THE MECHANISM OF ACTION OF A NEWLY DEVELOPED BLOOD GLUCOSE-LOWERING HORMONE

新开发的降血糖激素的作用机制

• 批准号: 7721088
• 负责人: GEORGE G HOLZ
• 金额: $ 1.13万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721088
• 关键词: Adolescent; Amides; Anabolism; Attention; Beta Cell; Biological; Blood Glucose; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Distal; Exhibits; Funding; Genetic Transcription; Glucose; Grant; Growth Factor; Hormones; Institution; Insulin; Intestines; Islets of Langerhans; L Cells; Membrane; Methods; Mitochondria; New York; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Pancreas; Peptides; Production; Proinsulin; Property; Purpose; Reporting; Research; Research Personnel; Resources; Rodent; Source; Structure of beta Cell of islet; United States National Institutes of Health; Universities; diabetic; glucagon-like peptide 1; glucose metabolism; insulin secretion; medical schools; novel therapeutics; programs

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: The research program under the direction of Dr. Holz at New York University School of Medicine is one in which he has sought to identify and characterize novel therapeutic strategies that might be of use for the treatment of type 2 (adult-onset) diabetes mellitus. To this end, he has focused on ascertaining the blood glucose-lowering properties of an insulinotropic hormone that is currently under clinical investigation. This hormone is glucagon-like peptide-1-(7-36)-amide (GLP-1), a peptide secreted by enteroendocrine L-cells of the distal intestine, and which when administered to type 2 diabetic subjects, lowers blood glucose concentration. GLP-1: GLP-1 exhibits a number of important biological actions at the endocrine pancreas. Earlier on it was recognized that GLP-1 stimulates pancreatic beta-cell insulin gene transcription, translational biosynthesis of proinsulin, and glucose-dependent insulin secretion. What has recently become appreciated is that GLP-1 also exerts growth factor-like effects on beta-cells. For example, GLP-1 stimulates the proliferation of rodent beta-cells, thereby increasing their number substantially. This growth factor-like action has attracted attention because it suggests that GLP-1 might stimulate an increase of beta-cell mass not only in type 2 diabetic subjects, but perhaps in type 1 (juvenile-onset) diabetic subjects as well. The purpose of the research relating to this Sub Proposal concerns the action of GLP-1 to stimulate pancreatic insulin secretion. We intend to develop a method for following the modulation of beta-cell glucose metabolism by GLP. The Central Hypothesis presented here is that GLP-1 upregulates beta-cell glucose metabolism, thereby facilitating membrane depolarization and Ca2+ influx that initiates beta-cell insulin secretion. This action of GLP-1 might relate to its reported ability to stimulate mitochondrial ATP production, as reported by Rutter and co-workers (Biochem. J. 2003).

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 简介：纽约大学医学院 Holz 博士领导的研究项目旨在寻找和表征可能用于治疗 2 型（成人发病）糖尿病的新型治疗策略梅利图斯。为此，他专注于确定目前正在进行临床研究的促胰岛素激素的降血糖特性。这种激素是胰高血糖素样肽-1-(7-36)-酰胺 (GLP-1)，一种由远端肠道肠内分泌 L 细胞分泌的肽，当给予 2 型糖尿病受试者时，可降低血糖浓度。 GLP-1：GLP-1 在内分泌胰腺中表现出许多重要的生物学作用。早些时候人们认识到 GLP-1 刺激胰腺 β 细胞胰岛素基因转录、胰岛素原的翻译生物合成以及葡萄糖依赖性胰岛素分泌。最近人们认识到 GLP-1 还对 β 细胞发挥生长因子样作用。例如，GLP-1 刺激啮齿动物 β 细胞的增殖，从而大幅增加其数量。这种生长因子样作用引起了人们的关注，因为它表明 GLP-1 不仅可能刺激 2 型糖尿病受试者的 β 细胞质量增加，而且可能也刺激 1 型（青少年发病）糖尿病受试者的 β 细胞质量增加。与本子提案相关的研究目的涉及 GLP-1 刺激胰腺胰岛素分泌的作用。我们打算开发一种通过 GLP 调节 β 细胞葡萄糖代谢的方法。这里提出的中心假设是 GLP-1 上调 β 细胞葡萄糖代谢，从而促进膜去极化和 Ca2+ 流入，从而启动 β 细胞胰岛素分泌。正如 Rutter 及其同事报道的那样，GLP-1 的这种作用可能与其刺激线粒体 ATP 产生的能力有关（Biochem. J. 2003）。