title: Investigations of Trace Amines and Fatty Acids as Essential  Endogenous Signaling Factors for β-Cell Activity  and Insulin Secretion
creator: Hauke, Sebastian
subject: 500
subject: 500 Natural sciences and mathematics
subject: 540
subject: 540 Chemistry and allied sciences
subject: 570
subject: 570 Life sciences
description: 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 β-cell physiology.  Sufficiently high blood insulin levels are ensured by the coupling of the secretory activity within  pancreatic islets. Intercellular and inter-islet coordination are partly mediated by small diffusible  ligands of GPCRs within the extracellular space of pancreatic islets. Therefore, insulin release is  considered a synchronized multi-cellular process. We show herein that β-cell activity and insulin  secretion essentially rely on the presence of extracellular endogenous (autocrine) signaling factors,  exemplified by two classes of small cellular metabolites.  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). In the  presented work, we identify TAs as essential autocrine signaling factors that maintain and regulate  oscillations of the intracellular Ca2+ concentration ([Ca2+]i oscillations) along with insulin secretion  from β-cells via TAAR1. We found that the modulation of endogenous TA levels by the selective  inhibition of TA biosynthetic pathways directly translated into changes of [Ca2+]i oscillations and  insulin secretion. Application of aromatic amine-withdrawing β-cyclodextrin temporarily reduced  [Ca2+]i oscillations. This demonstrates the essential role of TAs for β-cell activity as well as their  high metabolic turnover rates. Notably, herein applied inhibitors and synthetic TAAR1  (ant-)agonists are partly approved for the therapeutic modulation of biogenic amine levels within  the CNS, and hence for the treatment of common neurological disorders. According to our findings,  these drugs even affect β-cell activity and insulin secretion through pancreatic TAAR1.  With the discovery of the free fatty acid (FA) receptor GPR40 in β-cells, FAs have come into focus  as exogenous insulin secretagogues. However, the role of FAs as endogenous (local) signaling  factors of β-cells has not been considered so far. We show herein that lowering endogenous FAlevels  in the presence of FA-free bovine serum albumin (FAF-BSA) immediately reduced [Ca2+]i  oscillations and insulin secretion. [Ca2+]i oscillations resumed upon exchange of FAF-BSA by  buffer or upon restoration of extracellular FA pools. The latter was accomplished by the photolysis  of caged FAs on plasma membranes, by the addition of a recombinant lipase or of FA-loaded BSA.  Our approach to subordinate β-cell activity and insulin secretion to the presence of autocrine  signaling factors of the yet underestimated receptors TAAR1 and GPR40 in the pancreas  contributes to a more detailed and complete understanding of the fundamental regulation of β-cell  activity and insulin secretion.
date: 2019
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/26060/1/Dissertation%20S_Hauke.pdf
identifier: DOI:10.11588/heidok.00026060
identifier: urn:nbn:de:bsz:16-heidok-260602
identifier:   Hauke, Sebastian  (2019) Investigations of Trace Amines and Fatty Acids as Essential Endogenous Signaling Factors for β-Cell Activity and Insulin Secretion.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/26060/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng