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

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 ?-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.

SUBMITTER: Gupta R

PROVIDER: S-EPMC6254345 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Gupta Rajesh R Nguyen Dan C DC Schaid Michael D MD Lei Xia X Balamurugan Appakalai N AN Wong G William GW Kim Jeong-A JA Koltes James E JE Kimple Michelle E ME Bhatnagar Sushant S

The Journal of biological chemistry 20180918 47

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 ...[more]

PMID: 30228187

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Project description:BackgroundProper glycemic control is an important goal of critical care medicine, including perioperative patient care that can influence patients' prognosis. Insulin secretion from pancreatic β-cells is generally assumed to play a critical role in glycemic control in response to an elevated blood glucose concentration. Many animal and human studies have demonstrated that perioperative drugs, including volatile anesthetics, have an impact on glucose-stimulated insulin secretion (GSIS). However, the effects of the intravenous anesthetic propofol on glucose metabolism and insulin sensitivity are largely unknown at present.MethodsThe effect of propofol on insulin secretion under low glucose or high glucose was examined in mouse MIN6 cells, rat INS-1 cells, and mouse pancreatic β-cells/islets. Cellular oxygen or energy metabolism was measured by Extracellular Flux Analyzer. Expression of glucose transporter 2 (GLUT2), potassium channels, and insulin mRNA was assessed by qRT-PCR. Protein expression of voltage-dependent potassium channels (Kv2) was also assessed by immunoblot. Propofol's effects on potassium channels including stromatoxin-1-sensitive Kv channels and cellular oxygen and energy metabolisms were also examined.ResultsWe showed that propofol, at clinically relevant doses, facilitates insulin secretion under low glucose conditions and GSIS in MIN6, INS-1 cells, and pancreatic β-cells/islets. Propofol did not affect intracellular ATP or ADP concentrations and cellular oxygen or energy metabolism. The mRNA expression of GLUT2 and channels including the voltage-dependent calcium channels Cav1.2, Kir6.2, and SUR1 subunit of KATP, and Kv2 were not affected by glucose or propofol. Finally, we demonstrated that propofol specifically blocks Kv currents in β-cells, resulting in insulin secretion in the presence of glucose.ConclusionsOur data support the hypothesis that glucose induces membrane depolarization at the distal site, leading to KATP channel closure, and that the closure of Kv channels by propofol depolarization in β-cells enhances Ca2+ entry, leading to insulin secretion. Because its activity is dependent on GSIS, propofol and its derivatives are potential compounds that enhance and initiate β-cell electrical activity.

Dataset Information

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

Publications

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

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