ABSTRACT
The expression of short chain fatty acid receptors FFA2 and FFA3 in pancreatic islets raised interest in using them as drug targets for treating hyperglycemia in humans. This study aims to examine the efficacy of synthetic FFA2- and FFA3-ligands to modulate glucose-stimulated insulin secretion (GSIS) in human pseudoislets which display intact glucose responsiveness. The FFA2-agonists 4-CMTB and TUG-1375 inhibited GSIS, an effect reversed by the FFA2-antagonist CATPB. GSIS itself was not augmented by CATPB. The FFA3-agonists FHQC and 1-MCPC did not affect GSIS in human pseudoislets. For further drug evaluation we used mouse islets. The CATPB-sensitive inhibitory effect of 100 µM 4-CMTB on GSIS was recapitulated. The inhibition was partially sensitive to the Gi/o-protein inhibitor pertussis toxin. A previously described FFA2-dependent increase of GSIS was observed with lower concentrations of 4-CMTB (10 and 30 µM). The stimulatory effect of 4-CMTB on secretion was prevented by the Gq-protein inhibitor FR900359. As in human pseudoislets, in mouse islets relative mRNA levels were FFAR2 > FFAR3 and FFA3-agonists did not affect GSIS. The FFA3-agonists, however, inhibited GSIS in a pertussis toxin-sensitive manner in INS-1E cells and this correlated with relative mRNA levels of Ffar3 > > Ffar2. Thus, in humans, when FFA2-activation impedes GSIS, FFA2-antagonism may reduce glycemia.
Subject(s)
Depsipeptides/pharmacology , Glucose/metabolism , Insulin Secretion/drug effects , Insulin-Secreting Cells/drug effects , Receptors, Cell Surface/agonists , Receptors, G-Protein-Coupled/agonists , Adult , Animals , Blood Glucose/drug effects , Cells, Cultured , Fatty Acids, Volatile/agonists , Female , GTP-Binding Protein alpha Subunits, Gq-G11/metabolism , Humans , Insulin , Insulin-Secreting Cells/metabolism , Ligands , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Rats , Signal TransductionABSTRACT
Los efectos enterotróficos de los ácidos grasos de cadena corta son cadena complejos y problabemente multifatoriales. La adición directa de energía a la mucosa intestinal es una contribución moderada, mientras que el incremento en el flujo sanguíneo puede aportar una contribución ligeramente mayor al enterotrofismo. Los mecanismos mediados localmente solos, como se describe, no pueden explicar por completo los efectos tróficos de los ácidos grasos de cadena corta, debido a que el trofismo intestinal se presenta tanto local como distalmente al sitio de infusión. Los ácidos grasos de cadena corta estimulan el crecimiento del intestino delgado, lo mismo que del intestino grueso cuando se infunden al colon de ratas. El incremento de las secreciones endocrinas pancreáticas, la estimulación de las hormonas gastrointestinales enterotróficas y el incremento en el sistema nervioso autónomo pueden ser mediadores adicionales, tanto de los efectos enterotróficos locales, como de los efectos enterotróficos sistémicos de los ácidos grasos de cadena corta. Definir los mensajeros hormonales específicos y los procesos celulares mediante los cuales son liberados, es una área muy activa de la investigación actualmente en marcha.
