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

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

CLINICAL SCIENCE (LONDON, ENGLAND : 1979)

PORTLAND PRESS LTD

Año: 2017 vol. 131 p. 673 - 687

0143-5221

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a 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, β-cell mass,morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1)expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days)without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactivesubstances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significantreduction in β-cell mass was associated with an increased apoptotic rate andmorphological/ultrastructural changes indicative of autophagic activity. Allthese changes were prevented by either sitagliptin or exendin-4. In culturedislets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNAlevels and increased caspase-3 expression. Chloroquine reduced these changes,suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process againstF-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.