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This Article Full Text Full Text (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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Barbosa, H. C Articles by Boschero, A. C PubMed PubMed Citation Articles by Barbosa, H. C Articles by Boschero, A. C

Departamento de Fisiologia e Biofísica, Instituto de Biologia, Universidade Estadual de Campinas, 13083-970 Campinas-SP, São Paulo-SP, Brazil¹ Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05508-900 São Paulo-SP, Brazil² Beta Cell Development and Function Group, Division of Reproduction and Endocrinology, King's College London, SE1 1UL London, UK³ CENEXA, Centro de Endocrinología Experimental y Aplicada (UNLP-CONICET, Centro Colaborador de la OPS/OMS), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Argentina

(Correspondence should be addressed to A C Boschero; Email: boschero{at}unicamp.br)

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 s, 5, 15, and 30 min) significantly increased Akt1^-Ser473 and MAPK3/1^{-Thr202/Tyr204} phosphorylation and INGAP-PP also acutely increased insulin secretion from islets perifused with 2 and 20 mM glucose. Islets cultured for 4 days in the presence of INGAP-PP showed an increased expression of Akt1, Frap1, and Mapk1 mRNAs as well as of the muscarinic M3 receptor subtype, and phospholipase C (PLC)-β2 proteins. These islets also showed increased Akt1 and MAPK3/1 protein phosphorylation. Brief exposure of INGAP-PP-treated islets to carbachol (Cch) significantly increased P70S6K^-Thr389 and MAPK3/1 phosphorylation and these islets released more insulin when challenged with Cch that 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 the 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 MAPK3/1 phosphorylation and Cch-induced insulin secretion suggest a participation of the cholinergic pathway in INGAP-PP-mediated effects.