Regulation of glucose homeostasis by prokineticin 2 signaling

点击翻译按钮获取中文摘要

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.