title: Insulinotropic effects of GPR120 agonists are altered in obese diabetic and obese non-diabetic states.
abstract: G-protein-coupled receptor 120 (GPR120) is a putative target for obesity and diabetes therapies. However, it remains controversial whether resident GPR120 plays a direct regulatory role in islet β-cell insulin secretion. The present study examined this issue in isolated rodent islets and rat β-cell line INS-1E, and assessed the role of GPR120 in islet insulin secretion in obese non-diabetic (OND) and diabetic states. GPR120 expression was detected in rodent islet β-cells. Docosahexaenoic acid (DHA) and synthetic GPR120 agonist GSK137647 (GSK) augmented insulin release from rat/mouse islets and INS-1E; DHA effects were partially mediated by GPR40. GPR120 knockdown and overexpression attenuated and enhanced DHA effects in INS-1E respectively. DHA and GSK improved postprandial hyperglycaemia of diabetic mice. Inhibition of calcium signalling in INS-1E reduced GPR120 activation-induced insulinotropic effects. The insulinotropic effects of DHA/GSK were amplified in OND rat islets, but diminished in diabetic rat islets. GPR120 and peroxisome proliferator-activated receptor γ (PPARγ) expression were elevated in OND islets and palmitic acid (PA)-treated INS-1E, but reduced in diabetic islets and high glucose-treated INS-1E. PPARγ activation increased GPR120 expression in rat islets and INS-1E. DHA and GSK induced protein kinase B (Akt)/extracellular signal-regulated kinase (ERK) phosphorylation in rodent islets and INS-1E, and these effects were altered in OND and diabetic states. Taken together, the present study indicates that (i) GPR120 activation has an insulinotropic influence on β-cells with the involvement of calcium signalling; (ii) GPR120 expression in β-cells and GPR120-mediated insulinotropic effects are altered in OND and diabetic states in distinct ways, and these alterations may be mediated by PPARγ.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Wing Yan
authors.initials: WY
authors.lastname: So
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Shang Ying
authors.initials: SY
authors.lastname: Wu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
authors.forename: Qianni
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China psleung@cuhk.edu.hk.
authors.forename: Po Sing
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004281:Docosahexaenoic Acids; D055785:Gene Knockdown Techniques; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; C498007:FFAR4 protein, mouse; C533284:Ffar4 protein, rat; C473035:G-protein-coupled receptor 40, rat; C000621070:GSK137647; D007328:Insulin; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; D004281:Docosahexaenoic Acids; D051057:Proto-Oncogene Proteins c-akt
keywords: Type 2 diabetes mellitus (T2DM); calcium signalling; insulin secretion; non-diabetic obesity; peroxisome proliferator-activated receptor γ (PPARγ)