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




Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Angeles Mondragon, Daniel Davidsson, Styliana Kyriakoudi, Annika Bertling, Rosa Gomes-Faria, Patrizia Cohen, Stephen Rothery, Pau

Fuente: http://plos.srce.hr/



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