Hepatic endocrine suppression of the pancreatic beta-cell

胰腺β细胞的肝脏内分泌抑制

• 批准号: 9671615
• 负责人: Mehboob A Hussain
• 金额: $ 36.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9671615
• 关键词: Hepatic; endocrine; suppression; pancreatic; beta

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 ß-cells is a hallmark of diabetes mellitus. In this proposal we aim to elucidate molecular mechanism(s) underlying ß-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 ß-cells and acts through its receptor Kiss1R, which is located on ß-cells to inhibit cyclic AMP production. Reduction in ß-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 ß-cells; 2) it reduces the response to incretin hormones in potentiating glucose simulated insulin secretion; 3) by reducing cyclic AMP levels, it renders ß-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 ß-cell dysfunction and -death.

描述（由适用提供）：2型糖尿病是一种毁灭性疾病的流行比例疾病，它威胁到全球个人生活以及主权经济。产生胰岛素的胰腺β-细胞的功能和死亡是糖尿病的标志。在此提案中，我们旨在阐明β-细胞功能障碍和灭亡的分子机制，这些机制是由迄今未识别的肝脏释放的激素介导的：Kisspeptin1。在初步的发现中，我们在模仿人类糖尿病的小鼠模型中观察到，肝脏会产生并释放到循环中，超过了Kisspeptin1。 Kisspeptin1到达胰腺β细胞，并通过其受体Kiss1r作用，该受体Kiss1r位于ß细胞上以抑制环状AMP的产生。 ß细胞环状AMP水平的降低具有几种潜在的后果，这些后果在2型糖尿病的人类中观察到：1）它减少了从ß细胞中降低葡萄糖刺激的胰岛素分泌； 2）它减少了增强葡萄糖模拟胰岛素分泌的激素增加的反应； 3）通过降低环状AMP水平，它使ß细胞因细胞应激增加（内质网应激，未折叠的蛋白质反应和氧化应激）而容易受到程序性细胞死亡（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械基础，并测试这些发现是否适用于2型糖尿病的人类。拟议的研究之所以重要，是因为它们可能导致鉴定分子靶标和治疗方法，以治疗糖尿病，并防止或逆转ß细胞功能障碍和 - 死亡。