Transcription Factor FoxO1 Mediates Glucagon-Like Peptide-1 Effects on Pancreatic β-Cell Mass

Buteau, Jean; Spatz, Marianne L.; Accili, Domenico

doi:10.2337/db05-0825

Cited by 161 publications

(128 citation statements)

References 45 publications

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“…GLP-1 is known to activate insulin gene transcription (5), and although we did not directly measure insulin content, there was a trend toward increased insulin immunofluorescence in AdPC1͞3-transduced islet grafts. In addition, it has recently been reported that GLP-1's effects on ␤ cell growth and survival are mediated by means of phosphorylation-dependent nuclear exclusion of FoxO1, which in turn allows increased expression of the transcription factors Pdx1 and Foxa2 (29). Indeed, we did observe greater nuclear Pdx1 staining in the ␤ cells of AdPC1͞3-transduced grafts, suggesting that Pdx1 expression is upregulated in these islets and may contribute to the marked improvement of transplant outcomes.…”

Section: Discussionsupporting

confidence: 56%

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

Wideman¹,

Yu²,

Webber³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Glucagon-like peptide 1 (GLP-1) is a hormone that has received significant attention as a therapy for diabetes because of its ability to stimulate insulin biosynthesis and release and to promote growth and survival of insulin-producing ␤ cells. While GLP-1 is produced from the proglucagon precursor by means of prohormone convertase (PC) 1͞3 activity in enteroendocrine L cells, the same precursor is differentially processed by PC2 in pancreatic islet ␣ cells to release glucagon, leaving GLP-1 trapped within a larger fragment with no known function. We hypothesized that we could induce GLP-1 production directly within pancreatic islets by means of delivery of PC1͞3 and, further, that this intervention would improve the viability and function of islets. Here, we show that adenovirus-mediated expression of PC1͞3 in ␣ cells increases islet GLP-1 secretion, resulting in improved glucose-stimulated insulin secretion and enhanced survival in response to cytokine treatment. PC1͞3 expression in ␣ cells also improved performance after islet transplantation in a mouse model of type 1 diabetes, possibly by enhancing nuclear Pdx1 and insulin content of islet ␤ cells. These results demonstrate a unique strategy for liberating GLP-1 from directly within the target organ and highlight the potential for up-regulating islet GLP-1 production as a means of treating diabetes.diabetes ͉ islet transplantation ͉ prohormone convertase 1͞3

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Section: Discussionsupporting

confidence: 56%

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

Wideman¹,

Yu²,

Webber³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Transduced INS832/13 cells, with a constitutively nuclear FoxO1 mutant, resulted in inhibition of β-cell proliferation induced by GLP-1, suggesting an anti-proliferative role of FoxO1 in pancreatic β cells. Moreover, the effects of GLP-1 were suppressed by an inhibitor of PI-3K (11). In this study, we demonstrated that following exposure to 10 or 100 nM liraglutide for 24 h, the activation of FoxO1 was markedly down-regulated.…”

Section: A B C Dmentioning

confidence: 62%

“…A series of studies have suggested that FoxO1 has a direct effect on pancreatic β-cell differentiation, neogenesis, proliferation and stress resistance (10). A previous study revealed that FoxO1 mediated the proliferative and anti-apoptotic roles of human GLP-1 fragment 7-36 amide in pancreatic β cells (11). Furthermore, studies by Buteau et al demonstrated that GLP-1 increased FoxO1 phosphorylation via activation of phoshatidylinositol-3 kinase (PI-3K)/Akt (also known as protein kinase B, PKB) signaling (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…A previous study revealed that FoxO1 mediated the proliferative and anti-apoptotic roles of human GLP-1 fragment 7-36 amide in pancreatic β cells (11). Furthermore, studies by Buteau et al demonstrated that GLP-1 increased FoxO1 phosphorylation via activation of phoshatidylinositol-3 kinase (PI-3K)/Akt (also known as protein kinase B, PKB) signaling (11,12). PI-3K activates Akt through phosphorylation, and active Akt, in turn, inhibits the transcriptional activation of FoxO1 via phosphorylation-dependent nuclear exclusion.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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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.

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“…In the ␤-cell, insulin or growth factor PI3K/Akt-induced FoxO1 phosphorylation leads to its translocation from the nucleus to cytoplasm, relieving its inhibition of target gene transcription (14). The incretin hormones GIP and glucagon-like peptide 1 (GLP-1) also activate this sequence (19,20). Another is the balance between oxidative stress-induced FoxO1 acetylation and deacetylation (21).…”

Section: Peroxisome Proliferator-activated Receptor ␥ (Ppar␥)mentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

Gupta

Leahy

Monga

et al. 2013

Journal of Biological Chemistry

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Background:The molecular mechanisms for islet ␤-cell compensation and failure are not fully known. Results: FoxO1/PPAR␥ signaling regulates key ␤-cell genes, with this network being up-regulated in nondiabetic insulinresistant rats and impaired in rodents with diabetes. Conclusion: We examine the potential for the FoxO1/PPAR␥ network as a feature of ␤-cell compensation and failure. Significance: We identify targets for prevention of type 2 diabetes.

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Transcription Factor FoxO1 Mediates Glucagon-Like Peptide-1 Effects on Pancreatic β-Cell Mass

Cited by 161 publications

References 45 publications

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

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

Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

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