SAT-168 A Secreted Protein Complement 1q Like-3 Protein Inhibits Insulin Secretion by an Adhesion G-Protein Coupled Receptor, BAI3 in Pancreatic β-Cells

Secreted proteins are important metabolic regulators in both healthy and disease states. By using Bioinformatics approaches, we identified complement-1q-like-3 secreted protein that expressed in α-cells affects β-cell function in the pancreatic islets. Our objective was to investigate the mechanism by which C1ql3 regulates insulin secretion from pancreatic β-cells. Our data suggest that C1ql3 predominantly inhibits exendin-4 and cAMP-stimulated insulin secretion from mouse and human islets. Moreover, C1ql3 also attenuated insulin secretion stimulated by high KCl, a sulphonyl urea tolbutamide (potassium channel blocker) and high glucose to a lesser extent. Interestingly, C1ql3 failed to affect insulin secretion caused by fatty acids, amino acids, or mitochondrial metabolites, either at low or submaximal glucose concentrations. Furthermore, C1ql3 decreased islet-cAMP levels stimulated by high glucose, and insulin secretion caused by Epac2 (exchange protein directly activated by cAMP-2) and protein kinase A. Our data suggest that C1ql3 inhibits insulin secretion primarily by regulating cAMP signaling pathway. The cell adhesion G protein-coupled receptor, brain angiogenesis inhibitor-3 (BAI3), is a receptor for C1ql3. Knockdown of BAI3 by siRNA in INS1(832/13) cells increased glucose-stimulated insulin secretion in a dose dependent manner. In addition, incubating the mouse islets with soluble C1ql3-binding fragment of the BAI3 protein completely blocked the inhibitory effects of C1ql3 on insulin secretion in response to cAMP. These findings suggest that inhibitory effects of C1ql3 on insulin secretion from pancreatic β-cells is mediated by Bai3. Additionally, C1ql3 and BAI3 expression increases with obesity suggesting that novel C1ql3/BAI3 signaling, which causes an impairment of insulin secretion from β-cells, possibly contributing to the progression of type 2 diabetes in obesity.