Regulation of glucose homeostasis by prokineticin 2 signaling

描述（由申请人提供）：尽管取得了巨大的进步，但长期控制2型糖尿病的高血糖仍然是一个主要挑战。现有的高血糖控制药物包括双胍类药物、磺脲类药物、噻唑烷二酮类药物、α -葡萄糖苷酶抑制剂、胰岛素和肠促胰岛素等。目前的这些治疗方法通常与低血糖、体重增加或其他不良事件有关，如胃肠道不适、水肿、心力衰竭或骨折。能够长期纠正高血糖而不引起不良事件的新疗法是非常可取的。肠促胰岛素药物的成功支持了g蛋白偶联受体在胰岛素释放和葡萄糖稳态中的重要性。最近，我们已经积累了大量证据支持prokineticin 2 （PK2）的胰岛素抑制作用。PK2作为一种分泌调节肽，已被证明通过激活两个同源的G蛋白偶联受体，即前动素受体1 （PKR1）和前动素受体2 （PKR2）来调节多种生物过程。PK2以及PKR1和PKR2在胰腺β细胞中表达。pk2缺陷小鼠循环葡萄糖水平降低，空腹胰岛素水平升高，并在葡萄糖耐量试验中表现出增强的性能。外源性PK2可降低小鼠的葡萄糖清除能力。相反，小分子PK2受体拮抗剂可增强小鼠的葡萄糖清除率。PK2可能通过gi偶联途径降低急性分离胰岛和β细胞样MIN6细胞中葡萄糖刺激的胰岛素分泌。我们还表明，高葡萄糖处理诱导PK2从MIN6细胞释放到条件培养基中。我们进一步表明，高脂肪饮食诱导的高血糖可上调胰岛PK2的表达，这表明慢性高血糖时PK2表达的动态上调可能会破坏随后葡萄糖负荷下胰岛素的释放。综上所述，我们的初步研究结果表明PK2对胰腺β细胞的功能起反馈胰岛素抑制作用。我们建议进一步研究PK2信号在葡萄糖稳态中的作用。特别是，我们将进一步研究PK2拮抗剂对瘦小鼠和db/db小鼠口服葡萄糖的降血糖作用。我们将在体外和体内研究胰腺β细胞PK2表达在高糖环境下的动态变化。我们将进一步研究PK2信号在离体胰岛胰岛素释放中的作用和信号传导机制。最后，我们试图在PK2信号缺乏的人类受试者中验证我们的发现。这些研究的成功完成将导致胰岛素释放和葡萄糖稳态的新信号机制的验证。由于2型糖尿病的一个典型病理生理特征是葡萄糖从胰腺β细胞释放胰岛素不足，通过小分子拮抗剂拮抗PK2以减轻PK2的胰岛素抑制作用可能为控制高血糖提供一种潜在的新治疗途径。

DESCRIPTION (provided by applicant): Despite enormous advances, long term control of hyperglycemia for type 2 diabetes remains a major challenge. Existing pharmacological options of hyperglycemia control include biguanides, sulfonylureas, thiazolidinediones, alpha-glucosidase inhibitors, insulin and incretin agents. These current therapies are often associated with hypoglycemia, weight gain or other adverse events such as gastrointestinal discomfort, edema, cardiac failure or fractures. New therapies that can correct hyperglycemia on a long-term basis without causing adverse events are highly desirable. The success of incretin agents has supported the importance of G-protein coupled receptors on insulin release and therefore glucose homeostasis. Recently, we have accumulated substantial evidence that supports the insulinostatic effect of prokineticin 2 (PK2). PK2, as a secreted regulatory peptide, has previously been shown to regulate diverse biological processes via the activation of two cognate G protein-coupled receptors, prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). PK2 as well as PKR1 and PKR2 are expressed in pancreatic beta-cells. PK2-deficient mice have reduced circulating glucose levels, elevated fasting insulin levels, and exhibit enhanced performance in a glucose tolerance assay. Administration of exogenous PK2 was shown to diminish capabilities of glucose clearance in mice. Conversely, administration of a small molecule PK2 receptor antagonist enhances glucose clearance in mice. PK2 decreases glucose-stimulated insulin secretion in acutely isolated pancreatic islets as well as in beta-cell-like MIN6 cells, likely via Gi-coupled pathway. We have also shown that high glucose treatment induces the release of PK2 into conditioned media from MIN6 cells. We have further shown that high fat diet-induced hyperglycemia up-regulates PK2 expression in pancreas islets, indicating dynamic up-regulation of PK2 expression in response to chronic hyperglycemia may disrupt subsequent insulin release in response to glucose load. Taken together, our preliminary findings have indicated that PK2 plays a feedback insulinostatic role on the function of pancreatic beta-cells. We propose to further investigate the role of PK2 signaling on glucose homeostasis. Particularly, we will further examine the glucose-lowering effect of PK2 antagonists in response to oral glucose in lean mice as well as in db/db mice. We will investigate the dynamic change of PK2 expression in pancreas beta-cells in response to high glucose in vitro and in vivo. We will further investigate the role and signaling mechanism of PK2 signaling on insulin release with isolated pancreas islets. Finally, we seek to validate our findings with human subjects that are deficient in PK2 signaling. The successful completion of these studies will lead to the validation of a novel signaling mechanism for insulin release and glucose homeostasis. As one characteristic pathophysiological feature of type 2 diabetes is the inadequate release of insulin from pancreatic beta-cells by glucose, PK2 antagonism via small molecule antagonists to relieve the insulinostatic effect of PK2 may provide a potential novel therapeutic avenue for controlling hyperglycemia. PUBLIC HEALTH RELEVANCE: The prevalence of type 2 diabetes has risen dramatically during recent decades. Due to a variety of adverse effects associated with current pharmacological therapies, control of hyperglycemia for type 2 diabetes remains a major challenge. We propose to examine the role and mechanism of a novel regulatory peptide signaling in insulin release and glucose homeostasis. The successful completion of these studies may lead to the identification of a potential therapeutic strategy and agent for the treatment of type 2 diabetes.