Hepatic endocrine suppression of the pancreatic beta-cell

描述（由申请人提供）：2型糖尿病是一种具有流行性的毁灭性疾病，正在威胁着个人生命以及全球主权经济。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。在这项提案中，我们的目标是阐明β细胞功能障碍和死亡的分子机制，这是由肝脏释放的一种迄今尚未认识到的激素介导的：kisspeptin 1。在初步研究结果中，我们观察到在模拟人类糖尿病的小鼠模型中，肝脏产生并向循环中释放过量的kisspeptin 1。Kisspeptin 1到达胰腺β细胞并通过其受体Kiss 1 R起作用，Kiss 1 R位于β细胞上以抑制环AMP产生。β-细胞环AMP水平的降低具有在患有2型糖尿病的人中观察到的几种潜在后果：1）其减少葡萄糖刺激的胰岛素从β-细胞的分泌; 2）其减少在增强葡萄糖刺激的胰岛素分泌中对肠促胰岛素激素的响应; 3）通过降低环AMP水平，使β细胞易于程序性细胞死亡细胞凋亡是细胞应激（内质网应激、未折叠蛋白反应和氧化应激）增加的结果。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2型糖尿病患者。所提出的研究是重要的，因为它们可能导致识别用于治疗患有糖尿病的人类以及预防或逆转β细胞功能障碍和β细胞死亡的分子靶标和治疗方法。

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.