title: VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins.
abstract: 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-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with 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 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 against F-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.
authors.affiliation: Centro de Endocrinología Experimental y Aplicada (CENEXA), UNLP-CONICET, La Plata, Facultad de Ciencias Médicas UNLP, 60 y 120, 1900 La Plata, Argentina.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Maiztegui
authors.affiliation: Institute of Biochemistry and Molecular Medicine (IBIMOL), CONICET, Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, 956 Junin p5 1113, Buenos Aires, Argentina.
authors.forename: Verónica
authors.initials: V
authors.lastname: Boggio
authors.affiliation: Centro de Endocrinología Experimental y Aplicada (CENEXA), UNLP-CONICET, La Plata, Facultad de Ciencias Médicas UNLP, 60 y 120, 1900 La Plata, Argentina.
authors.forename: Carolina L
authors.initials: CL
authors.lastname: Román
authors.affiliation: Centro de Endocrinología Experimental y Aplicada (CENEXA), UNLP-CONICET, La Plata, Facultad de Ciencias Médicas UNLP, 60 y 120, 1900 La Plata, Argentina.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Flores
authors.affiliation: Centro de Endocrinología Experimental y Aplicada (CENEXA), UNLP-CONICET, La Plata, Facultad de Ciencias Médicas UNLP, 60 y 120, 1900 La Plata, Argentina.
authors.forename: Héctor Del
authors.initials: HD
authors.lastname: Zotto
authors.affiliation: Institute of Biochemistry and Molecular Medicine (IBIMOL), CONICET, Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, 956 Junin p5 1113, Buenos Aires, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ropolo
authors.affiliation: Institute of Biochemistry and Molecular Medicine (IBIMOL), CONICET, Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, 956 Junin p5 1113, Buenos Aires, Argentina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grasso
authors.affiliation: Institute of Biochemistry and Molecular Medicine (IBIMOL), CONICET, Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, 956 Junin p5 1113, Buenos Aires, Argentina.
authors.forename: María I
authors.initials: MI
authors.lastname: Vaccaro
authors.affiliation: Centro de Endocrinología Experimental y Aplicada (CENEXA), UNLP-CONICET, La Plata, Facultad de Ciencias Médicas UNLP, 60 y 120, 1900 La Plata, Argentina cenexaar@yahoo.com.ar.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gagliardino
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight; D002478:Cells, Cultured; D004032:Diet / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D002149:Energy Intake; D000077270:Exenatide; D005632:Fructose / Q000008:administration & dosage / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054795:Incretins / Q000494:pharmacology*; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008854:Microscopy, Electron; D010455:Peptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D017208:Rats, Wistar; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D008565:Membrane Proteins; D010455:Peptides; D012333:RNA, Messenger; C446296:VMP1 protein, rat; D014688:Venoms; D005632:Fructose; D000077270:Exenatide; D000068900:Sitagliptin Phosphate
keywords: autophagy; fructose-induced β-cell injury; incretins; β-cell function; β-cell mass