Islet Neogenesis Associated Protein signaling in neonatal pancreatic rat islets: involvement of the cholinergic pathway

BARBOSA H; BORDIN S; ANHE G; PERSAUD S; BOWE J; BORELLI M; GAGLIARDINO J; BOSCHERO A

JOURNAL OF ENDOCRINOLOGY

Society for endocrinology

Año: 2008 vol. 199 p. 299 - 306

0022-0795

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-_2 proteins. These islets also showed increased Akt and ERK1/2 protein phosphorylation. Brief exposure of INGAP-PPtreated 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-_2 proteins, enhanced P70S6K and ERK1/2 phosphorylation and Cch-induced insulin secretion suggest a participation of the Cholinergic pathway in INGAP-PP-mediated effects.