Hepatic endocrine suppression of the pancreatic beta-cell

胰腺β细胞的肝脏内分泌抑制

• 批准号: 8817887
• 负责人: Mehboob A Hussain
• 金额: $ 51.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8817887
• 关键词: Ablation; Acute; Address; Adult; Anabolism; Apoptosis; Blood Circulation; Cell physiology; Cells; Cellular Stress; Cessation of life; Chemosensitization; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Endocrine; Epidemic; Exhibits; Functional disorder; Gastric Inhibitory Polypeptide; Gene Expression Profiling; Genes; Glucagon; Glucagon Receptor; Glucose; Hepatic; Hepatocyte; Hormones; Human; Hyperglycemia; In Vitro; Individual; Inflammation; Infusion procedures; Insulin; Insulin Resistance; Intake; Lead; Liver; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Molecular; Molecular Target; Mus; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Obesity; Oxidative Stress; Pancreas; Pathogenesis; Peptide Receptor; Plasma; Production; Protein Biosynthesis; Proteins; Receptor Activation; Role; Signal Transduction; Simulate; Stress; Structure of beta Cell of islet; Testing; Therapeutic; Up-Regulation; Wild Type Mouse; endoplasmic reticulum stress; glucagon-like peptide; glucose tolerance; hepatic gluconeogenesis; hyperglucagonemia; improved; in vivo; incretin hormone; insulin secretion; islet; kisspeptin; mouse model; novel; prevent; public health relevance; receptor; response; small hairpin RNA

DESCRIPTION (provided by applicant): Type 2 diabetes Mellitus is a devastating disease of epidemic proportions, which is threatening individual lives as well as sovereign economies worldwide. Defective function and death of insulin-producing pancreatic β-cells is a hallmark of diabetes mellitus. In this proposal we aim to elucidate molecular mechanism(s) underlying β-cell dysfunction and demise, which are mediated by a thus far unrecognized hormone released by the liver: kisspeptin1. In preliminary findings, we observe in mouse models which mimic human diabetes mellitus, the liver produces and releases into the circulation excessive amounts of kisspeptin1. Kisspeptin1 reaches the pancreatic β-cells and acts through its receptor Kiss1R, which is located on β-cells to inhibit cyclic AMP production. Reduction in β-cell cyclic AMP levels has several potential consequences which are observed in humans with type 2 diabetes mellitus: 1) it reduces glucose-stimulated insulin secretion from β-cells; 2) it reduces the response to incretin hormones in potentiating glucose simulated insulin secretion; 3) by reducing cyclic AMP levels, it renders β-cells susceptible to programmed cell death (apoptosis) as a consequence of increased cellular stress (endoplasmic reticulum stress, unfolded protein response and oxidative stress). The proposed studies aim to further elucidate the mechanistic underpinnings of our preliminary findings and to test whether the findings apply to humans with type 2 diabetes mellitus. The proposed studies are significant because they may lead to identification of molecular targets and therapeutic approaches for treating humans with diabetes mellitus and preventing or reversing β-cell dysfunction and -death.

描述（由申请人提供）：2 型糖尿病是一种毁灭性的流行病，正在威胁个人生命以及全世界的主权经济体。产生胰岛素的胰腺β细胞的功能缺陷和死亡是糖尿病的标志。在本提案中，我们的目标是阐明 β 细胞功能障碍和死亡的分子机制，这些机制是由肝脏释放的一种迄今为止未被识别的激素：kisspeptin1 介导的。在初步研究中，我们在模拟人类糖尿病的小鼠模型中观察到，肝脏产生并向循环系统释放过量的 Kisspeptin1。 Kisspeptin1 到达胰腺 β 细胞，并通过其受体 Kiss1R 发挥作用，该受体位于 β 细胞上，抑制环 AMP 的产生。 β 细胞环磷酸腺苷水平的降低具有在 2 型糖尿病患者中观察到的几个潜在后果：1) 它减少了 β 细胞葡萄糖刺激的胰岛素分泌； 2) 它降低了对肠促胰岛素激素的反应，增强了葡萄糖模拟胰岛素的分泌； 3) 通过降低环磷酸腺苷水平，它使 β 细胞由于细胞应激（内质网应激、未折叠蛋白反应和氧化应激）增加而容易受到程序性细胞死亡（细胞凋亡）的影响。拟议的研究旨在进一步阐明我们初步发现的机制基础，并测试这些发现是否适用于患有 2 型糖尿病的人类。拟议的研究意义重大，因为它们可能导致识别分子靶标和治疗人类糖尿病以及预防或逆转 β 细胞功能障碍和死亡的治疗方法。