The glucagon-like peptide 1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β- and α-cell function and relative volumes, islet cell apoptosis and replication in nondiabetic non-human primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an L-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated and the remnant pancreas (head-body) harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by approximately 2-fold. β-, α-, and δ-cell relative volumes in exenatide-treated baboons were significantly increased compared to saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β-, α-, and δ-cells and produces a robust increase in insulin sensitivity in non-human primates.

Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas / T.V. Fiorentino, F. Casiraghi, A.M. Davalli, G. Finzi, S. La Rosa, P.B. Higgins, G.A. Abrahamian, A. Marando, F. Sessa, C. Perego, R. Guardado-Mendoza, S. Kamath, A. Ricotti, P. Fiorina, G. Daniele, A.M. Paez, F. Andreozzi, R.A. Bastarrachea, A.G. Comuzzie, A. Gastaldelli, A.O. Chavez, E.S. Di Cairano, P.A. Frost, L. Luzi, E.J. Dick, G.A. Halff, R.A. DeFronzo, F. Folli. - In: JCI INSIGHT. - ISSN 2379-3708. - 4:20(2019 Oct 17), pp. e93091.1-e93091.17.

Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas

F. Casiraghi
Investigation
;
A.M. Davalli
Writing – Review & Editing
;
C. Perego
Investigation
;
P. Fiorina
Data Curation
;
E.S. Di Cairano
Investigation
;
L. Luzi
Data Curation
;
F. Folli
Writing – Review & Editing
2019-10-17

Abstract

The glucagon-like peptide 1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β- and α-cell function and relative volumes, islet cell apoptosis and replication in nondiabetic non-human primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an L-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated and the remnant pancreas (head-body) harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by approximately 2-fold. β-, α-, and δ-cell relative volumes in exenatide-treated baboons were significantly increased compared to saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β-, α-, and δ-cells and produces a robust increase in insulin sensitivity in non-human primates.
B cells; Endocrinology; Glucose metabolism; Insulin signaling, non human primate, baboon, GLP1 receptor, exenatide, GLP1 receptor agonist
Settore MED/13 - Endocrinologia
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/677525
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