scholarly journals Human Islet Amyloid Polypeptide Overexpression in INS-1E Cells Influences Amylin Oligomerization under ER Stress and Oxidative Stress

2021 ◽  
Vol 22 (21) ◽  
pp. 11341
Author(s):  
Yeong-Min Yoo ◽  
Seong Soo Joo
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Islet Amyloid Polypeptide ◽  
Stress Conditions ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Study Results ◽  
Human Amylin ◽  
And Oxidative Stress

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.

scholarly journals Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues

2019 ◽  
Vol 8 (9) ◽  
pp. 1385 ◽  
Author(s):  
Burgos-Morón ◽  
Abad-Jiménez ◽  
Marañón ◽  
Iannantuoni ◽  
Escribano-López ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Current Knowledge ◽  
Β Cells ◽  
The Relationship ◽  
And Oxidative Stress

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAMs) means that the ROS generated in mitochondria promote ER stress. Therefore, a state of stress and mitochondrial dysfunction are consequences of this vicious cycle. The implication of mitochondria in insulin release and the exposure of pancreatic β-cells to hyperglycemia make them especially susceptible to oxidative stress and mitochondrial dysfunction. In fact, crosstalk between both mechanisms is related with alterations in glucose homeostasis and can lead to the diabetes-associated insulin-resistance status. In the present review, we discuss the current knowledge of the relationship between oxidative stress, mitochondria, ER stress, inflammation, and lipotoxicity in T2D.

scholarly journals Graphene quantum dots rescue protein dysregulation of pancreatic β-cells exposed to human islet amyloid polypeptide

Nano Research ◽  
2019 ◽  
Vol 12 (11) ◽  
pp. 2827-2834 ◽  
Author(s):  
Ava Faridi ◽  
Yunxiang Sun ◽  
Monika Mortimer ◽  
Ritchlynn R. Aranha ◽  
Aparna Nandakumar ◽  
...  
Keyword(s):  
Quantum Dots ◽  
Islet Amyloid Polypeptide ◽  
Graphene Quantum Dots ◽  
Human Islet ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Biologically active human islet amyloid polypeptide/amylin in transgenic mice

1997 ◽  
Vol 136 (1) ◽  
pp. 107-113 ◽  
Author(s):  
Karen L van Hulst ◽  
Walter Born ◽  
Roman Muff ◽  
Cor Oosterwijk ◽  
Marinus A Blankenstein ◽  
...  
Keyword(s):  
Biological Activity ◽  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Cell Protein ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Human And Mouse

Abstract Objective: Human islet amyloid polypeptide (hIAPP), also named amylin, is a pancreatic β cell protein implicated in the pathogenesis of pancreatic islet amyloid formation and type 2 diabetes mellitus. To study the (patho)physiological roles of hIAPP, we have generated transgenic mice that overexpress hIAPP mRNA, in relation to endogenous mouse IAPP (mIAPP) mRNA, in pancreatic β cells. The biological activity of human and mouse IAPP derived from pancreatic extracts was determined. Methods: Pancreatic and plasma extracts of transgenic and control mice were analyzed by reversedphase high-performance liquid chromatography (HPLC) and radioimmunoassay, yielding a separation of hIAPP from mIAPP. Biological activity of immunoreactive human and mouse IAPP components derived from pancreatic extracts was assessed by calcitonin receptor-mediated stimulation of cyclic AMP accumulation in T47D human breast carcinoma cells. Results: The predominant immunoreactive human and mouse IAPP gene products had the retention times on HPLC analysis of the corresponding synthetic peptides. The ratio of bioactive over immunoreactive hIAPP and mIAPP was 0·93 ±0·18 and 1·19 ±0·56 respectively. In extracts of two plasma pools from 4 transgenic animals, hIAPP was 4·6- to 7-fold more abundant than mIAPP. Conclusion; This study has shown that correctly processed hIAPP produced in transgenic mouse pancreatic β cells exhibits full biological activity. The results validate these transgenic mice for the study of (patho)physiological roles of hIAPP in vivo. European Journal of Endocrinology 136 107–113

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

2010 ◽  
Vol 28 (5) ◽  
pp. 387-393 ◽  
Author(s):  
Ryu Tominaga ◽  
Suguru Yamaguchi ◽  
Chihiro Satake ◽  
Masahiro Usui ◽  
Yasuhiro Tanji ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Conditions ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Jnk Pathway

The sensitivity of pancreatic β-cells to mitochondrial injuries triggered by lipotoxicity and oxidative stress

2008 ◽  
Vol 36 (5) ◽  
pp. 930-934 ◽  
Author(s):  
Ning Li ◽  
Francesca Frigerio ◽  
Pierre Maechler
Keyword(s):  
Oxidative Stress ◽  
Current Knowledge ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Primary Target ◽  
Glucose Homoeostasis ◽  
Insulin Secreting Cells ◽  
And Oxidative Stress

Pancreatic β-cells are essential for the maintenance of glucose homoeostasis, and dysfunction of these insulin-secreting cells results in the development of diabetes. In the course of events leading from obesity to Type 2 diabetes, several mechanisms are currently envisaged. Among them, lipids and oxidative stress are considered as toxic candidates for the β-cell. The cellular link between fatty acids and ROS (reactive oxygen species) is essentially the mitochondrion, a key organelle for the control of insulin secretion. Mitochondria are the main source of ROS and are also the primary target of oxidative attacks. The present review presents the current knowledge of lipotoxicity related to oxidative stress in the context of mitochondrial function in the β-cell.

