Niacin-induced hyperglycemia is partially mediated via niacin receptor GPR109a in pancreatic islets

Mol Cell Endocrinol. 2015 Mar 15:404:56-66. doi: 10.1016/j.mce.2015.01.029. Epub 2015 Jan 23.

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.

Keywords: G-protein coupled receptor; Glucose homeostasis; Insulin secretion; Islet function; Pancreas; Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Disease Models, Animal
  • Glucose / metabolism
  • Hyperglycemia / chemically induced*
  • Hyperglycemia / metabolism
  • Hyperglycemia / physiopathology
  • Hypolipidemic Agents / administration & dosage*
  • Hypolipidemic Agents / adverse effects
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • Ion Channels / metabolism
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / metabolism
  • Niacin / administration & dosage
  • Niacin / adverse effects*
  • Obesity / drug therapy*
  • Obesity / physiopathology
  • PPAR gamma / metabolism
  • Rats
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Nicotinic / metabolism*
  • Uncoupling Protein 2

Substances

  • Hcar2 protein, mouse
  • Hcar2 protein, rat
  • Hypolipidemic Agents
  • Insulin
  • Ion Channels
  • Mitochondrial Proteins
  • PPAR gamma
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • Ucp2 protein, mouse
  • Ucp2 protein, rat
  • Uncoupling Protein 2
  • Niacin
  • Glucose