FFA2-, but not FFA3-agonists inhibit GSIS of human pseudoislets: a comparative study with mouse islets and rat INS-1E cells
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FFA2-, but not FFA3-agonists inhibit GSIS of human pseudoislets : a comparative study with mouse islets and rat INS-1E cells. / Lorza-Gil, Estela; Kaiser, Gabriele; Ulven, Elisabeth Rexen; Koenig, Gabriele M.; Gerst, Felicia; Oquendo, Morgana Barroso; Birkenfeld, Andreas L.; Haering, Hans-Ulrich; Kostenis, Evi; Ulven, Trond; Ullrich, Susanne.
In: Scientific Reports, Vol. 10, No. 1, 16497, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - FFA2-, but not FFA3-agonists inhibit GSIS of human pseudoislets
T2 - a comparative study with mouse islets and rat INS-1E cells
AU - Lorza-Gil, Estela
AU - Kaiser, Gabriele
AU - Ulven, Elisabeth Rexen
AU - Koenig, Gabriele M.
AU - Gerst, Felicia
AU - Oquendo, Morgana Barroso
AU - Birkenfeld, Andreas L.
AU - Haering, Hans-Ulrich
AU - Kostenis, Evi
AU - Ulven, Trond
AU - Ullrich, Susanne
PY - 2020
Y1 - 2020
N2 - 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 mu M 4-CMTB on GSIS was recapitulated. The inhibition was partially sensitive to the G(i/o)-protein inhibitor pertussis toxin. A previously described FFA2-dependent increase of GSIS was observed with lower concentrations of 4-CMTB (10 and 30 mu M). 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.
AB - 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 mu M 4-CMTB on GSIS was recapitulated. The inhibition was partially sensitive to the G(i/o)-protein inhibitor pertussis toxin. A previously described FFA2-dependent increase of GSIS was observed with lower concentrations of 4-CMTB (10 and 30 mu M). 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.
KW - CHAIN FATTY-ACIDS
KW - PANCREATIC BETA-CELLS
KW - INSULIN-SECRETION
KW - FUNCTIONAL-CHARACTERIZATION
KW - GENE-EXPRESSION
KW - PYY SECRETION
KW - RECEPTOR 2
KW - PROTEIN
KW - GPR43
KW - AGONISTS
U2 - 10.1038/s41598-020-73467-5
DO - 10.1038/s41598-020-73467-5
M3 - Journal article
C2 - 33020504
VL - 10
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 16497
ER -
ID: 254671559