Azadirachtin inhibits amyloid formation, disaggregates pre-formed fibrils and protects pancreatic β-cells from human islet amyloid polypeptide/amylin-induced cytotoxicity

2019 ◽  
Vol 476 (5) ◽  
pp. 889-907 ◽  
Author(s):  
Richa Dubey ◽  
Ketaki Patil ◽  
Sarath C. Dantu ◽  
Devika M. Sardesai ◽  
Parnika Bhatia ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Dynamics Simulation ◽  
Major Constituent ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Abstract The human islet amyloid polypeptide (hIAPP) or amylin is the major constituent of amyloidogenic aggregates found in pancreatic islets of type 2 diabetic patients that have been associated with β-cell dysfunction and/or death associated with type 2 diabetes mellitus (T2DM). Therefore, developing and/or identifying inhibitors of hIAPP aggregation pathway and/or compound that can mediate disaggregation of preformed aggregates holds promise as a medical intervention for T2DM management. In the current study, the anti-amyloidogenic potential of Azadirachtin (AZD)—a secondary metabolite isolated from traditional medicinal plant Neem (Azadirachta indica)—was investigated by using a combination of biophysical and cellular assays. Our results indicate that AZD supplementation not only inhibits hIAPP aggregation but also disaggregates pre-existing hIAPP fibrils by forming amorphous aggregates that are non-toxic to pancreatic β-cells. Furthermore, AZD supplementation in pancreatic β-cells (INS-1E) resulted in inhibition of oxidative stress; along with restoration of the DNA damage, lipid peroxidation and the associated membrane damage, endoplasmic reticulum stress and mitochondrial membrane potential. AZD treatment also restored glucose-stimulated insulin secretion from pancreatic islets exposed to hIAPP. All-atom molecular dynamics simulation studies on full-length hIAPP pentamer with AZD suggested that AZD interacted with four possible binding sites in the amyloidogenic region of hIAPP. In summary, our results suggest AZD to be a promising candidate for combating T2DM and related amyloidogenic disorders.

Expression of human islet amyloid polypeptide/amylin impairs insulin secretion in mouse pancreatic β cells

Metabolism ◽  
1997 ◽  
Vol 46 (9) ◽  
pp. 1044-1051 ◽  
Author(s):  
Tatsuhiko Tokuyama ◽  
Kazuo Yagui ◽  
Takahide Yamaguchi ◽  
Choung I. Huang ◽  
Nobuhiko Kuramoto ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

scholarly journals FoxA2 and RNA Pol II Mediate Human Islet Amyloid Polypeptide Turnover in ER-stressed Pancreatic β-cells

2021 ◽  
Author(s):  
Diti Chatterjee Bhowmick ◽  
Lydia Burnett ◽  
Zhanar Kudaibergenova ◽  
Aleksandar Jeremic
Keyword(s):  
Er Stress ◽  
High Glucose ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Nucleolar Organization ◽  
Insulinoma Cells ◽  
Rat Insulinoma

Here, we investigated transcriptional and trafficking mechanisms of human islet amyloid polypeptide (hIAPP) in normal and stressed β-cells. In high glucose-challenged human islets and rat insulinoma cells overexpressing hIAPP, cell fractionation studies revealed increased accumulation of hIAPP. Unexpectedly, a significant fraction (up to 22%) of hIAPP was found in the nuclear soluble and chromatin-enriched fractions of cultured human islet and rat insulinoma cells. The nucleolar accumulation of monomeric forms of hIAPP did not have any adverse effect on the proliferation of β-cells nor did it affect nucleolar organization or function. However, intact nucleolar organization and function were essential for hIAPP expression under normal and ER-stress conditions as RNA polymerase II inhibitor, α-amanitin, reduced hIAPP protein expression evoked by high glucose and thapsigargin. Promoter activity studies revealed the essential role of transcription factor FoxA2 in hIAPP promoter activation in ER-stressed β-cells. Transcriptome and secretory studies demonstrate that the biosynthetic and secretory capacity of islet β-cells was preserved during ER stress. Thus, the main reason for increased intracellular hIAPP accumulation is its enhanced biosynthesis under these adverse conditions.

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