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

Rajesh Gupta, Dan C. Nguyen, Michael D. Schaid, Xia Lei, Appakalai N. Balamurugan, Guang William Wong, Jeong A. Kim, James E. Koltes, Michelle E. Kimple, Sushant Bhatnagar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)18086-18098
Number of pages13
JournalThe Journal of biological chemistry
Volume293
Issue number47
DOIs
StatePublished - Nov 23 2018

Fingerprint

Complement C1q
Angiogenesis Inhibitors
Cell adhesion
G-Protein-Coupled Receptors
Cell Adhesion
Brain
Insulin
Proteins
Glucose
Potassium Channel Blockers
Tolbutamide
Medical problems
Metabolites
Cyclic AMP-Dependent Protein Kinases
Metabolism
Type 2 Diabetes Mellitus
Small Interfering RNA

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein-coupled receptor BAI3. / Gupta, Rajesh; Nguyen, Dan C.; Schaid, Michael D.; Lei, Xia; Balamurugan, Appakalai N.; Wong, Guang William; Kim, Jeong A.; Koltes, James E.; Kimple, Michelle E.; Bhatnagar, Sushant.

In: The Journal of biological chemistry, Vol. 293, No. 47, 23.11.2018, p. 18086-18098.

Research output: Contribution to journalArticle

Gupta, R, Nguyen, DC, Schaid, MD, Lei, X, Balamurugan, AN, Wong, GW, Kim, JA, Koltes, JE, Kimple, ME & Bhatnagar, S 2018, 'Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein-coupled receptor BAI3', The Journal of biological chemistry, vol. 293, no. 47, pp. 18086-18098. https://doi.org/10.1074/jbc.RA118.005403
Gupta, Rajesh ; Nguyen, Dan C. ; Schaid, Michael D. ; Lei, Xia ; Balamurugan, Appakalai N. ; Wong, Guang William ; Kim, Jeong A. ; Koltes, James E. ; Kimple, Michelle E. ; Bhatnagar, Sushant. / Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein-coupled receptor BAI3. In: The Journal of biological chemistry. 2018 ; Vol. 293, No. 47. pp. 18086-18098.
@article{2185e3af3f9f4f2bbd001fe71fa253de,
title = "Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-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 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 = "beta cell (B-cell), brain angiogenesis inhibitor 3, complement 1q-like 3, cyclic AMP (cAMP), G protein-coupled receptor (GPCR), glucagon-like peptide-1, insulin secretion, obesity, second messenger, type 2 diabetes",
author = "Rajesh Gupta and Nguyen, {Dan C.} and Schaid, {Michael D.} and Xia Lei and Balamurugan, {Appakalai N.} and Wong, {Guang William} and Kim, {Jeong A.} and Koltes, {James E.} and Kimple, {Michelle E.} and Sushant Bhatnagar",
year = "2018",
month = "11",
day = "23",
doi = "10.1074/jbc.RA118.005403",
language = "English (US)",
volume = "293",
pages = "18086--18098",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "47",

}

TY - JOUR

T1 - Complement 1q-like-3 protein inhibits insulin secretion from pancreatic β-cells via the cell adhesion G protein-coupled receptor BAI3

AU - Gupta, Rajesh

AU - Nguyen, Dan C.

AU - Schaid, Michael D.

AU - Lei, Xia

AU - Balamurugan, Appakalai N.

AU - Wong, Guang William

AU - Kim, Jeong A.

AU - Koltes, James E.

AU - Kimple, Michelle E.

AU - Bhatnagar, Sushant

PY - 2018/11/23

Y1 - 2018/11/23

N2 - 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.

AB - 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.

KW - beta cell (B-cell)

KW - brain angiogenesis inhibitor 3

KW - complement 1q-like 3

KW - cyclic AMP (cAMP)

KW - G protein-coupled receptor (GPCR)

KW - glucagon-like peptide-1

KW - insulin secretion

KW - obesity

KW - second messenger

KW - type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85057135412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057135412&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA118.005403

DO - 10.1074/jbc.RA118.005403

M3 - Article

C2 - 30228187

AN - SCOPUS:85057135412

VL - 293

SP - 18086

EP - 18098

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 47

ER -