Niacin-induced hyperglycemia is partially mediated via niacin receptor GPR109a in pancreatic islets.
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.
['Chen|Lihua|L|', 'So|Wing Yan|WY|', 'Li|Stephen Y T|SY|', 'Cheng|Qianni|Q|', 'Boucher|Barbara J|BJ|', 'Leung|Po Sing|PS|']
D000818:Animals D002460:Cell Line D004195:Disease Models, Animal D005947:Glucose D006943:Hyperglycemia D000960:Hypolipidemic Agents D007328:Insulin D000078790:Insulin Secretion D050417:Insulin-Secreting Cells D007473:Ion Channels D008564:Membrane Potentials D051379:Mice D008810:Mice, Inbred C57BL D024101:Mitochondrial Proteins D009525:Niacin D009765:Obesity D047495:PPAR gamma D051381:Rats D043562:Receptors, G-Protein-Coupled D011978:Receptors, Nicotinic D000071246:Uncoupling Protein 2
Insulin secretion Reactive oxygen species G-protein coupled receptor Glucose homeostasis Islet function Pancreas