期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 293, 期 47, 页码 18086-18098出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.005403
关键词
beta cell (B-cell); insulin secretion; cyclic AMP (cAMP); G protein-coupled receptor (GPCR); second messenger; brain angiogenesis inhibitor 3; complement 1q-like 3; glucagon-like peptide-1; obesity; type 2 diabetes
资金
- National Institutes of Health NLM traineeship Grant [T15 LM007359]
- National Institutes of Health NIDDK [4 R00 DK95975-03, DK084171]
- Diabetes Research Center (DRC) [P30 DK079626]
- National Institutes of Health NHLBI [R01HL128695]
- DRC [P30 DK079626]
- American Diabetes Association (ADA) [ADA1-18-PDF-103]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL128695] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK079626, R00DK095975, R01DK084171] Funding Source: NIH RePORTER
- NATIONAL LIBRARY OF MEDICINE [T15LM007359] Funding Source: NIH RePORTER
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 -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 -cells and in mouse and human islets, but its function in -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 -cells. These findings demonstrate a novel regulatory mechanism by which C1ql3/BAI3 signaling causes an impairment of insulin secretion from -cells, possibly contributing to the progression of type 2 diabetes in obesity.
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