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

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.

Liraglutide protects against glucolipotoxicity‐induced RIN‐m5F β‐cell apoptosis through restoration of PDX1 expression

“…These findings indicate that restoration of PDX1 by inhibition of Mst1 cleavage may play a protective role against glucolipotoxicity‐induced β‐cell damage. Interestingly, liraglutide has been demonstrated to promote pancreatic β‐cell survival through inhibition of caspase‐3 activation . Mst1 alone sufficiently induces caspase activation, and activation of the caspase machinery (particularly caspase‐3) may be essential to the cleavage of Mst1.…”

Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas

“…Drugs affecting islet cells' proliferation and apoptosis are well known, but they have been studied mainly in rodent models (35)(36)(37)(38) and never in nonhuman primates or humans. Recently, liraglutide, a human GLP-1 analog, was shown to increase islet mass by stimulating β cell proliferation and reducing β cell apoptosis by enhancing nephrin expression, a protein involved in β cell survival signaling, and by stimulating PI3K-dependent Akt phosphorylation (39). Conversely, in the study by Bunck et al (19), 52 weeks of exenatide treatment did not exert any proliferative effect on β cell mass because within weeks of discontinuing exenatide therapy in patients with T2D, insulin secretion declined to pretreatment level.…”

Anti‐incretin effect: The other face of Janus in human glucose homeostasis

“…This leads to the phosphorylation, hence, inactivation of the proapoptotic protein BAD and inhibition of FoxO1 transcription factor. 19 The unrestrained anti-apoptotic effects of incretins however may pose a potential risk of unlimited proliferation of cells expressing incretin peptide receptors (like beta cells). The short half-life (2-7 min) of incretin peptides resulting from rapid enzymatic degradation may be a way to prevent unlimited proliferative effects.…”