» Articles » PMID: 28232493

Glucagon-Like Peptide 1 Protects Pancreatic β-Cells From Death by Increasing Autophagic Flux and Restoring Lysosomal Function

Overview
Journal Diabetes
Specialty Endocrinology
Date 2017 Feb 25
PMID 28232493
Citations 70
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

Autophagy-lysosome pathway in insulin & glucagon homeostasis.

Wu Y, Wang H, Xu H Front Endocrinol (Lausanne). 2025; 16:1541794.

PMID: 39996055 PMC: 11847700. DOI: 10.3389/fendo.2025.1541794.


Effects of different hypoglycaemic drugs on beta-cell function in type 2 diabetes mellitus: a systematic review and network meta-analysis.

Guo Z, Huang L, Jiang Z, Bai X, Wang Z, Huang H Eur J Med Res. 2025; 30(1):121.

PMID: 39985051 PMC: 11843998. DOI: 10.1186/s40001-025-02368-y.


Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity.

Austin M, Muralidharan C, Roy S, Crowder J, Piganelli J, Linnemann A Front Immunol. 2025; 16:1504583.

PMID: 39944686 PMC: 11814175. DOI: 10.3389/fimmu.2025.1504583.


Programmed cell death and melatonin: A comprehensive review.

Rafiyian M, Reiter R, Rasooli Manesh S, Asemi R, Sharifi M, Mohammadi S Funct Integr Genomics. 2024; 24(5):169.

PMID: 39313718 DOI: 10.1007/s10142-024-01454-4.


Puerarin ameliorates high glucose-induced MIN6 cell injury by activating PINK1/Parkin-mediated mitochondrial autophagy.

Zhu H, Yu Y, Li Y, Chang S, Liu Y Heliyon. 2024; 10(16):e36176.

PMID: 39224278 PMC: 11367457. DOI: 10.1016/j.heliyon.2024.e36176.