VMP1-RELATED AUTOPHAGY AS A REACTIVE PROCESS AGAINST ISLET DYSFUNCTION INDUCED BY FRUCTOSE: ITS PREVENTION BY EXENDIN-4

BOGGIO V; MAIZTEGUI B; ROMAN CL; FLORES L; DEL ZOTTO H; ROPOLO A; GRASSO D; VACCARO MI; GAGLIARDINO JJ

Buenos Aires

Congreso; 21st IAP Meeting pancreas 2017; 2017

International Association of Pancreatology

Aim: To demonstrate the role of autophagy and incretins on fructose-induced alteration in B-cell mass and function. Methods: Normal Wistar rats were fed (3 weeks) with commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, B-cell mass, morphology/ultrastructure and apoptosis, VMP1 expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary, islets isolated from normal rats were cultured (3 days) without (C) or with F and F plus exendin-4 (FE) or chloroquine (FCQ). Expression of autophagy related-proteins (VMP1 and LC3), apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. Results: F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triglyceride, TBARS, insulin levels, HOMA-IR and HOMA-B indexes. Significant B-cell mass reduction was associated to an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes suggesting autophagy participation in this process. Indeed, F induced the increase of both, VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured B-cell. Exendin-4 prevented islet-cell damage and autophagy development. Conclusions: VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help to use autophagy as potential target for preventing progression from IGT to T2DM.