Liraglutide, a human glucagon-like peptide-1 analogue, stimulates AKT-dependent survival signalling and inhibits pancreatic β-cell apoptosis

J Cell Mol Med. 2018 Jun;22(6):2970-2980. doi: 10.1111/jcmm.13259. Epub 2018 Mar 10.

Abstract

Liraglutide, a human long-lasting GLP-1 analogue, is currently regarded as a powerful treatment option for type 2 diabetes. Apart from glucoregulatory and insulinotropic actions, liraglutide increases β-cell mass through stimulation of β-cell proliferation and islet neogenesis, as well as inhibition of β-cell apoptosis. However, the underline molecular mechanisms have not been fully characterized. In this study, we investigated the mechanism by which liraglutide preserves islet β-cells in an animal model of overt diabetes, the obese db/db mice, and protects a mouse pancreatic β-cell line (βTC-6 cells) against apoptosis. Treatment of 12-week-old diabetic mice with liraglutide for 2 weeks had no appreciable effects on blood non-fasting glucose concentration, islet insulin content and body weight. However, morphological and biochemical examination of diabetic mouse pancreatic islets demonstrated that liraglutide restores islet size, reduces islet β-cell apoptosis and improves nephrin expression, a protein involved in β-cell survival signalling. Our results indicated that liraglutide protects βTC-6 cells from serum withdrawal-induced apoptosis through inhibition of caspase-3 activation. The molecular mechanism of the anti-apoptotic action of liraglutide in βTC-6-cells comprises stimulation of PI3-kinase-dependent AKT phosphorylation leading to the phosphorylation, hence inactivation of the pro-apoptotic protein BAD and inhibition of FoxO1 transcription factor. In conclusion, we provided evidence that the GLP-1 analogue liraglutide exerts important beneficial effects on pancreatic islet architecture and β-cell survival by protecting cells against apoptosis. These findings extend our understanding of the actions of liraglutide and further support the use of GLP-1R agonists in the treatment of patients with type 2 diabetes.

Keywords: BAD inactivation; FoxO1 inhibition; Liraglutide; Nephrin; PI3K-AKT survival signalling; Pancreatic β-cells; apoptosis; db/db diabetic mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / pathology
  • Forkhead Box Protein O1 / genetics
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / genetics*
  • Glucagon-Like Peptide 1 / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology
  • Liraglutide / administration & dosage*
  • Liraglutide / pharmacology
  • Mice
  • Mice, Obese
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / genetics
  • Signal Transduction / drug effects

Substances

  • Forkhead Box Protein O1
  • Hypoglycemic Agents
  • Insulin
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt