Trace Amines are Essential Metabolites for the Autocrine Regulation of β-Cell Signaling and Insulin Secretion

Abstract

Secretion of insulin in response to extracellular stimuli, such as elevated glucose levels and small molecules that act on G-protein coupled receptors (GPCRs), is the hallmark of {beta}-cell physiology. Trace amines (TAs) are small aromatic metabolites that were identified as low-abundant ligands of the trace amine-associated receptor 1 (TAAR1) in the central nervous system (CNS), a GPCR that is also expressed by pancreatic {beta}-cells. In the present work, we identify TAs as essential autocrine signaling factors for {beta}-cell activity and insulin secretion. We find that {beta}-cells are producing TAs in significant amounts and that the modulation of endogenous TA levels by the selective inhibition of TA biosynthetic pathways directly translated into changes of oscillations of the intracellular Ca2+ concentration ([Ca2+]i oscillations) and insulin secretion. Selective TAAR1 agonists or inhibitors of monoamine oxidases increased [Ca2+]i oscillations and insulin secretion. Opposite effects were mediated by selective TAAR1 antagonists, by recombinant monoamine oxidase action and by the inhibition of amino acid decarboxylase. As the modulation of TA biochemical pathways immediately translated into changes of [Ca2+]i oscillations, we inferred high metabolic turnover rates of TAs and autocrine feedback. We found that psychotropic drugs modulate [Ca2+]i oscillations and insulin secretion, either directly acting on TAAR1 or by altering endogenous TA levels. Our combined data support the hypothesis of TAs as essential autocrine signaling factors for {beta}-cell activity and insulin secretion as well as TAAR1 as an important mediator of amine-modulated insulin secretion.