Regulation of glucose homeostasis by prokineticin 2 signaling

通过前动力蛋白 2 信号传导调节葡萄糖稳态

• 批准号: 8095574
• 负责人: QUN-YONG ZHOU
• 金额: $ 24.02万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095574
• 关键词: 2,4-thiazolidinedione; Adverse effects; Adverse event; Alpha-glucosidase; Animal Welfare; Beta Cell; Biguanides; Biological Assay; Biological Process; Cell physiology; Cells; Characteristics; Chronic; Clinical; Conditioned Culture Media; Coupled; Diet; Edema; Endocrine-Gland-Derived Vascular Endothelial Growth Factor; Exhibits; Fasting; Fatty acid glycerol esters; Feedback; Fracture; G-Protein-Coupled Receptors; Gastric Inhibitory Polypeptide; Gastrointestinal tract structure; Genes; Glucose; Glucosidase Inhibitor; Heart failure; Human; Hyperglycemia; Hypoglycemia; In Situ Hybridization; In Vitro; Insulin; Islets of Langerhans; Lead; Maintenance; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; OGTT; Oral; Pancreas; Pathway interactions; Peptide Signal Sequences; Peptides; Performance; Plasma; Play; Prevalence; Proteins; Regulation; Role; Signal Transduction; Signaling Molecule; Structure of beta Cell of islet; Sulfonylurea Compounds; Therapeutic; Thiazolidinediones; Time; Up-Regulation; Validation; Weight Gain; base; blood glucose regulation; db/db mouse; gastrointestinal; glucagon-like peptide; glucose tolerance; human subject; in vivo; incretin hormone; insulin secretion; islet; loss of function mutation; mortality; novel; novel therapeutics; operation; receptor; receptor coupling; response; small molecule; success

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.

描述（由申请人提供）：尽管进步巨大，但长期控制2型糖尿病的高血糖仍然是一个主要挑战。高血糖控制的现有药理学选择包括Biguanides，磺酰氟菌，硫胆苷二酮，α-葡萄糖苷酶抑制剂，胰岛素和肠降凝蛋白剂。这些当前的疗法通常与低血糖，体重增加或其他不良事件有关，例如胃肠道不适，水肿，心脏衰竭或骨折。非常需要长期纠正高血糖的新疗法是非常需要的。肠降血糖素剂的成功支持了G蛋白偶联受体在胰岛素释放和葡萄糖稳态上的重要性。最近，我们积累了大量证据，以支持脑力下2（PK2）的胰岛素抑制作用。作为一种分泌的调节肽，PK2先前已通过激活两个同源G蛋白偶联受体，促动蛋白受体1（PKR1）和原蛋白毒素受体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。缺乏PK2的小鼠可降低循环葡萄糖水平，空腹胰岛素水平升高，并在葡萄糖耐受性测定中表现出增强的性能。外源性PK2的给药显示可降低小鼠葡萄糖清除的能力。相反，施用小分子PK2受体拮抗剂可增强小鼠的葡萄糖清除率。 PK2降低了急性分离的胰岛以及类似β细胞的MIN6细胞中的葡萄糖刺激的胰岛素分泌，这可能是通过GI偶联途径。我们还表明，高葡萄糖处理可诱导PK2从MIN6细胞中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症上调胰腺胰岛中的PK2表达，表明响应慢性高血糖的PK2表达动态上调可能会破坏随后胰岛素释放，以响应葡萄糖负荷。综上所述，我们的初步发现表明，PK2在胰腺β细胞的功能上起反馈胰岛素的作用。我们建议进一步研究PK2信号在葡萄糖稳态上的作用。特别是，我们将进一步研究瘦小小鼠以及DB/DB小鼠中PK2拮抗剂对口服葡萄糖的降糖作用。我们将研究胰腺β细胞中PK2表达的动态变化，以响应高葡萄糖体外和体内。我们将进一步研究PK2信号传导在胰岛素释放中的作用和信号传导机制。最后，我们试图用缺乏PK2信号传导的人类受试者来验证我们的发现。这些研究的成功完成将导致验证一种新型的胰岛素释放和葡萄糖稳态的信号传导机制。由于2型糖尿病的一种特征性病理生理特征是葡萄糖从胰腺β细胞中释放胰岛素不足，因此通过小分子拮抗剂PK2拮抗作用是PK2的PK2拮抗作用，无法缓解PK2的胰岛素替代作用，可以缓解一种潜在的新型治疗方法来控制超级葡萄球菌。 公共卫生相关性：近几十年来，2型糖尿病的患病率急剧上升。由于与当前药理疗法相关的多种不良反应，控制2型糖尿病的高血糖仍然是一个主要挑战。我们建议检查新型调节性肽信号传导在胰岛素释放和葡萄糖稳态中的作用和机制。这些研究的成功完成可能会导致鉴定潜在的治疗策略和治疗2型糖尿病的药物。