Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion

Michael J. Cripps; Marta Bagnati; Tania A. Jones; Babatunji W. Ogunkolade; Sophie R. Sayers; Paul W. Caton; Katie Hanna; Merell P. Billacura; Kathryn Fair; Carl Nelson; Robert Lowe; Graham A. Hitman; Mark D. Berry; Mark D. Turner

doi:10.1016/j.bcp.2019.113685

Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion

Michael J. Cripps, Marta Bagnati, Tania A. Jones, Babatunji W. Ogunkolade, Sophie R. Sayers, Paul W. Caton, Katie Hanna, Merell P. Billacura, Kathryn Fair, Carl Nelson, Robert Lowe, Graham A. Hitman, Mark D. Berry, Mark D. Turner^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

Abstract

The worldwide prevalence of diabetes has reached 8.5% among adults, and this is characterised by elevated glucose concentrations and failing insulin secretion. Furthermore, most people with type 2 diabetes are either obese or overweight, with the associated dyslipidaemia contributing to the development of insulin resistance and increased cardiovascular risk. Here we incubated INS-1 pancreatic β-cells for 72 h in RPMI-1640 media, or media supplemented with 28 mM glucose, 200 µM palmitic acid, and 200 µM oleic acid as a cellular model of diabetic glucolipotoxicity. Illumina HiSeq gene expression analysis showed the trace amine-associated receptor (TAAR) family to be among the most highly downregulated by glucolipotoxicity. Importantly, MetaCore integrated knowledge database, from Clarivate Analytics, indicated potential TAAR impact on insulin secretion through adenylyl cyclase signalling pathways. We therefore investigated the effect of TAAR ligands on cAMP signalling and insulin secretion, and found that only the branch of the TAAR family tree that is activated by isopentylamine, 2-phenylethylamine, p-tyramine, and agmatine significantly increased intracellular cAMP and resulted in increased insulin secretion from INS-1 cells and primary mouse islets under normal conditions. Crucially however, this enhancement was not evident when the receptor family was downregulated by glucolipotoxic conditions. This data indicates that a subset of TAARs are regulators of insulin secretion in pancreatic β-cells, and that their downregulation contributes to glucolipotoxic inhibition of insulin secretion. As such they may be potential targets for treatment of type 2 diabetes.

Original language	English
Article number	113685
Journal	Biochemical Pharmacology
Volume	171
DOIs	https://doi.org/10.1016/j.bcp.2019.113685
Publication status	Published - 1 Jan 2020

Keywords

Adenylyl cyclase
cAMP
G-protein coupled receptor
Glucotoxicity
Lipotoxicity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bcp.2019.113685

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Cripps, M. J., Bagnati, M., Jones, T. A., Ogunkolade, B. W., Sayers, S. R., Caton, P. W., Hanna, K., Billacura, M. P., Fair, K., Nelson, C., Lowe, R., Hitman, G. A., Berry, M. D., & Turner, M. D. (2020). Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion. Biochemical Pharmacology, 171, Article 113685. https://doi.org/10.1016/j.bcp.2019.113685

@article{35b3ef3aa2be4ad9a1b06f5a2fc54ecc,

title = "Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion",

abstract = "The worldwide prevalence of diabetes has reached 8.5% among adults, and this is characterised by elevated glucose concentrations and failing insulin secretion. Furthermore, most people with type 2 diabetes are either obese or overweight, with the associated dyslipidaemia contributing to the development of insulin resistance and increased cardiovascular risk. Here we incubated INS-1 pancreatic β-cells for 72 h in RPMI-1640 media, or media supplemented with 28 mM glucose, 200 µM palmitic acid, and 200 µM oleic acid as a cellular model of diabetic glucolipotoxicity. Illumina HiSeq gene expression analysis showed the trace amine-associated receptor (TAAR) family to be among the most highly downregulated by glucolipotoxicity. Importantly, MetaCore integrated knowledge database, from Clarivate Analytics, indicated potential TAAR impact on insulin secretion through adenylyl cyclase signalling pathways. We therefore investigated the effect of TAAR ligands on cAMP signalling and insulin secretion, and found that only the branch of the TAAR family tree that is activated by isopentylamine, 2-phenylethylamine, p-tyramine, and agmatine significantly increased intracellular cAMP and resulted in increased insulin secretion from INS-1 cells and primary mouse islets under normal conditions. Crucially however, this enhancement was not evident when the receptor family was downregulated by glucolipotoxic conditions. This data indicates that a subset of TAARs are regulators of insulin secretion in pancreatic β-cells, and that their downregulation contributes to glucolipotoxic inhibition of insulin secretion. As such they may be potential targets for treatment of type 2 diabetes.",

keywords = "Adenylyl cyclase, cAMP, G-protein coupled receptor, Glucotoxicity, Lipotoxicity",

author = "Cripps, {Michael J.} and Marta Bagnati and Jones, {Tania A.} and Ogunkolade, {Babatunji W.} and Sayers, {Sophie R.} and Caton, {Paul W.} and Katie Hanna and Billacura, {Merell P.} and Kathryn Fair and Carl Nelson and Robert Lowe and Hitman, {Graham A.} and Berry, {Mark D.} and Turner, {Mark D.}",

