Arun Kumar -May 7


INTRODUCTION: The increasing prevalence of type 2 diabetes, both in Canada and globally, requires development of novel therapies. Trace amines are endogenously present in all vertebrates and mediate their effects through a family of G protein-coupled receptors known as trace amine-associated receptors (TAAR). Most studies have focused on TAAR1 and its role in the central nervous system while peripheral TAAR1 has received less attention. TAAR1 expression is particularly prevalent in pancreatic beta cells, where it has been reported to potentiate insulin secretion in response to glucose. The molecular basis by which TAAR1 brings about this enhanced secretion is unknown. This study further investigates the mechanism by which TAAR1 regulates insulin secretion from pancreatic beta cells.
METHOD: The insulin secreting rat INS-1E beta cell line was used. Insulin secretion assays were conducted in HBSS buffer. Cells were pre-starved (30 minutes) and then incubated with varying concentrations of glucose (2.5 – 20 mM) or KCl (3.6 – 60 mM) for 2 hours in the absence and presence of various concentrations of the selective TAAR1 agonist RO5256390. Following incubation, buffer was collected, and secreted insulin quantified by ELISA. Insulin secretion was normalized to the total protein content of individual cultures.
RESULTS: Both glucose (P = 0.0018) and KCl (P = 0.0006) caused concentration dependent increase in insulin secretion. RO5256390 significantly enhanced insulin secretion in response to elevated (≥ 10 mM) glucose levels (P < 0.0001) in a dose-dependent manner. No effect of RO5256390 at any concentration was observed on KCl stimulated insulin secretion.
CONCLUSION: TAAR1 activation selectively increases glucose-dependent insulin secretion. The lack of effect on KCl-stimulated insulin secretion suggests that TAAR1 interacts with a component of the glucose signaling pathway and is not non-selectively increasing exocytotic release or insulin synthesis. The molecular component of the glucose-stimulated pathway targeted by TAAR1 is currently under investigation.



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