Hepatic endocrine suppression of the pancreatic beta-cell

描述(申请人提供)：2型糖尿病是一种流行程度的破坏性疾病，它威胁着个人生命和世界各地的主权经济。产生胰岛素的胰腺β细胞功能缺陷和死亡是糖尿病的一个标志。在这项建议中，我们旨在阐明β细胞功能障碍和死亡的分子机制(S)，这是由肝脏释放的一种迄今未被识别的激素：Kispeptin1介导的。在初步发现中，我们在模拟人类糖尿病的小鼠模型中观察到，肝脏产生并释放过量的Kispeptin到循环中。Kisspeptin1到达胰腺β细胞，并通过其位于β细胞上的受体Kiss1R发挥作用，以抑制环磷酸腺苷的产生。在人类2型糖尿病患者中观察到的β细胞环磷酸腺苷水平降低有几个潜在的后果：1)它减少了β细胞由葡萄糖刺激的胰岛素分泌；2)它减少了对胰岛素激素的反应，促进了葡萄糖模拟的胰岛素分泌；3)通过降低环磷酸腺苷水平，它使β细胞更容易由于细胞应激(内质网应激、未折叠蛋白反应和氧化应激)的增加而发生程序性细胞死亡(凋亡)。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。拟议的研究具有重要意义，因为它们可能导致确定治疗人类糖尿病的分子靶点和治疗方法，并防止或逆转β细胞功能障碍和死亡。

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.