248-LB: Spexin Promotes Insulin Secretion and ß-Cell Proliferation

Abstract

Spexin was firstly discovered as a neuropeptide and was also detected in peripheral tissues including liver, fat and pancreatic islets. Recently, studies documents that diabetes patients had lower circulation level of Spexin. It is unclear whether Spexin exerts glucose homeostasis regulating effects. Here, we provide evidence that Spexin stimulates β cell proliferation and insulin secretion in mice and human islets. Acute administration of Spexin prior glucose challenge promoted insulin secretion and improved glucose tolerance in a dose dependent manner (35-200 μg/kg BW). Meanwhile, Spexin treatment had no effect on insulin tolerance. The addition of Spexin to mouse islets increased β cell proliferation demonstrated by 2-fold increase of BrdU(+) β-cells. Spexin promoted cell growth of INS-1 cells in a dose dependent manner with maximum effect at dose of 25 ng/ml. In a high-fat diet (HFD)-induced β cell proliferation and β cell mass expansion model, the percentage of Ki67(+) β-cells increased by 2-fold compared to chow diet (CD)-fed mice. Spexin provoked further 80% increase. Consistently, HFD feeding increased β-cell mass by 2-fold and Spexin made further 58% increase. To identify the mechanism of Spexin-stimulated β cell proliferation, we tested whether the expression of well-established β cell cycle regulators was controlled by Spexin. Spexin treatment of INS-1 cells for 24 h significantly increased mRNA levels of cyclin D1 and Cyclin E1 compared with controls. Spexin stimulated the phosphorylation of CREB (p-CREB) with a peak at 10 min. The addition of H89, a potent PKA inhibitor blocked the effect of Spexin on activation of p-CREB and stimulation of the expression of Ki67, Cyclin D1 and Cyclin E1. Furthermore, Spexin stimulated the p-CREB, promoted insulin secretion and increased β cell proliferation in human islets. Thus, Spexin is an important factor for islet β cell proliferation, and our study provides previously unrecognized evidence of a factor governing endocrine pancreas growth and function. Disclosure R. Liu: None. Funding National Natural Science Foundation of China (81200622, 81570518, 81630020)