The Akt/FoxO1/p27 pathway mediates the proliferative action of liraglutide in β cells

Abstract

Abstract. Numerous studies have shown that liraglutide, a modified form of human glucagon-like peptide-1 (GLP-1), increases β-cell mass. However, the underlying molecular mechanisms remain unclear. In the present study, we investigated the role of Akt/FoxO1/p27 signaling in liraglutide-induced β-cell proliferation. INS-1 rat insulinoma cells were exposed to two different concentrations of liraglutide. MTT assay was performed to evaluate β-cell proliferation. The expression of Akt/FoxO1/p27 was detected by quantitative real-time PCR and Western blotting. The results revealed that in comparison to the non-treatment group, stimulating INS-1 cells with 10 and 100 nM liraglutide caused β-cell proliferation to be significantly enhanced. The mRNA levels of p27 in INS-1 cells declined upon treatment with liraglutide compared to the non-treatment group. Western blot analysis revealed that the phosphorylation of Akt and FoxO1 was markedly elevated following exposure to liraglutide. Moreover, LY294002, a phosphatidylinositol 3-kinase (PI-3K) inhibitor, significantly abrogated liraglutide-induced effects. Therefore, we conclude that liraglutide increased the β-cell mass by upregulating β-cell proliferation and that the proliferative action of liraglutide in β cells was mediated by activation of PI-3K/Akt, which resulted in inactivation of FoxO1 and decreased p27.

MicroRNA-223 is essential for maintaining functional β-cell mass during diabetes through inhibiting both FOXO1 and SOX6 pathways

“…Furthermore, Foxo1 inhibits cell proliferation via up-regulating cyclindependent kinase inhibitor such as p27 (26). In fact, inactivation of Foxo1-p27 cascade mediates the proliferative action of liraglutide in ␤-cells (33). In accordance with current literature, our study presented here shows that miR-223 is essential for ␤-cell proliferation via targeting the Foxo1 signaling pathway.…”

“…However, Alk5 inhibitor II can also inhibit SMAD7-induced ␤-cell proliferation, which reiterates the intriguing hypothesis that ␤-cell dedifferentiation proceeds before proliferation. Indeed, as Alk5 inhibitor II reverses ␤-cell dedifferentiation under cytokine stress condition, it increases gene expression of Foxo1, which has been widely reported as a repressor of ␤-cell proliferation (26,33). In contrast, it has been shown that ␤-cells with Foxo1 deficiency could undergo dedifferentiation (10).…”

Exenatide ameliorates hepatic steatosis and attenuates fat mass and FTO gene expression through PI3K signaling pathway in nonalcoholic fatty liver disease

“…Li and coworkers ( 26 ) found that Akt could regulate the process of hepatic glucose and lipid metabolism by suppressing fatty acid oxidation gene expression. GLP-1R activation has been shown in vitro to promote peripheral cell/tissue differentiation and proliferation by engaging PI3K/Akt, as well as to prevent apoptosis via a PKA/PI3K/Akt-dependent pathway ( 27 , 28 ). In the present study, we found that the effects of exenatide were associated with activation of p-Akt, which may suppress fatty acid oxidation gene and promote hepatocyte regeneration, thus inhibiting the development of NAFLD.…”

Effects of insulin analogs and glucagon-like peptide-1 receptor agonists on proliferation and cellular energy metabolism in papillary thyroid cancer

“…Moreover, Fang et al and Wei et al indicated that liraglutide stimulated β-cell proliferation, which is mediated by the PI3K/Akt signaling pathway. 28 , 29 A study focusing on 3T3-L1 cells found that GLP-1 could promote 3T3-L1 cell proliferation and differentiation via the PI3K/Akt and MAPK/Erk signaling pathways. 30 Both studies showed that GLP-1-based medicines could influence these signaling pathways, at least in some types of cells.…”