TY - JOUR
T1 - Integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas
AU - Fiorentino, Teresa Vanessa
AU - Casiraghi, Francesca
AU - Davalli, Alberto M.
AU - Finzi, Giovanna
AU - Rosa, Stefano La
AU - Higgins, Paul B.
AU - Abrahamian, Gregory A.
AU - Marando, Alessandro
AU - Sessa, Fausto
AU - Perego, Carla
AU - Guardado-Mendoza, Rodolfo
AU - Kamath, Subhash
AU - Ricotti, Andrea
AU - Fiorina, Paolo
AU - Daniele, Giuseppe
AU - Paez, Ana M.
AU - Andreozzi, Francesco
AU - Bastarrachea, Raul A.
AU - Comuzzie, Anthony G.
AU - Gastaldelli, Amalia
AU - Chavez, Alberto O.
AU - Di Cairano, Eliana S.
AU - Frost, Patrice
AU - Luzi, Livio
AU - Dick, Edward J.
AU - Halff, Glenn A.
AU - DeFronzo, Ralph A.
AU - Folli, Franco
N1 - Funding Information:
We thank Andrea Caumo, Department of Health Science, University of Milan, Italy, for his support in the analyses regarding relationship between insulin sensitivity and secretion in the 3 study groups at baseline and at the end of the study. This investigation was partially supported by NIH R01 DK080148 (to FF) and resources from the Southwest National Primate Research Center grant P51 OD011133 from the Office of Research Infrastructure Programs, NIH. TVF was supported in part by a fellowship from Fondazione Diabete Ricerca della SID, Italy. FF is grateful to Leslie David Hillis and Sylka Rodovalho for support throughout the course of the studies and preparation of the manuscript.FF is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Publisher Copyright:
© 2019 American Society for Clinical Investigation. All rights reserved.
PY - 2019/9/19
Y1 - 2019/9/19
N2 - 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 cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman 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) was 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 about 2-fold. β, α, and cell relative volumes in exenatide-Treated baboons were significantly increased compared with 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 cells and produces a robust increase in insulin sensitivity in nonhuman primates.
AB - 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 cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman 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) was 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 about 2-fold. β, α, and cell relative volumes in exenatide-Treated baboons were significantly increased compared with 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 cells and produces a robust increase in insulin sensitivity in nonhuman primates.
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U2 - 10.1172/jci.insight.93091
DO - 10.1172/jci.insight.93091
M3 - Article
C2 - 31536476
AN - SCOPUS:85077585482
SN - 2379-3708
VL - 4
JO - JCI insight
JF - JCI insight
IS - 20
M1 - e93091
ER -