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Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia

AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the...

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Autores principales: Mondragon, Angeles, Davidsson, Daniel, Kyriakoudi, Styliana, Bertling, Annika, Gomes-Faria, Rosa, Cohen, Patrizia, Rothery, Stephen, Chabosseau, Pauline, Rutter, Guy A., da Silva Xavier, Gabriela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132080/
https://www.ncbi.nlm.nih.gov/pubmed/25119717
http://dx.doi.org/10.1371/journal.pone.0104873
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author Mondragon, Angeles
Davidsson, Daniel
Kyriakoudi, Styliana
Bertling, Annika
Gomes-Faria, Rosa
Cohen, Patrizia
Rothery, Stephen
Chabosseau, Pauline
Rutter, Guy A.
da Silva Xavier, Gabriela
author_facet Mondragon, Angeles
Davidsson, Daniel
Kyriakoudi, Styliana
Bertling, Annika
Gomes-Faria, Rosa
Cohen, Patrizia
Rothery, Stephen
Chabosseau, Pauline
Rutter, Guy A.
da Silva Xavier, Gabriela
author_sort Mondragon, Angeles
collection PubMed
description AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse. METHODS: C57BL6 mice were maintained for 131 days on a normal diet (ND) or a diet comprising 60% fat (HFD) before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices. RESULTS: Whereas liraglutide (200 µg/kg) and exendin-4 (10 µg/kg) treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg) was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice. CONCLUSIONS: Liraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis.
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spelling pubmed-41320802014-08-19 Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia Mondragon, Angeles Davidsson, Daniel Kyriakoudi, Styliana Bertling, Annika Gomes-Faria, Rosa Cohen, Patrizia Rothery, Stephen Chabosseau, Pauline Rutter, Guy A. da Silva Xavier, Gabriela PLoS One Research Article AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse. METHODS: C57BL6 mice were maintained for 131 days on a normal diet (ND) or a diet comprising 60% fat (HFD) before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices. RESULTS: Whereas liraglutide (200 µg/kg) and exendin-4 (10 µg/kg) treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg) was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice. CONCLUSIONS: Liraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis. Public Library of Science 2014-08-13 /pmc/articles/PMC4132080/ /pubmed/25119717 http://dx.doi.org/10.1371/journal.pone.0104873 Text en © 2014 Mondragon et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Mondragon, Angeles
Davidsson, Daniel
Kyriakoudi, Styliana
Bertling, Annika
Gomes-Faria, Rosa
Cohen, Patrizia
Rothery, Stephen
Chabosseau, Pauline
Rutter, Guy A.
da Silva Xavier, Gabriela
Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia
title Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia
title_full Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia
title_fullStr Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia
title_full_unstemmed Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia
title_short Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia
title_sort divergent effects of liraglutide, exendin-4, and sitagliptin on beta-cell mass and indicators of pancreatitis in a mouse model of hyperglycaemia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4132080/
https://www.ncbi.nlm.nih.gov/pubmed/25119717
http://dx.doi.org/10.1371/journal.pone.0104873
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