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doi = "10.1016/j.bcp.2019.113685",

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Cripps, MJ, Bagnati, M, Jones, TA, Ogunkolade, BW, Sayers, SR , Caton, PW, Hanna, K, Billacura, MP, Fair, K, Nelson, C, Lowe, R, Hitman, GA, Berry, MD & Turner, MD 2020, 'Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion', Biochemical Pharmacology, vol. 171, 113685. https://doi.org/10.1016/j.bcp.2019.113685

TY - JOUR

T1 - Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion

AU - Cripps, Michael J.

AU - Bagnati, Marta

AU - Jones, Tania A.

AU - Ogunkolade, Babatunji W.

AU - Sayers, Sophie R.

AU - Caton, Paul W.

AU - Hanna, Katie

AU - Billacura, Merell P.

AU - Fair, Kathryn

AU - Nelson, Carl

AU - Lowe, Robert

AU - Hitman, Graham A.

AU - Berry, Mark D.

AU - Turner, Mark D.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - The worldwide prevalence of diabetes has reached 8.5% among adults, and this is characterised by elevated glucose concentrations and failing insulin secretion. Furthermore, most people with type 2 diabetes are either obese or overweight, with the associated dyslipidaemia contributing to the development of insulin resistance and increased cardiovascular risk. Here we incubated INS-1 pancreatic β-cells for 72 h in RPMI-1640 media, or media supplemented with 28 mM glucose, 200 µM palmitic acid, and 200 µM oleic acid as a cellular model of diabetic glucolipotoxicity. Illumina HiSeq gene expression analysis showed the trace amine-associated receptor (TAAR) family to be among the most highly downregulated by glucolipotoxicity. Importantly, MetaCore integrated knowledge database, from Clarivate Analytics, indicated potential TAAR impact on insulin secretion through adenylyl cyclase signalling pathways. We therefore investigated the effect of TAAR ligands on cAMP signalling and insulin secretion, and found that only the branch of the TAAR family tree that is activated by isopentylamine, 2-phenylethylamine, p-tyramine, and agmatine significantly increased intracellular cAMP and resulted in increased insulin secretion from INS-1 cells and primary mouse islets under normal conditions. Crucially however, this enhancement was not evident when the receptor family was downregulated by glucolipotoxic conditions. This data indicates that a subset of TAARs are regulators of insulin secretion in pancreatic β-cells, and that their downregulation contributes to glucolipotoxic inhibition of insulin secretion. As such they may be potential targets for treatment of type 2 diabetes.

AB - The worldwide prevalence of diabetes has reached 8.5% among adults, and this is characterised by elevated glucose concentrations and failing insulin secretion. Furthermore, most people with type 2 diabetes are either obese or overweight, with the associated dyslipidaemia contributing to the development of insulin resistance and increased cardiovascular risk. Here we incubated INS-1 pancreatic β-cells for 72 h in RPMI-1640 media, or media supplemented with 28 mM glucose, 200 µM palmitic acid, and 200 µM oleic acid as a cellular model of diabetic glucolipotoxicity. Illumina HiSeq gene expression analysis showed the trace amine-associated receptor (TAAR) family to be among the most highly downregulated by glucolipotoxicity. Importantly, MetaCore integrated knowledge database, from Clarivate Analytics, indicated potential TAAR impact on insulin secretion through adenylyl cyclase signalling pathways. We therefore investigated the effect of TAAR ligands on cAMP signalling and insulin secretion, and found that only the branch of the TAAR family tree that is activated by isopentylamine, 2-phenylethylamine, p-tyramine, and agmatine significantly increased intracellular cAMP and resulted in increased insulin secretion from INS-1 cells and primary mouse islets under normal conditions. Crucially however, this enhancement was not evident when the receptor family was downregulated by glucolipotoxic conditions. This data indicates that a subset of TAARs are regulators of insulin secretion in pancreatic β-cells, and that their downregulation contributes to glucolipotoxic inhibition of insulin secretion. As such they may be potential targets for treatment of type 2 diabetes.

KW - Adenylyl cyclase

KW - cAMP

KW - G-protein coupled receptor

KW - Glucotoxicity

KW - Lipotoxicity

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DO - 10.1016/j.bcp.2019.113685

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AN - SCOPUS:85074497979

SN - 0006-2952

VL - 171

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

M1 - 113685

ER -

Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion

Abstract

Keywords

UN SDGs

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