2. Academic Validation
  3. Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein-coupled receptor BAI3

Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein-coupled receptor BAI3

  • J Biol Chem. 2018 Nov 23;293(47):18086-18098. doi: 10.1074/jbc.RA118.005403.
Rajesh Gupta 1,  Dan C Nguyen 1,  Michael D Schaid 2,  Xia Lei 3,  Appakalai N Balamurugan 4,  G William Wong 3,  Jeong-A Kim 1,  James E Koltes 5,  Michelle E Kimple 6,  Sushant Bhatnagar 7
Affiliations

Affiliations

  • 1 From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Comprehensive Diabetes Center, University of Alabama, Birmingham, Alabama 35294.
  • 2 the Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706,; the William S. Middleton Memorial Veterans Hospital, Research Service, Madison, Wisconsin 53705.
  • 3 the Department of Physiology and Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
  • 4 the Department of Surgery, University of Louisville, Louisville, Kentucky 40202, and.
  • 5 the Department of Animal Science, Iowa State University, Ames, Iowa 50011.
  • 6 the Interdisciplinary Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706,; the William S. Middleton Memorial Veterans Hospital, Research Service, Madison, Wisconsin 53705,; the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and the Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin 53705.
  • 7 From the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Comprehensive Diabetes Center, University of Alabama, Birmingham, Alabama 35294,. Electronic address: sushantbhatnagar@uabmc.edu.
PMID: 30228187 DOI: 10.1074/jbc.RA118.005403
Abstract

Secreted proteins are important metabolic regulators in both healthy and disease states. Here, we sought to investigate the mechanism by which the secreted protein complement 1q-like-3 (C1ql3) regulates Insulin secretion from pancreatic β-cells, a key process affecting whole-body glucose metabolism. We found that C1ql3 predominantly inhibits exendin-4- and cAMP-stimulated Insulin secretion from mouse and human islets. However, to a lesser extent, C1ql3 also reduced Insulin secretion in response to KCl, the Potassium Channel blocker tolbutamide, and high glucose. Strikingly, C1ql3 did not affect Insulin secretion stimulated by fatty acids, Amino acids, or mitochondrial metabolites, either at low or submaximal glucose concentrations. Additionally, C1ql3 inhibited glucose-stimulated cAMP levels, and Insulin secretion stimulated by exchange protein directly activated by cAMP-2 and protein kinase A. These results suggest that C1ql3 inhibits Insulin secretion primarily by regulating cAMP signaling. The cell adhesion G protein-coupled receptor, brain angiogenesis inhibitor-3 (BAI3), is a C1ql3 receptor and is expressed in β-cells and in mouse and human islets, but its function in β-cells remained unknown. We found that siRNA-mediated Bai3 knockdown in INS1(832/13) cells increased glucose-stimulated Insulin secretion. Furthermore, incubating the soluble C1ql3-binding fragment of the BAI3 protein completely blocked the inhibitory effects of C1ql3 on Insulin secretion in response to cAMP. This suggests that BAI3 mediates the inhibitory effects of C1ql3 on Insulin secretion from pancreatic β-cells. These findings demonstrate a novel regulatory mechanism by which C1ql3/BAI3 signaling causes an impairment of Insulin secretion from β-cells, possibly contributing to the progression of type 2 diabetes in obesity.

Keywords

G protein-coupled receptor (GPCR); beta cell (B-cell); brain angiogenesis inhibitor 3; complement 1q-like 3; cyclic AMP (cAMP); glucagon-like peptide-1; insulin secretion; obesity; second messenger; type 2 diabetes.

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