Glucagon-like peptide-1 improves beta-cell antioxidant capacity via extracellular regulated kinases pathway and Nrf2 translocation

Free Radic Biol Med. 2016 Jun:95:16-26. doi: 10.1016/j.freeradbiomed.2016.03.002. Epub 2016 Mar 9.


Oxidative stress plays an important role in the development of beta-cell dysfunction and insulin resistance, two major pathophysiological abnormalities of type 2 diabetes. Expression levels of antioxidant enzymes in beta cells are very low, rendering them more susceptible to damage caused by reactive oxygen species (ROS). Although the antioxidant effects of glucagon-like peptide-1 (GLP-1) and its analogs have been previously reported, the exact mechanisms involved are still unclear. In this study, we demonstrated that GLP-1 was able to effectively inhibit oxidative stress and cell death of INS-1E beta cells induced by the pro-oxidant tert-butyl hydroperoxide (tert-BOOH). Incubation with GLP-1 enhanced cellular levels of glutathione and the activity of its related enzymes, glutathione-peroxidase (GPx) and -reductase (GR) in beta cells. However, inhibition of ERK, but not of the PI3K/AKT pathway abolished, at least in part, the antioxidant effect of GLP-1. Moreover, ERK activation seems to be protein kinase A (PKA)-dependent because inhibition of PKA with H-89 was sufficient to block the GLP-1-derived protective effect on beta cells. GLP-1 likewise increased the synthesis of GR and favored the translocation of the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Glucose-stimulated insulin secretion was also preserved in beta-cells challenged with tert-BOOH but pre-treated with GLP-1, probably through the down-regulation of the mitochondrial uncoupling-protein2 (UCP2). Thus, our results provide additional mechanisms of action of GLP-1 to prevent oxidative damage in beta cells through the modulation of signaling pathways involved in antioxidant enzyme regulation.

Keywords: Beta cell; GLP-1; Glutathione-related enzymes; Oxidative stress.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Glucagon-Like Peptide 1 / genetics*
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucose / metabolism
  • Glutathione / biosynthesis
  • Glutathione Reductase / biosynthesis
  • Glutathione Reductase / genetics
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Isoquinolines / pharmacology
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress / genetics
  • Rats
  • Reactive Oxygen Species / metabolism
  • Sulfonamides / pharmacology
  • Uncoupling Protein 2 / genetics*
  • Uncoupling Protein 2 / metabolism
  • tert-Butylhydroperoxide / metabolism


  • Antioxidants
  • Insulin
  • Isoquinolines
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, rat
  • Reactive Oxygen Species
  • Sulfonamides
  • Uncoupling Protein 2
  • Glucagon-Like Peptide 1
  • tert-Butylhydroperoxide
  • Glutathione Reductase
  • Cyclic AMP-Dependent Protein Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Glutathione
  • Glucose
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide