The central role of glutathione peroxidase 4 in the regulation of ferroptosis and its implications for pro-inflammatory cytokine-mediated beta-cell death

Aims: GPR40/FFAR1 mediates palmitate-induced stimulation of insulin secretion but its involvement in lipotoxicity is controversial. Our previous observations suggest that FFAR1/GPR40 agonists protect against lipotoxicity although the underlying mechanism remains elusive. The present study examines the role of ERK1/2 and GPR40/FFAR1 in palmitate-induced stimulation of insulin secretion and beta cell death. Methods: Insulin secretion of INS-1E cells was measured by radioimmunoassay. Protein phosphorylation was examined on Western blots. Apoptosis was assessed by TUNEL staining. Results: Palmitate and the GPR40/FFAR1 agonist TUG-469 increased phosphorylation of ERK1/2 at low (2.8 mmol/L) and high (12 mmol/L) glucose but stimulated insulin secretion only at high glucose. The MEK1 inhibitor PD98059 significantly reduced phosphorylation of ERK1/2 but did not reverse the stimulation of secretion induced by glucose, palmitate or TUG-469. PD98059 rather augmented glucose-induced secretion. Prolonged exposure to palmitate stimulated apoptosis, an effect counteracted by TUG-469. PD98059 accentuated palmitate-induced apoptosis and reversed TUG-469-mediated inhibition of cell death. Conclusions: Activation of ERK1/2 by palmitate and GPR40/FFAR1 agonist correlates neither with stimulation of insulin secretion nor with induction of apoptosis. The results suggest a significant anti-apoptotic role of ERK1/2 under conditions of lipotoxicity.

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Role of Pancreatic β-Cell Death and Cell Death-Associated Inflammation in Diabetes

Current Molecular Medicine ◽

10.2174/156652412803833553 ◽

2012 ◽

Vol 12 (10) ◽

pp. 1297-1310 ◽

Cited By ~ 9

Author(s):

M.-S. Lee ◽

K.-A. Kim ◽

H.S. Kim

Keyword(s):

Cell Death ◽

Beta Cell ◽

Pancreatic Beta Cell ◽

Beta Cell Death

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The Protective Role of Calbindin-D9k on Endoplasmic Reticulum Stress-Induced Beta Cell Death

International Journal of Molecular Sciences ◽

10.3390/ijms20215317 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5317

Author(s):

Changhwan Ahn ◽

Eui-Man Jung ◽

Beum-Soo An ◽

Eui-Ju Hong ◽

Yeong-Min Yoo ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Beta Cell ◽

Er Stress ◽

Cell Survival ◽

Pancreatic Beta Cell ◽

Beta Cell Death ◽

Calbindin D9k ◽

Islet Volume

Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. In this study, we aimed to investigate the effect of CaBP-9k on cell survival in pancreatic beta cells. Six-month-old wildtype CaBP-9k, CaBP-28k, and CaBP-9k/28k knockout (KO) mice were used to compare the pathological phenotypes of calcium-binding protein-deleted mice. Subsequently, the endoplasmic reticulum (ER) stress reducer tauroursodeoxycholic acid (TUDCA) was administered to wildtype and CaBP-9k KO mice. In vitro assessment of the role of CaBP-9k was performed following CaBP-9k overexpression and treatment with the ER stress inducer thapsigargin. Six-month-old CaBP-9k KO mice showed reduced islet volume and up-regulation of cell death markers resulting from ER stress, which led to pancreatic beta cell death. TUDCA treatment recovered islet volume, serum insulin level, and abdominal fat storage by CaBP-9k ablation. CaBP-9k overexpression elevated insulin secretion and recovered thapsigargin-induced ER stress in the INS-1E cell line. The results of this study show that CaBP-9k can protect pancreatic beta cell survival from ER stress and contribute to glucose homeostasis, which can reduce the risk of type 1 diabetes and provide the molecular basis for calcium supplementation to diabetic patients.

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