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Identification of a subset of trace amine-associated receptors and ligands as potential modulators of insulin secretion
- Source :
- Biochemical pharmacology. 171
- Publication Year :
- 2019
-
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.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Palmitic Acid
Type 2 diabetes
Ligands
Biochemistry
Receptors, G-Protein-Coupled
Adenylyl cyclase
03 medical and health sciences
chemistry.chemical_compound
Islets of Langerhans
Mice
0302 clinical medicine
Insulin resistance
Downregulation and upregulation
Internal medicine
Diabetes mellitus
Cell Line, Tumor
Insulin-Secreting Cells
Insulin Secretion
medicine
Animals
Humans
Receptor
Trace amine-associated receptor
Pharmacology
Chemistry
Gene Expression Profiling
medicine.disease
Rats
030104 developmental biology
Endocrinology
Glucose
Lipotoxicity
Diabetes Mellitus, Type 2
030220 oncology & carcinogenesis
Insulin Resistance
Oleic Acid
Subjects
Details
- ISSN :
- 18732968 and 00062952
- Volume :
- 171
- Database :
- OpenAIRE
- Journal :
- Biochemical pharmacology
- Accession number :
- edsair.doi.dedup.....ccf1ae5a86906b524f46dbb6c523ad0e