Impact Factor 3.519
2017 JCR, Clarivate Analytics 2018

Frontiers journals are at the top of citation and impact metrics

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Endocrinol. | doi: 10.3389/fendo.2019.00052

Autophagy regulates the function and survival of human pancreatic beta cells under endoplasmic reticulum stress and in type 2 diabetes

 Marco Bugliani1, Sandra Mossuto1, Francesca Grano1, Mara Suleiman1,  Lorella Marselli1, Ugo Boggi2,  Piero Marchetti1 and  Vincenzo De Tata3, 4*
  • 1Department of Clinical and Experimental Medicine, University of Pisa, Italy
  • 2Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell'Area Critica, Università degli Studi di Pisa, Italy
  • 3University of Pisa, Italy
  • 4Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, Italy

Autophagy is the major mechanism involved in degradation and recycling of intracellular components, and its alterations have been proposed to cause beta cell dysfunction. In this study, we explored the effects of autophagy modulation in human islets under conditions associated to endoplasmic reticulum (ER) stress. Human pancreatic islets were isolated by enzymatic digestion and density gradient purification from pancreatic samples of non-diabetic (ND; n=17; age 65±21 years; gender: 5M/12F; BMI 23.4±3.3 kg/m2) and T2D (n=9; age 76±6 years; 4M/5F; gender: BMI 25.4±3.7 kg/m2) organ donors. Nine ND organ donors were treated for hypertension and 1 for both hypertension and hypercholesterolemia. T2D organ donors were treated with metformin (4), oral hypoglycemic agents (2), diet+oral hypoglycemic agents (1), insulin (1) or insulin plus metformin (1) as for antidiabetic therapy and, of these, 3 were treated also for hypertension and 6 for both hypertension and hypercholesterolemia. Two days after isolation, they were cultured for 1-5 days with 10 ng/ml rapamycin (autophagy inducer), 5 mM 3-methyladenine (3-MA) or 1.0 nM concanamycin-A (ConcA) (autophagy blockers), either in the presence or not of metabolic (0.5 mM palmitate) or chemical (0.1 ng/ml brefeldin A) ER stressors. In ND islets palmitate exposure induced a 4-5 fold increase of beta cell apoptosis, which was significantly prevented by rapamycin and exacerbated by 3-MA. Substantially similar results were observed with brefeldin treatment. Glucose-stimulated insulin secretion from ND islets was reduced by palmitate (- 40-50%) and brefeldin (- 60-70%), and rapamycin counteracted palmitate, but not brefeldin, cytostatic action. Both palmitate and brefeldin induced PERK, CHOP and Bip gene expression, which was partially, but significantly prevented by rapamycin. With T2D islets, rapamycin alone reduced the amount of p62. Compared to untreated T2D cells, rapamycin-exposed diabetic islets showed improved insulin secretion, reduced proportion of beta cells showing signs of apoptosis and better preserved insulin granules, mitochondria and ER ultrastructure; this was associated with significant reduction of PERK, CHOP and Bip gene expression. This study emphasizes the importance of autophagy modulation in human beta cell function and survival, particularly in situations of ER stress. Tuning autophagy could be a tool for beta cell protection.

Keywords: Autophagy, Type 2 diabetes (DM2), er stress, Human islets of Langerhans, insulin secretion

Received: 06 Jul 2018; Accepted: 21 Jan 2019.

Edited by:

Antonello Lorenzini, University of Bologna, Italy

Reviewed by:

James Harper, Sam Houston State University, United States
Chad A. Lerner, Buck Institute for Research on Aging, United States  

Copyright: © 2019 Bugliani, Mossuto, Grano, Suleiman, Marselli, Boggi, Marchetti and De Tata. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Vincenzo De Tata, University of Pisa, Pisa, Italy,