VMP1-Related autophagy induced by fructose rich diet in β-cells: its prevention by incretins.

BOGGIO, V.; GRASSO, D.; FLORES, L. E.; ALEJANDRO JAVIER ROPOLO; ROMAN, C. L.; VACCARO, M. I.; MAIZTEGUI, B.; DEL ZOTTO, H.; GAGLIARDINO, J. J.

Buenos Aires

Congreso; III International Congress in Translational Medicine; 2016

International Master/PhD Program in Biomedical Sciences (IMBS). Facultad de Farmacia y Bioquímica y Facultad de Medicina, Universidad de Buenos Aires.

Aim: To demonstrate the role of autophagy and incretins on fructose-induced alteration in β-cell mass and function. Methods: 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, β-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-β indexes. β-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 β-cell. Exendin-4 prevented islet-cell damage and the development of autophagy. Conclusions: 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.