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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