Abstract
Lixisenatide, a glucagon-like peptide-1 receptor agonist, is used to stimulate insulin secretion in patients with type 2 diabetes mellitus. However, its effect on insulin secretion in cancer patients, particularly during the cachexia course, has not yet been evaluated. The purpose of this study was to investigate the lixisenatide effect on INS secretion decline during the cachexia course (2, 6, and 12 days of tumor) in pancreatic islets isolated from Walker-256 tumor-bearing rats. Pancreatic islets of healthy and tumor-bearing rats were incubated in the presence or absence of lixisenatide (10 nM). Tumor-bearing rats showed reduction of body weight and fat and muscle mass, characterizing the development of cachexia, as well as reduction of insulinemia and INS secretion stimulated by glucose (5.6, 8.3, 11.1, 16.7, and 20 mM) on days 2, 6, and/or 12 of tumor. Lixisenatide increased the 16.7 mM glucose-stimulated insulin secretion, but not by 5.6 mM glucose, in the islets of healthy rats, without changing the insulin intracellular content. However, lixisenatide did not prevent the decreased 16.7 mM glucose-stimulated insulin secretion in the pancreatic islets of rats with 2, 6, and 12 days of tumor and neither the decreased insulin intracellular content of rats with 12 days of tumor. In consistency, in vivo treatment with lixisenatide (50 μg kg−1, SC, once daily, for 6 days) visually increased insulinemia of healthy fasted rats, but did not prevent hypoinsulinemia of tumor-bearing rats. In conclusion, Walker-256 tumor-bearing rats showed early decline (2 days of tumor) of insulin secretion, which followed the cachexia course (6 and 12 days of tumor) and was not improved by lixisenatide, evidencing that this insulin secretagogue, used to treat type 2 diabetes, does not have beneficial effect in cancer bearing-rats.
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Acknowledgements
We thank Dr.Sabrina Grassiolli and Letícia Cristina Limieri for the valuable collaboration in the experiments.
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Research supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES—Scholarship).
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Almost all experiments were performed at the State University of Londrina, except for the insulin dosage by radioimmunoassay, that was performed at the University of São Paulo. H.M.S. and G.L.B: experimental design. D.L.Q., D.R.M., W.B.S.G., M.O.R.C.R., C.F.L., M.M.R.V., and M.F.R.G.: acquisition and analysis of data. D.L.Q., H.M.S., M.F.R.G., and G.L.B.: interpretation of data and preparation of figures and drafting the manuscript. All authors read and approved the manuscript and declare that all data were generated in-house and that no paper mill was used.
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Quintilhano, D.L., Miksza, D.R., de Souza Galia, W.B. et al. Insulin secretion decline in Walker-256 tumor-bearing rats is early, follows the course of cachexia, and is not improved by lixisenatide. Naunyn-Schmiedeberg's Arch Pharmacol 394, 697–705 (2021). https://doi.org/10.1007/s00210-020-02006-w
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DOI: https://doi.org/10.1007/s00210-020-02006-w