Glucagon-Like Peptide 1 Protects Pancreatic β-Cells From Death by Increasing Autophagic Flux and Restoring Lysosomal Function
| Autor: | Penny E. Lovat, Kirsty S. Cullen, Catherine Arden, James Shaw, Minna Honkanen-Scott, Francesco P Zummo |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
0301 basic medicine Programmed cell death Small interfering RNA Cell Survival Endocrinology Diabetes and Metabolism Blotting Western Palmitates Cathepsin D Apoptosis 030209 endocrinology & metabolism Biology Real-Time Polymerase Chain Reaction Incretins Cell Line Islets of Langerhans Mice 03 medical and health sciences 0302 clinical medicine Glucagon-Like Peptide 1 Insulin-Secreting Cells Autophagy Internal Medicine Animals Humans RNA Small Interfering Reverse Transcriptase Polymerase Chain Reaction Venoms Middle Aged Immunohistochemistry Rats Cell biology Glucose Editorial 030104 developmental biology Diabetes Mellitus Type 2 Case-Control Studies Exenatide Signal transduction Lysosomes Peptides Microtubule-Associated Proteins Flux (metabolism) Homeostasis |
| Zdroj: | Diabetes. 66:1272-1285 |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db16-1009 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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