Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells

Moon, Seoil; Jung, Hye Seung

doi:10.4093/dmj.2022.0070

Cited by 17 publications

(12 citation statements)

References 81 publications

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“…In diabetes-related toxic environments, including those with high glucose and NEFA levels, pancreatic β-cells are particularly exposed to heavy stresses because of their ability to produce and release insulin. Recently, regulation of the autophagy system has been considered to play a key role in overcoming stress [52]. In this context, we showed that DHA protects insulin-secreting cells against PA-induced apoptosis via autophagy activation and that this effect is mediated by GPR120 and specific mTOR phosphorylation on S2448.…”

Section: Discussionmentioning

confidence: 78%

Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells

Hong,

Lee,

Moon

et al. 2024

Endocrinol Metab

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Background: Polyunsaturated fatty acids (PUFAs) reportedly have protective effects on pancreatic β-cells; however, the underlying mechanisms are unknown.Methods: To investigate the cellular mechanism of PUFA-induced cell protection, mouse insulinoma 6 (MIN6) cells were cultured with palmitic acid (PA) and/or docosahexaenoic acid (DHA), and alterations in cellular signaling and apoptosis were examined.Results: DHA treatment remarkably repressed caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL)-positive red dot signals in PA-treated MIN6 cells, with upregulation of autophagy, an increase in microtubule- associated protein 1-light chain 3 (LC3)-II, autophagy-related 5 (Atg5), and decreased p62. Upstream factors involved in autophagy regulation (Beclin-1, unc51 like autophagy activating kinase 1 [ULK1], phosphorylated mammalian target of rapamycin [mTOR], and protein kinase B) were also altered by DHA treatment. DHA specifically induced phosphorylation on S2448 in mTOR; however, phosphorylation on S2481 decreased. The role of G protein-coupled receptor 120 (GPR120) in the effect of DHA was demonstrated using a GPR120 agonist and antagonist. Additional treatment with AH7614, a GPR120 antagonist, significantly attenuated DHA-induced autophagy and protection. Taken together, DHA-induced autophagy activation with protection against PA-induced apoptosis mediated by the GPR120/mTOR axis.Conclusion: These findings indicate that DHA has therapeutic effects on PA-induced pancreatic β-cells, and that the cellular mechanism of β-cell protection by DHA may be a new research target with potential pharmacotherapeutic implications in β-cell protection.

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Section: Discussionmentioning

confidence: 78%

Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells

Hong,

Lee,

Moon

et al. 2024

Endocrinol Metab

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“…demonstrated that knocking down of EIF2AK3 in tissue or cells resulted in develop significant diabetes ( 32 ). In addition, EIF2AK3 has been recognized as an endoplasmic reticulum-related protein involved in β-cell death ( 33 ). These findings suggest that downregulated EIF2AK3 may induce the dysfunction of autophagy and β-cell death, therefore leading to T2DM.…”

Section: Discussionmentioning

confidence: 99%

Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes

Chen

2023

Front. Endocrinol.

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IntroductionAutophagy, an innate safeguard mechanism for protecting the organism against harmful agents, is implicated in the survival of pancreatic â cells and the development of type 2 diabetes mellitus (T2DM). Potential autophagy-related genes (ARGs) may serve as potential biomarkers for T2DM treatment.MethodsThe GSE25724 dataset was downloaded from the Gene Expression Omnibus (GEO) database, and ARGs were obtained from the Human Autophagy Database. The differentially expressed autophagy-related genes (DEARGs) were screened at the intersection of ARGs and differentially expressed genes (DEGs) between T2DM and non-diabetic islet samples, which were subjected to functional enrichment analyses. A protein–protein interaction (PPI) network was constructed to identify hub DEARGs. Expressions of top 10 DEARGs were validated in human pancreatic â-cell line NES2Y and rat pancreatic INS-1 cells using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and insulin secretion were measured after cell transfection with lentiviral vector EIF2AK3 or RB1CC1 into islet cells.ResultsIn total, we discovered 1,270 DEGs (266 upregulated and 1,004 downregulated genes) and 30 DEARGs enriched in autophagy- and mitophagy-related pathways. In addition, we identified GAPDH, ITPR1, EIF2AK3, FOXO3, HSPA5, RB1CC1, LAMP2, GABARAPL2, RAB7A, and WIPI1 genes as the hub ARGs. Next, qRT-PCR analysis revealed that expressions of hub DEARGs were consistent with findings from bioinformatics analysis. EIF2AK3, GABARAPL2, HSPA5, LAMP2, and RB1CC1 were both differentially expressed in the two cell types. Overexpression of EIF2AK3 or RB1CC1 promoted cell viability of islet cells and increased the insulin secretion.DiscussionThis study provides potential biomarkers as therapeutic targets for T2DM.

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“…Autophagy plays an important role in beta-cell homeostasis and survival (1). In fact, it has been extensively studied in the context of type 2 diabetes, beta-cell homeostasis (2), and ER stress response (43).…”

Section: Discussionmentioning

confidence: 99%

Real TimeIn vivoAnalysis of Pancreatic Beta-cell Autophagic Flux Reveals Impairment Before Onset of Autoimmune Diabetes

Melnyk,

Muralidharan,

Duffett

et al. 2023

Preprint

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The catabolic pathway of autophagy is critical for pancreatic beta-cell function and is defective in established type 1 diabetes (T1D). However, it is unclear when and how this critical cell process becomes defective during diabetes pathogenesis. To study the nature of autophagy dysfunction in the context of autoimmune diabetes, we utilized intravital microscopy to study autophagic flux in vivo in real time. We generated a custom AAV8-packaged mCherry-eGFP-LC3B biosensor driven by the insulin promoter for beta-cell-selective expression. For real time autophagic flux evaluation, fluorescent signal from eGFP and mCherry fluorophores was correlated in space and time to follow the process of autophagosome-lysosome fusion. We observed autophagic flux defects in the beta-cells of non-obese diabetic (NOD) mouse model of T1D prior to hyperglycemia onset that were less apparent in mice without a functional immune system. We also evaluated autophagic flux in human donor islets that were transplanted under the kidney capsule of immune incompetent mice. Collectively, we provide the first evaluation of autophagic flux in vivo in 4D and demonstrate that autophagy defects precede hyperglycemia in NOD mice suggesting a potential causative role for these defects in beta-cell demise during T1D pathogenesis.

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Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells

Cited by 17 publications

References 81 publications

Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells

Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells

Identification and analysis of type 2 diabetes-mellitus-associated autophagy-related genes

Real TimeIn vivoAnalysis of Pancreatic Beta-cell Autophagic Flux Reveals Impairment Before Onset of Autoimmune Diabetes

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