Activation of GPR119 by fatty acid agonists augments insulin release from clonal β-cells and isolated pancreatic islets and improves glucose tolerance in mice

Abstract

G-protein coupled receptor 119 (GPR119) is emerging as a potential target for the treatment of type 2 diabetes with beneficial effects on glucose homeostasis. This study assessed the insulin-secreting properties of various GPR119 agonists and the distribution of GPR119 in pancreatic islets. Endogenous ligands [oleoylethanolamide (OEA), palmitoylethanolamine (PEA)] and chemically synthetic analogues (AS-1269574, PSN-375963) were investigated in clonal BRIN-BD11 cells and mouse pancreatic islets. Secondary messenger assays such as intracellular Ca²⁺ and cAMP in response to agonists at normoglycaemic and hyperglycaemic conditions were assessed. Cytotoxicity was assessed by LDH release. AS-1269574 was the most potent and selective agonist tested in isolated islets, with an EC₅₀ value of 9.7×10⁻⁷ mol/l, enhancing insulin release maximally by 63.2%. Stimulation was also observed with GPR119 ligands; OEA (3.0×10⁻⁶ mol/l; 37.5%), PSN-375963 (2.4×10⁻⁶ mol/l; 28.7%) and PEA (1.2×10⁻⁶ mol/l; 22.2%). Results were corroborated by studies using BRIN-BD11 cells, which revealed augmentation of intracellular Ca²⁺ and cAMP. Both OEA and AS-1269574 enhanced insulin release and improved glucose tolerance in vivo in NIH Swiss mice. These results demonstrate the cellular localisation of GPR119 on islet cells (β and pancreatic polypeptide cells), its activation of the β-cell stimulus-secretion coupling pathway and glucose lowering effects in vivo.

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

“…GPR119 is a G␣s-coupled receptor that was originally proposed to stim-ulate insulin secretion in response to oleoylethanolamine. 24 While activation of GPR119 in isolated islets increases insulin secretion, the deletion of the gene GPR119 from beta cells in mice surprisingly did not reduce insulin secretion or blunt response to GPR119 agonists, indicating that GPR119 in beta cells is dispensable for GPR119-mediated insulin secretion in vivo. 25 It was proposed that GPR119 increases GSIS indirectly through incretin release mediated by the GPR119 receptor in enteroendocrine cells.…”

“…11 However, the expression level of FFAR1 in human islets is reported to correlate with insulin secretion and T2D status, indicating that a reduction of FFAR1 may play an active role in impaired insulin secretion in human T2D. 24 While activation of GPR119 in isolated islets increases insulin secretion, the deletion of the gene GPR119 from beta cells in mice surprisingly did not reduce insulin secretion or blunt response to GPR119 agonists, indicating that GPR119 in beta cells is dispensable for GPR119-mediated insulin secretion in vivo. Indeed, the first-generation FFAR1 agonists, such as TAK-875 and MK-8666, showed promise in human clinical trials by improving hyperglycemia.…”

Leptogenic effects of NAPE require activity of NAPE-hydrolyzing phospholipase D

“…AEA is a potent agonist for endocannabinoid receptor 1 (CB 1 ). In contrast to AEA, OEA and PEA are not agonists for CB 1 (16,17), but are agonists for PPAR (18,19), TRPV1 (18,19), GPR119 (20,21), and GPR55 (22,23) and the activation of these receptors by OEA and PEA (16,19,24,25) or other agonists reduces food intake and increases fatty acid oxidation (26)(27)(28)(29)(30).…”

Therapeutic application of GPR119 ligands in metabolic disorders

“…Proposed signaling pathway(s) and physiological/pharmacological effects of GPR119 activation in diverse tissues . Abbreviations: ABCA1, ATP‐binding cassette subfamily A1; ACC, acetyl‐CoA carboxylase; AMPK, AMP‐activated protein kinase; CB1, cannabinoid receptor type 1; CPT1, carnitine palmitoyltransferase‐1; CTGF, connective tissue growth factor; FAS, fatty acid synthase; GIP, glucose‐dependent insulinotropic peptide; GLP‐1, glucagon‐like peptide‐1; Gαs, stimulatory G protein α‐subunit; NFATc1, nuclear factor of activated T cells, cytoplasmic 1; OEA, oleoylethanolamide; Ox‐LDL, oxidized low‐density lipoprotein; PDK4, pyruvate dehydrogenase kinase isozyme 4; PGC1α, peroxisome proliferator‐activated receptor‐α coactivator 1‐α; PKA, protein kinase A; PPARα, peroxisome proliferator‐activated receptor‐α; SCD1, stearoyl‐CoA desaturase‐1; SREBP‐1, sterol regulatory element binding protein‐1…”

“…5 The islets Proposed signaling pathway(s) and physiological/pharmacological effects of GPR119 activation in diverse tissues. 5,6,[13][14][15][16][17][18][19][20][21][22] Abbreviations: ABCA1, ATP-binding cassette subfamily A1; ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; CB1, cannabinoid receptor type 1; CPT1, carnitine palmitoyltransferase-1; CTGF, connective tissue growth factor; FAS, fatty acid synthase; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; Gαs, stimulatory G protein α-subunit; NFATc1, nuclear factor of activated T cells, cytoplasmic 1; OEA, oleoylethanolamide; Ox-LDL, oxidized low-density lipoprotein; PDK4, pyruvate dehydrogenase kinase isozyme 4; PGC1α, peroxisome proliferator-activated receptor-α coactivator 1-α; PKA, protein kinase A; PPARα, peroxisome proliferatoractivated receptor-α; SCD1, stearoyl-CoA desaturase-1; SREBP-1, sterol regulatory element binding protein-1 in GPR119-deficient mice were also normal in terms of morphology and response to glucose and GLP-1, 5 but glucose-induced GLP-1 secretion was reduced. 18 Interestingly, GLP-1 secretion stimulated by triglycerides was significantly attenuated in GPR119-deficient mice, but not in FFAR1-or FFAR4-deficient mice, suggesting the essential role of GPR119 in the regulation of GLP-1 release.…”