1255-P: The Role of BAI3 Adhesion G-Protein Coupled Receptor in Insulin Secretion and Glucose Tolerance

Abstract

Insulin secretion from beta-cells of pancreatic islets is essential for regulating whole-blood glucose homeostasis. Impaired insulin secretion is an early event in the development of obesity-linked type 2 diabetes (T2D). However, underlying molecular mechanisms that cause a reduction in insulin secretion are not completely understood. We recently identified that brain angiogenesis inhibitor-3 (BAI3) adhesion G-protein coupled receptor is expressed in beta-cells, and when activated by its native ligand, complement-1q like-3 (C1ql3), blunts insulin secretion in response to cyclic adenosine monophosphate (cAMP) in an autocrine/paracrine manner. The expression of BAI3 is conserved in human islets, yet the role of islet BAI3 in whole-body glucose homeostasis remains uncharacterized. We generated C57BL6/J mice that are homozygous for the loss of the BAI3 gene by using CRISPR technology. Our data show that the BAI3-/- mice have reduced body weight and impaired glucose tolerance compared to the wild-type control (WT) mice. These mice have elevated in vivo insulin secretion after 10 min of glucose challenge and an increased ex vivo islet insulin secretion in response to stimulation by 40 mM KCL and 11 mM glucose with no effect observed at 2.8 mM glucose. Concomitantly, the insulin action is decreased in the BAI3-/- mice. These outcomes show that increased insulin secretion from beta-cells due to the loss of the BAI3 gene contributes to reduced insulin sensitivity and glucose tolerance. The expression of BAI3 is increased by obesity, indicating that the activation of BAI3 signaling may contribute to reduced insulin secretion, causing beta-cell dysfunction in T2D. In sum, we have established an important role of an understudied BAI3 GPCR signaling in inhibiting insulin secretion, potentially identifying an attractive target for novel T2D therapeutics. Disclosure H. Alsharif: None. M. Rahman: None. A. Pathak: None. J. E. Trombley: None. S. Bhatnagar: None. Funding National Institutes of Health (R01DK120684-01)