1251-P: Pancreatic ß-Cell Specific Deletion of Complement 1q Like-3 Secreted Protein Improves Glucose Tolerance by Increasing Insulin Secretion

Abstract

Secreted proteins are important metabolic regulators in the healthy and disease states. Using network biology approaches, our laboratory identified that complement-1q like-3 (C1ql3) secreted protein has a role in affecting pancreatic islet function. We demonstrated that the recombinant C1ql3 protein inhibits insulin secretion in response to stimulation by exendin-4 (an agonist for the stimulatory Gs-coupled GLP-1 receptor) from human and mouse islets. C1ql3 is expressed in β-cells but not in α- or δ-cells of mouse islets. Its expression is also conserved in human islets. Our goal is to investigate the role of β-cell C1ql3 in whole-body glucose homeostasis. We generated mice with β-cell-specific deletion of C1ql3 (βKO) by crossing C1ql3fl/fl and RIP-Cre+ mice. Preliminary data show that C1ql3 βKO mice have increased body weight with no change in fasting plasma glucose levels than the control mice. The glucose clearance was significantly improved after oral glucose challenge, whereas no difference in insulin action was observed in the C1ql3 βKO vs. control mice. Moreover, the plasma insulin levels were significantly increased at 15 min after the glucose challenge in the C1ql3 βKO vs. control mice. These results suggest that the loss of C1ql3 in β-cells increases insulin secretion to improve glucose tolerance. The expression-coupled secretion of C1ql3 from islets is increased with obesity. Interestingly, reduction in C1ql3 secretion is inversely correlated with increased insulin secretion from islets of C1ql3 βKO Leptinob/ob compared to Leptinob/ob control mice. These findings identify that C1ql3 in an autocrine manner inhibits insulin secretion from β-cells to regulate whole-body glucose homeostasis. Our work identifies a novel C1ql3-signaling pathway that may contribute to the observed β-cell dysfunction in obesity and type 2 diabetes. Disclosure M. Rahman: None. H. Alsharif: None. J. E. Trombley: None. A. Pathak: None. S. Bhatnagar: None.