Endogenous GLP-1 as a key self-defense molecule against lipotoxicity in pancreatic islets

Int J Mol Med. 2015 Jul;36(1):173-85. doi: 10.3892/ijmm.2015.2207. Epub 2015 May 12.


The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Diet, High-Fat*
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor / agonists
  • Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors
  • Glucagon-Secreting Cells / cytology*
  • Homeodomain Proteins / antagonists & inhibitors
  • Inflammation / pathology
  • Insulin-Secreting Cells / metabolism*
  • Liraglutide / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / physiology
  • Palmitates / pharmacology*
  • Peptide Fragments / pharmacology
  • Proprotein Convertase 1 / biosynthesis
  • Proprotein Convertase 1 / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / physiology
  • Trans-Activators / antagonists & inhibitors
  • Transcription Factor RelA / biosynthesis


  • Glucagon-Like Peptide-1 Receptor
  • Homeodomain Proteins
  • Palmitates
  • Peptide Fragments
  • Reactive Oxygen Species
  • Rela protein, mouse
  • Trans-Activators
  • Transcription Factor RelA
  • pancreatic and duodenal homeobox 1 protein
  • exendin (9-39)
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Proprotein Convertase 1
  • Acetylcysteine