A Self-defeating Anabolic Program Leads to β-Cell Apoptosis in Endoplasmic Reticulum Stress-induced Diabetes via Regulation of Amino Acid Flux

Abstract

Background: Protein synthesis control is important for ␤-cell fate during ER stress. Results: Increased protein synthesis during chronic ER stress in ␤-cells involves the transcriptional induction of an amino acid transporter network. Conclusion: Increased amino acid uptake in ␤-cells during ER stress promotes apoptosis. Significance: Induced expression of a network of amino acid transporters in islets can contribute to chronic ER stress-induced diabetes.

Coordinated Regulation of the Neutral Amino Acid Transporter SNAT2 and the Protein Phosphatase Subunit GADD34 Promotes Adaptation to Increased Extracellular Osmolarity

“…Induction of this transporter is a crucial part of the TonEBP transcription program and mediates a volume increase in response to mild hyperosmotic stress (3). The induction of GADD34 has been associated with both prosurvival and proapoptotic outcomes in response to diverse stress conditions (27,41,42). Several lines of evidence support prosurvival functions of GADD34 during hyperosmotic stress, especially under mild stress condi-FIGURE 8.…”

“…Transport assays were performed in Earle's balanced salt solution containing Pro (100 M, 4 Ci/ml) at 37°C for 2 min (27). For assays in Na ϩ -free medium, the NaCl in Earle's balanced salt solution was replaced with choline chloride.…”

“…The salubrinal derivative Sal003 (Sal) was from Tocris, and MG132 was from Enzo Life Sciences. Thapsigargin (Tg, Sigma-Aldrich) was used at 400 nM as described previously (27), and actinomycin D was from Sigma-Aldrich.…”

Translational Control during Endoplasmic Reticulum Stress beyond Phosphorylation of the Translation Initiation Factor eIF2α

“…We have recently shown that the cellular response to endoplasmic reticulum (ER) stress involves mechanisms similar to nutritional stress caused by amino acid starvation (26). Although ER stress is the result of the accumulation of unfolded/misfolded proteins in the ER and amino acid starvation induces the accumulation of some deacylated tRNAs, both stresses activate specific kinases that phosphorylate eIF2␣, inhibit protein synthesis, and initiate the ISR program (27).…”

Endoplasmic reticulum stress and renal lesion in mice with combination of high-fat diet and streptozotocin-induced diabetes

“…Because pancreatic β-cells possess a highly-developed ER system, these cells are sensitive to the alteration of ER during the process of T2DM. Accumulating evidence has revealed that ER stress contributed to insulin resistance, aggravated β-cell burden, and reduced β-cell mass, resulting in T2DM 9 . Though two recent studies have proved that ER stress is activated in the kidney of diabetic rats 10,11 , whether ER stress influences renal tissue in Kunming (KM) mice treated with high-fat diet and streptozotocin (STZ) is poorly understood.…”