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

Autor: Cripps MJ; Centre for Diabetes, Chronic Diseases and Ageing, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, UK., Bagnati M; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK., Jones TA; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK., Ogunkolade BW; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK., Sayers SR; Diabetes and Nutritional Sciences Division, King's College London, London SE1 1UL, United Kingdom., Caton PW; Diabetes and Nutritional Sciences Division, King's College London, London SE1 1UL, United Kingdom., Hanna K; Centre for Diabetes, Chronic Diseases and Ageing, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, UK., Billacura MP; Centre for Diabetes, Chronic Diseases and Ageing, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, UK., Fair K; Centre for Diabetes, Chronic Diseases and Ageing, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, UK., Nelson C; Centre for Diabetes, Chronic Diseases and Ageing, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, UK., Lowe R; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK., Hitman GA; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK., Berry MD; Department of Biochemistry, Memorial University of Newfoundland, St. John's A1B 3X9, Canada., Turner MD; Centre for Diabetes, Chronic Diseases and Ageing, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS, UK. Electronic address: mark.turner@ntu.ac.uk.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2020 Jan; Vol. 171, pp. 113685. Date of Electronic Publication: 2019 Nov 01.
DOI: 10.1016/j.bcp.2019.113685
Abstrakt: 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.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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