VMP1-related autophagy induced by fructose rich diet in ß-cells: Its prevention by incretins

VERÓNICA BOGGIO; DANIEL GRASSO; JUAN JOSÉ GAGLIARDINO; ALEJANDRO ROPOLO; LUIS FLORES; BÁRBARA MAIZTEGUI; HORACIO DEL ZOTTO; MARIA INES VACCARO

Buenos Aires

Congreso; International Association of Pancreatology Meeting 2017; 2017

International Association of Pancreatology

Aim: To demonstrate the role of autophagy and incretins on fructose-induced alteration in ß-cell mass and function.Method: Normal Wistar rats were fed (3 weeks) with commercial diet without (C) or with 10% fructose in drinking water alone (F) or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, ß-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 significant increase in plasma triglyceride, TBARS, insulin, HOMA-IR and HOMA-ß; indexes. ß-cell mass was significantly reduced 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 VMP1 and LC3 II/LC3 I ratio, suggesting that VMP1-related autophagy is activated in injured ß-cell. Exendin-4 prevented islet-cell damage and the development of autophagy.Conclusion: VMP1-related autophagy is a reactive process against F-induced islet dysfunction, effect that is prevented by incretin treatment. This knowledge could help to use autophagy as potential target for preventing progression from IGT to T2DM.