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

Cripps, M.J., Bagnati, M., Jones, T.A., Ogunkolade, B.W., Sayers, S.R., Caton, P.W., Hanna, K., Billacura, M., Fair, K., Nelson, C.P. ORCID: 0000-0003-1034-140X, Lowe, R., Hitman, G.A., Berry, M.D. and Turner, M.D. ORCID: 0000-0001-7175-1053, 2020. Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion. Biochemical Pharmacology, 171: 113685. ISSN 0006-2952

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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.

Item Type: Journal article
Publication Title: Biochemical Pharmacology
Creators: Cripps, M.J., Bagnati, M., Jones, T.A., Ogunkolade, B.W., Sayers, S.R., Caton, P.W., Hanna, K., Billacura, M., Fair, K., Nelson, C.P., Lowe, R., Hitman, G.A., Berry, M.D. and Turner, M.D.
Publisher: Elsevier
Date: January 2020
Volume: 171
ISSN: 0006-2952
Identifiers:
NumberType
10.1016/j.bcp.2019.113685DOI
1214346Other
S0006295219303843Publisher Item Identifier
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 15 Nov 2019 15:23
Last Modified: 15 Nov 2019 15:23
URI: http://irep.ntu.ac.uk/id/eprint/38327

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