Glycated albumin causes pancreatic β-cells dysfunction through autophagy dysfunction

Area of Science:

• Cell Biology
• Endocrinology
• Metabolic Disease Research

Background:

• Advanced glycation end-products (AGEs) are implicated in pancreatic beta-cell cytotoxicity.
• Glycated albumin (GA) is an early precursor of AGEs, suggesting a potential role in beta-cell dysfunction.

Purpose of the Study:

• To investigate if glycated albumin (GA) induces pancreatic beta-cell dysfunction and apoptosis.
• To elucidate the cellular mechanisms underlying GA-induced beta-cell apoptosis.

Main Methods:

• INS-1 cells and isolated rat islets were treated with GA under high-glucose conditions.
• Autophagy markers (GFP-LC3, LC3-II/I, SQSTM1/p62) were assessed.
• The nuclear factor-kappaB (NF-κB) pathway, inducible nitric oxide synthase (iNOS), and caspase-3 activation were analyzed.
• Endoplasmic reticulum (ER) stress markers and the effect of 4-phenylbutyric acid were evaluated.

Main Results:

• GA treatment decreased INS-1 cell viability and increased apoptosis.
• GA reduced insulin content and glucose-stimulated insulin secretion in isolated islets.
• GA inhibited autophagy induction and flux, leading to SQSTM1/p62 accumulation.
• Accumulated SQSTM1/p62 activated the NF-κB-iNOS-caspase-3 cascade.
• ER stress was exacerbated, and inhibiting autophagy flux worsened GA-induced cell death.

Conclusions:

• Glycated albumin (GA) induces pancreatic beta-cell death by inhibiting autophagy and activating the NF-κB-iNOS-caspase-3 pathway.
• GA exacerbates endoplasmic reticulum and oxidative stress, contributing to beta-cell apoptosis.
• Targeting autophagy or the NF-κB pathway may offer therapeutic strategies for GA-induced beta-cell damage.