FFA2-, but not FFA3-agonists inhibit GSIS of human pseudoislets: a comparative study with mouse islets and rat INS-1E cells

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.

Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction

“…In contrast, butyrate downregulated several IL-1β-induced inflammatory genes encoding chemokines, interleukins, immunoproteasome subunits, and enzymes producing inflammatory mediators. Other studies have also reported on the anti-inflammatory properties of butyrate, which are thought to be mediated through inhibition of NFκB [37][38][39][40]. In vivo downregulation of chemokines such as Cxcl1 and Cxcl10 may be important to reduce the recruitment and activation of immune cells, thereby reducing islet inflammation and improving beta cell function [41].…”

Butyrate and Class I Histone Deacetylase Inhibitors Promote Differentiation of Neonatal Porcine Islet Cells into Beta Cells

“…In primary isolated human islets, butyrate did not significantly stimulate GSIS. Insulin secretion of human islets were inhibited when treated with specific GPR43 agonists [29]. Therefore, it can be speculated that butyrate treatment increased beta cell maturation, but in parallel attenuated GSIS of NPICCs by binding to GPR43.…”

Metabolic Functions of G Protein-Coupled Receptors and β-Arrestin-Mediated Signaling Pathways in the Pathophysiology of Type 2 Diabetes and Obesity

“…PA ((S)-2-(4-chlorophenyl)-3,3-dimethyl- N -(5-phenylthiazol-2-yl)butanamide), a synthetic GPR43 agonist, potentiated insulin secretion in isolated murine islets, human islets, and Min6 cells in vitro by increasing intracellular IP3 and Ca 2+ levels in a GPR43-, G q -, and PLC-dependent manner ( 23 ). However, another GPR43 synthetic agonist, 4-CMTB (4-Chloro-α-(1-methylethyl)-N-2-thiazolyl-benzeneacetamide), invariably inhibited GSIS in human pseudoislets, contrary to mouse islets, where it augmented GSIS ( 88 ). This finding that mouse and human islets responded differently to acetate and GPR43 agonists in GSIS assay will require close attention in future studies, since GPR43 is considered as a potential T2D target.…”