title: Niacin-induced hyperglycemia is partially mediated via niacin receptor GPR109a in pancreatic islets.
abstract: The widely used lipid-lowering drug niacin is reported to induce hyperglycemia during chronic and high-dose treatments, but the mechanism is poorly understood. Recently, the niacin receptor [G-protein-coupled receptor, (GPR) 109a], has been localized to islet cells while its potential role therein remains unclear. We, therefore, aimed at investigating how GPR109a regulates islet beta-cell function and its downstream signaling using high-fat diet-induced obese mice and INS-1E beta cells. Eight-week niacin treatment elevated blood glucose concentration in obese mice with increased areas under the curve at oral glucose and intraperitoneal insulin tolerance tests. Additionally, niacin treatment significantly decreased glucose-stimulated insulin secretion (GSIS) but induced peroxisome proliferator-activated receptor gamma (Pparg) and GPR109a expression in isolated pancreatic islets; concomitantly, reactive oxygen species (ROS) were transiently increased, with decreases in GSIS, intracellular cyclic adenosine monophosphate (cAMP) accumulation and mitochondrial membrane potential (ΔΨm), but with increased expression of uncoupling protein 2 (Ucp2), Pparg and Gpr109a in INS-1E cells. Corroborating these findings, the decreases in GSIS, ΔΨm and cAMP production and increases in ROS, Pparg and GPR109a expression were abolished in INS-1E cells by GPR109a knockdown. Our data indicate that niacin-induced pancreatic islet dysfunction is probably modulated through activation of the islet beta-cell GPR109a-induced ROS-PPARγ-UCP2 pathways.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, 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, Hong Kong, China.
authors.forename: Stephen Y T
authors.initials: SY
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Qianni
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Centre for Diabetes, The Blizard Institute, Queen Mary University of London, London, UK.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Boucher
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: psleung@cuhk.edu.hk.
authors.forename: Po Sing
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007473:Ion Channels / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism; D009525:Niacin / Q000008:administration & dosage / Q000009:adverse effects*; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D000071246:Uncoupling Protein 2
chemical_list: C473652:Hcar2 protein, mouse; C554445:Hcar2 protein, rat; D000960:Hypolipidemic Agents; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D009525:Niacin; D005947:Glucose
keywords: G-protein coupled receptor; Glucose homeostasis; Insulin secretion; Islet function; Pancreas; Reactive oxygen species