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

Autor: Kapodistria K; Institute of Biosciences and Applications, National Centre for Scientific Research, N.C.S.R. 'Demokritos', Terma Patriarchou Grigoriou & Neapoleos, Attiki, Greece., Tsilibary EP; Institute of Biosciences and Applications, National Centre for Scientific Research, N.C.S.R. 'Demokritos', Terma Patriarchou Grigoriou & Neapoleos, Attiki, Greece., Kotsopoulou E; Institute of Biosciences and Applications, National Centre for Scientific Research, N.C.S.R. 'Demokritos', Terma Patriarchou Grigoriou & Neapoleos, Attiki, Greece., Moustardas P; Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece., Kitsiou P; Institute of Biosciences and Applications, National Centre for Scientific Research, N.C.S.R. 'Demokritos', Terma Patriarchou Grigoriou & Neapoleos, Attiki, Greece.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2018 Jun; Vol. 22 (6), pp. 2970-2980. Date of Electronic Publication: 2018 Mar 10.
DOI: 10.1111/jcmm.13259
Abstrakt: 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.
(© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
Databáze: MEDLINE
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