们将测试血管紧张素（1-7）的促胰岛素作用是否需要其水解， 与体外的情况一样，后者对于 T2D 的临床管理非常重要，因为它将提供信息。 目前正在开发的基于抗水解血管紧张素（1-7）的药物的用途。