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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0309v1 199/2/299    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Barbosa, H. Articles by Boschero, A. Search for Related Content PubMed PubMed Citation Articles by Barbosa, H. Articles by Boschero, A.

H Barbosa, Physiology & Biophysics, State University of Campinas, Campinas, Brazil
S Bordin, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
G Anhe, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
S Persaud, Division of Reproduction and Endocrinology, King's College London, London, United Kingdom
J Bowe, Division of Reproduction and Endocrinology, King's College London, London, United Kingdom
M Borelli, Facultad de Ciencias Médicas, CENEXA (UNLP-CONICET), La Plata, Argentina
J Gagliardino, Facultad de Ciencias Médicas, CENEXA (UNLP-CONICET),, La Plata, Argentina
A Boschero, Physiology & Biophysics, State University of Campinas, Campinas, Brazil

Correspondence: Antonio Boschero, Email: boschero{at}unicamp.br

Abstract

Islet neogenesis associated protein (INGAP) increases islet mass and insulin secretion in neonatal and adult rat islets. In the present study, we measured the short- and long-term effects of INGAP-PP (a pentadecapeptide having the 104-118 amino acid sequence of INGAP) upon islet protein expression and phosphorylation of components of the PI3K, MAPK and cholinergic pathways, and on insulin secretion. Short-term exposure of neonatal islets to INGAP-PP (90 sec, 5, 15 and 30 min) significantly increased Akt-Ser473 and ERK1/2-Thr202/Tyr204 phosphorylation and INGAP-PP also acutely increased insulin secretion from islets perifused with 2 and 20 mM glucose. Islets cultured for four days in the presence of INGAP-PP showed an increased expression of Akt1, mTOR and ERK2 mRNAs as well as of the muscarinic M3 receptor subtype, and PLC-β2 proteins. These islets also showed increased Akt and ERK1/2 protein phosphorylation. Brief exposure of INGAP-PP-treated islets to carbachol (Cch) significantly increased P70S6K-Thr389 and ERK1/2 phosphorylation and these islets released more insulin when challenged with Cch which was prevented by the M3 receptor antagonist 4-DAMP, in a concentration-dependent manner. In conclusion, these data indicate that short- and long-term exposure to INGAP-PP significantly affects the expression and phosphorylation of proteins involved in islet PI3K and MAPK signaling pathways. The observations of INGAPP-PP-stimulated up-regulation of cholinergic M3 receptors and PLC-β2 proteins, enhanced P70S6K and ERK1/2 phosphorylation and Cch-induced insulin secretion suggest a participation of the cholinergic pathway in INGAP-PP-mediated effects.