The JNK pathway modulates expression and phosphorylation of 4E-BP1 in MIN6 pancreatic β-cells under oxidative stress conditions

Human amylin or islet amyloid polypeptide (hIAPP) is synthesized in the pancreatic β-cells and has been shown to contribute to the pathogenesis of type 2 diabetes (T2D) in vitro and in vivo. This study compared amylin oligomerization/expression and signal transduction under endoplasmic reticulum (ER) stress and oxidative stress. pCMV-hIAPP-overexpressing INS-1E cells presented different patterns of amylin oligomerization/expression under ER stress and oxidative stress. Amylin oligomerization/expression under ER stress showed three amylin oligomers of less than 15 kDa size in pCMV-hIAPP-overexpressing cells, while one band was detected under oxidative stress. Under ER stress conditions, HIF1α, p-ERK, CHOP, Cu/Zn-SOD, and Bax were significantly increased in pCMV-hIAPP-overexpressing cells compared to the pCMV-Entry-expressing cells (control), whereas p-Akt, p-mTOR, Mn-SOD, catalase, and Bcl-2 were significantly decreased. Under oxidative stress conditions, HIF1α, p-ERK, CHOP, Mn-SOD, catalase, and Bcl-2 were significantly reduced in pCMV-hIAPP-overexpressing cells compared to the control, whereas p-mTOR, Cu/Zn-SOD, and Bax were significantly increased. In mitochondrial oxidative phosphorylation (OXPHOS), the mitochondrial complex I and complex IV were significantly decreased under ER stress conditions and significantly increased under oxidative stress conditions in pCMV-hIAPP-overexpressing cells compared to the control. The present study results demonstrate that amylin undergoes oligomerization under ER stress in pCMV-hIAPP-overexpressing cells. In addition, human amylin overexpression under ER stress in the pancreatic β cells may enhance amylin protein aggregation, resulting in β-cell dysfunction.

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Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

International Journal of Molecular Sciences ◽

10.3390/ijms22031059 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1059

Author(s):

Bodo C. Melnik

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Dopaminergic Neurons ◽

Vagal Nerve ◽

Β Cells ◽

Pancreatic Β Cells ◽

The Brain

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

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Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic β-Cells

Cellular Physiology and Biochemistry ◽

10.1159/000495200 ◽

2018 ◽

Vol 51 (1) ◽

pp. 201-216 ◽

Cited By ~ 8

Author(s):

Arwa M.T. Al-Nahdi ◽

Annie John ◽

Haider Raza

Keyword(s):

Oxidative Stress ◽

Insulin Secretion ◽

Molecular Mechanisms ◽

Protective Action ◽

Mitochondrial Enzymes ◽

Partial Recovery ◽

Β Cells ◽

Pancreatic Β Cells ◽

Mitochondrial Energy Metabolism ◽

Mitochondrial Functions

Background/Aims: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic β-cells. Methods: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH-dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques. Results: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells. Conclusion: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic β-cells against STZ-induced cytotoxicity.

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Free fatty acids stimulate autophagy in pancreatic β-cells via JNK pathway

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2010.09.101 ◽

2010 ◽

Vol 401 (4) ◽

pp. 561-567 ◽

Cited By ~ 71

Author(s):

Koji Komiya ◽

Toyoyoshi Uchida ◽

Takashi Ueno ◽

Masato Koike ◽

Hiroko Abe ◽

...

Keyword(s):

Fatty Acids ◽

Free Fatty Acids ◽

Β Cells ◽

Pancreatic Β Cells ◽

Jnk Pathway

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HIV‐1 protease inhibitors suppress insulin secretion in pancreatic β cells : role of oxidative stress and endoplasmic reticulum stress and protection by thymoquinone (TQ)

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.1131.2 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Surabhi Chandra ◽

Debasis Mondal ◽

Krishna C Agrawal

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Insulin Secretion ◽

Endoplasmic Reticulum Stress ◽

Protease Inhibitors ◽

Β Cells ◽

Pancreatic Β Cells ◽

Hiv 1

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Unraveling the molecular machinery that promotes pancreatic β-cell dysfunction during oxidative stress: focus on “Phagocyte-like NADPH oxidase promotes cytokine-induced mitochondrial dysfunction in pancreatic β-cells: evidence for regulation by Rac1”

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00722.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. R9-R11 ◽

Cited By ~ 4

Author(s):

Martin Jastroch

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Mitochondrial Dysfunction ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Cell Dysfunction ◽

