Pancreatic beta-cell specific BAG3 knockout results in chronic hyperinsulinemia inducing insulin resistance.

Autor:	Damiani V; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy., Lamolinara A; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. D'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy., Cicalini I; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy., Cufaro MC; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy., Del Pizzo F; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy., Di Marco F; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy., Del Boccio P; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Pharmacy, University 'G. d'Annunzio' of Chieti-Pescara, 66100, Chieti, Italy., Dufrusine B; Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, 64100, Teramo, Italy., Hahne M; IGMM, CNRS, University of Montpellier, 34090, Montpellier, France., Lattanzio R; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy., Pieragostino D; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy., Iezzi M; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. D'Annunzio University of Chieti-Pescara, 66100, Chieti, Italy., Federici M; Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy., Turco MC; Department of Medicine, Surgery and Dentistry, University of Salerno, 84081, Baronissi, Italy., Maiorana A; Division of Metabolism, Department of Pediatrics Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 00100, Rome, Italy., Dionisi-Vici C; Division of Metabolism, Department of Pediatrics Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico), 00100, Rome, Italy., De Laurenzi V; Center for Advanced Studies and Technology (CAST), 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy; Department of Innovative Technologies in Medicine and Dentistry, 'G. d'Annunzio' University of Chieti-Pescara, 66100, Chieti, Italy. Electronic address: delaurenzi@unich.it.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2023 Aug; Vol. 74, pp. 101752. Date of Electronic Publication: 2023 Jun 10.
DOI:	10.1016/j.molmet.2023.101752
Abstrakt:	Background: Insulin, secreted from pancreatic islets of Langerhans, is of critical importance in regulating glucose homeostasis. Defective insulin secretion and/or the inability of tissues to respond to insulin results in insulin resistance and to several metabolic and organ alterations. We have previously demonstrated that BAG3 regulates insulin secretion. Herein we explored the consequences of beta-cells specific BAG3 deficiency in an animal model. Methods: We generated a beta-cells specific BAG3 knockout mouse model. Glucose and insulin tolerance tests, proteomics, metabolomics, and immunohistochemical analysis were used to investigate the role of BAG3 in regulating insulin secretion and the effects of chronic exposure to excessive insulin release in vivo. Results: Beta-cells specific BAG3 knockout results in primary hyperinsulinism due to excessive insulin exocytosis finally leading to insulin resistance. We demonstrate that resistance is mainly muscle-dependent while the liver remains insulin sensitive. The chronically altered metabolic condition leads in time to histopathological alterations in different organs. We observe elevated glycogen and lipid accumulation in the liver reminiscent of non-alcoholic fatty liver disease as well as mesangial matrix expansion and thickening of the glomerular basement membrane, resembling the histology of chronic kidney disease. Conclusion: Altogether, this study shows that BAG3 plays a role in insulin secretion and provides a model for the study of hyperinsulinemia and insulin resistance. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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