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

Katerina Kapodistria, Effie Photini Tsilibary, Eleni Kotsopoulou, Petros Moustardas, Paraskevi Kitsiou

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2970-2980
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Volume22
Issue number6
DOIs
StatePublished - Jun 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by a grant from the General Secretariat of Research and Technology, Ministry of Education and Religious Affairs through the Operational Programme ‘Education and Lifelong Learning, ESPA 2007–2013’ Action: ‘Collaboration 2011’, Title: ‘Pancreatic beta cells functionality and regeneration: the role of liraglutide’ 11ΣYN_1_1496 (grant to E.F.T. and P.K.). The funding source had no involvement in study design, in the collection, analysis and interpretation of data, in the preparation and writing of the article and also in the decision to submit the paper for publication. The authors wish to thank Dr. Aristidis Charonis (Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens (BRFAA), for providing the db/db animals and Tsalavoutas-Psarras, M.Sc. and Michalis Zachariadis, Ph.D. (Institute of Biosciences & Applications, N.C.S.R. ‘Demokritos’) for expert technical assistance in confocal microscopy. This manuscript was supported by a grant from Novo Nordisk in respect of publication costs. Novo Nordisk has not influenced the content of the publication nor been involved in the study design, data collection, analysis or reporting.

Funding Information:
This work was supported by a grant from the General Secretariat of Research and Technology, Ministry of Education and Religious Affairs through the Operational Programme ‘Education and Lifelong Learning, ESPA 2007–2013’ Action: ‘Collaboration 2011’, Title: ‘Pancreatic beta cells functionality and regeneration: the role of liraglutide’ 11ΣYN_1_1496 (grant to E.F.T. and P.K.). The funding source had no involvement in study design, in the collection, analysis and interpretation of data, in the preparation and writing of the article and also in the decision to submit the paper for publication. The authors wish to thank Dr. Aristidis Charonis (Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens (BRFAA), for providing the db/db animals and Tsalavoutas-Psarras, M.Sc. and Michalis Zachariadis, Ph.D. (Institute of Biosciences & Applications, N.C.S.R. ‘Demokritos’) for expert technical assistance in confocal microscopy. This manuscript was supported by a grant from Novo Nordisk in respect of publication costs. Novo Nordisk has not influenced the content of the publication nor been involved in the study design, data collection, analysis or reporting. K.K. performed acquisition of data, analysis and interpretation of data, drafting of manuscript, critical revision of the article. E.F.T. performed study conception and design, funding acquisition, critical revision of the article. E.K. performed acquisition of data and critical revision of the article. P.M. performed acquisition of data, analysis and interpretation of data and critical revision of the article. P.K. performed study conception and design, analysis and interpretation of data, funding acquisition, drafting of manuscript and critical revision of the article.

Keywords

  • BAD inactivation
  • FoxO1 inhibition
  • Liraglutide
  • Nephrin
  • PI3K-AKT survival signalling
  • Pancreatic β-cells
  • apoptosis
  • db/db diabetic mouse

Fingerprint Dive into the research topics of 'Liraglutide, a human glucagon-like peptide-1 analogue, stimulates AKT-dependent survival signalling and inhibits pancreatic β-cell apoptosis'. Together they form a unique fingerprint.

Cite this