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: 8313920
• 负责人: QUN-YONG ZHOU
• 金额: $ 18.87万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313920
• 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.

描述（由申请人提供）：尽管取得了巨大进展，但长期控制2型糖尿病的高血糖仍然是一个重大挑战。控制高血糖症的现有药物选择包括双胍类、磺酰脲类、噻唑烷二酮类、α-葡萄糖苷酶抑制剂、胰岛素和肠促胰岛素。这些目前的治疗通常与低血糖、体重增加或其他不良事件（如胃肠道不适、水肿、心力衰竭或骨折）相关。非常需要能够长期纠正高血糖而不引起不良事件的新疗法。肠促胰岛素制剂的成功支持了G蛋白偶联受体对胰岛素释放的重要性，因此支持了葡萄糖稳态。最近，我们已经积累了大量的证据，支持促动力素2（PK 2）的胰岛素抑制作用。PK 2作为一种分泌性调节肽，先前已被证明通过激活两种同源G蛋白偶联受体，前动力蛋白受体1（PKR 1）和前动力蛋白受体2（PKR 2）来调节多种生物学过程。PK 2以及PKR 1和PKR 2在胰腺β细胞中表达。PK 2缺陷小鼠具有降低的循环葡萄糖水平、升高的空腹胰岛素水平，并且在葡萄糖耐量测定中表现出增强的性能。外源性PK 2的给药显示降低小鼠的葡萄糖清除能力。相反，小分子PK 2受体拮抗剂的施用增强小鼠中的葡萄糖清除。PK 2在急性分离的胰岛以及β细胞样MIN 6细胞中降低葡萄糖刺激的胰岛素分泌，可能通过Gi偶联途径。我们还表明，高糖处理诱导PK 2从MIN 6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上调了胰岛中PK 2的表达，这表明PK 2表达响应慢性高血糖的动态上调可能会破坏随后响应葡萄糖负荷的胰岛素释放。综上所述，我们的初步研究结果表明，PK 2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PK 2信号传导对葡萄糖稳态的作用。特别是，我们将进一步研究PK 2拮抗剂对瘦小鼠以及db/db小鼠口服葡萄糖的降糖作用。我们将在体外和体内研究高糖对胰腺β细胞PK 2表达的动态变化。我们将进一步研究PK 2信号通路在胰岛细胞胰岛素释放中的作用及其信号机制。最后，我们试图用PK 2信号传导缺陷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型糖尿病的一个特征性病理生理学特征是葡萄糖导致胰岛素从胰腺β细胞释放不足，因此通过小分子拮抗剂拮抗PK 2以减轻PK 2的胰岛素抑制作用可能为控制高血糖症提供潜在的新治疗途径。