Molecular Machinery

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Bridges between mitochondrial oxidative stress, ER stress and mTOR signaling in pancreatic β cells

Cellular Signalling ◽

10.1016/j.cellsig.2016.05.007 ◽

2016 ◽

Vol 28 (8) ◽

pp. 1099-1104 ◽

Cited By ~ 65

Author(s):

Jing Wang ◽

Xin Yang ◽

Jingjing Zhang

Keyword(s):

Oxidative Stress ◽

Er Stress ◽

Mtor Signaling ◽

Β Cells ◽

Pancreatic Β Cells ◽

Mitochondrial Oxidative Stress

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Bach1 deficiency protects pancreatic β-cells from oxidative stress injury

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00120.2013 ◽

2013 ◽

Vol 305 (5) ◽

pp. E641-E648 ◽

Cited By ~ 20

Author(s):

Keiichi Kondo ◽

Yasushi Ishigaki ◽

Junhong Gao ◽

Tetsuya Yamada ◽

Junta Imai ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Pancreatic Islets ◽

Antioxidative Enzymes ◽

Heme Oxygenase 1 ◽

Β Cells ◽

Pancreatic Β Cells ◽

Stress Injury ◽

Induced Apoptosis ◽

Deficient Mice

BTB and CNC homology 1 (Bach1) is a transcriptional repressor of antioxidative enzymes, such as heme oxygenase-1 (HO-1). Oxidative stress is reportedly involved in insulin secretion impairment and obesity-associated insulin resistance. However, the role of Bach1 in the development of diabetes is unclear. HO-1 expression in the liver, white adipose tissue, and pancreatic islets was markedly upregulated in Bach1-deficient mice. Unexpectedly, glucose and insulin tolerance tests showed no differences in obese wild-type (WT) and obese Bach1-deficient mice after high-fat diet loading for 6 wk, suggesting minimal roles of Bach1 in the development of insulin resistance. In contrast, Bach1 deficiency significantly suppressed alloxan-induced pancreatic insulin content reduction and the resultant glucose elevation. Furthermore, TUNEL-positive cells in pancreatic islets of Bach1-deficient mice were markedly decreased, by 60%, compared with those in WT mice. HO-1 expression in islets was significantly upregulated in alloxan-injected Bach1-deficient mice, whereas expression of other antioxidative enzymes, e.g., catalase, superoxide dismutase, and glutathione peroxidase, was not changed by either alloxan administration or Bach1 deficiency. Our results suggest that Bach1 deficiency protects pancreatic β-cells from oxidative stress-induced apoptosis and that the enhancement of HO-1 expression plays an important role in this protection.

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Reducing sugars trigger oxidative modification and apoptosis in pancreatic β-cells by provoking oxidative stress through the glycation reaction

Biochemical Journal ◽

10.1042/bj3200855 ◽

1996 ◽

Vol 320 (3) ◽

pp. 855-863 ◽

Cited By ~ 162

Author(s):

Hideaki KANETO ◽

Junichi FUJII ◽

Theingi MYINT ◽

Nobuko MIYAZAWA ◽

Kazi N. ISLAM ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Cleavage ◽

Reducing Sugars ◽

Islet Cells ◽

Chromatin Condensation ◽

Oxidative Modification ◽

Lipid Peroxidation Product ◽

Β Cells ◽

Pancreatic Β Cells ◽

Peroxidation Product

Several reducing sugars brought about apoptosis in isolated rat pancreatic islet cells and in the pancreatic β-cell-derived cell line HIT. This apoptosis was characterized biochemically by internucleosomal DNA cleavage and morphologically by nuclear shrinkage, chromatin condensation and apoptotic body formation. N-Acetyl-l-cysteine, an antioxidant, and aminoguanidine, an inhibitor of the glycation reaction, inhibited this apoptosis. We also showed directly that proteins in β-cells were actually glycated by using an antibody which can specifically recognize proteins glycated by fructose, but not by glucose. Furthermore, fluorescence-activated cell sorting analysis using dichlorofluorescein diacetate showed that reducing sugars increased intracellular peroxide levels prior to the induction of apoptosis. Levels of carbonyl, an index of oxidative modification, and of malondialdehyde, a lipid peroxidation product, were also increased. Taken together, these results suggest that reducing sugars trigger oxidative modification and apoptosis in pancreatic β-cells by provoking oxidative stress mainly through the glycation reaction, which may explain the deterioration of β-cells under conditions of diabetes.

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