title: Glucagon-Like Peptide 1 Protects Pancreatic β-Cells From Death by Increasing Autophagic Flux and Restoring Lysosomal Function.
abstract: Studies in animal models of type 2 diabetes have shown that glucagon-like peptide 1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown. In this study, we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5 mmol/L palmitate and 25 mmol/L glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilization and release of cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Cotreatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. Small interfering RNA knockdown showed the restoration of autophagic flux is also essential for the protective effects of exendin-4. Collectively, our data highlight lysosomal dysfunction as a critical mediator of β-cell loss and shows that exendin-4 improves cell survival via restoration of lysosomal function and autophagic flux. Modulation of autophagy/lysosomal homeostasis may thus define a novel therapeutic strategy for type 2 diabetes, with the GLP-1 signaling pathway as a potential focus.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, U.K.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Zummo
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, U.K.
authors.forename: Kirsty S
authors.initials: KS
authors.lastname: Cullen
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, U.K.
authors.forename: Minna
authors.initials: M
authors.lastname: Honkanen-Scott
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, U.K.
authors.forename: James A M
authors.initials: JAM
authors.lastname: Shaw
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, U.K.
authors.forename: Penny E
authors.initials: PE
authors.lastname: Lovat
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, U.K. catherine.arden@ncl.ac.uk.
authors.forename: Catherine
authors.initials: C
authors.lastname: Arden
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D016022:Case-Control Studies; D002402:Cathepsin D / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D054795:Incretins / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010168:Palmitates / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D034741:RNA, Small Interfering; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014688:Venoms / Q000494:pharmacology
chemical_list: D002402:Cathepsin D; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D054795:Incretins; D008869:Microtubule-Associated Proteins; D010168:Palmitates; D010455:Peptides; D034741:RNA, Small Interfering; D014688:Venoms; C526109:Anxa3 protein, rat; C477012:MAP1LC3A protein, human; C480860:Map1lc3b protein, mouse