Author Correction: Molecular mechanisms involved in the non-monotonic effect of bisphenol-a on Ca2+ entry in mouse pancreatic β-cells

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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Selenoprotein P as a significant regulator of pancreatic β cell function

The Journal of Biochemistry ◽

10.1093/jb/mvz061 ◽

2019 ◽

Cited By ~ 1

Author(s):

Yoshiro Saito

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Molecular Mechanisms ◽

Cell Function ◽

Insulin Signalling ◽

Selenoprotein P ◽

Β Cells ◽

Pancreatic Β Cells ◽

Β Cell Function

Abstract Selenoprotein P (SeP; encoded by SELENOP) is selenium (Se)-rich plasma protein that is mainly produced in the liver. SeP functions as a Se-transport protein to deliver Se from the liver to other tissues, such as the brain and testis. The protein plays a pivotal role in Se metabolism and antioxidative defense, and it has been identified as a ‘hepatokine’ that causes insulin resistance in type 2 diabetes. SeP levels are increased in type 2 diabetes patients, and excess SeP impairs insulin signalling, promoting insulin resistance. Furthermore, increased levels of SeP disturb the functioning of pancreatic β cells and inhibit insulin secretion. This review focuses on the biological function of SeP and the molecular mechanisms associated with the adverse effects of excess SeP on pancreatic β cells’ function, particularly with respect to redox reactions. Interactions between the liver and pancreas are also discussed.

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Evidence for Rapamycin Toxicity in Pancreatic β-Cells and a Review of the Underlying Molecular Mechanisms

Diabetes ◽

10.2337/db13-0106 ◽

2013 ◽

Vol 62 (8) ◽

pp. 2674-2682 ◽

Cited By ~ 113

Author(s):

Adam D. Barlow ◽

Michael L. Nicholson ◽

Terry P. Herbert

Keyword(s):

Molecular Mechanisms ◽

Β Cells ◽

Pancreatic Β Cells

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Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22084285 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4285

Author(s):

Jan Šrámek ◽

Vlasta Němcová-Fürstová ◽

Jan Kovář

Keyword(s):

Fatty Acids ◽

Er Stress ◽

Membrane Fluidity ◽

Molecular Mechanisms ◽

Mitochondrial Pathway ◽

Signalling Pathways ◽

Apoptosis Induction ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.

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Regulatory effects of N-3 PUFAs on pancreatic β-cells and insulin-sensitive tissues

Current Drug Metabolism ◽

10.2174/1389200222666211126104002 ◽

2021 ◽

Vol 22 ◽

Author(s):

Wen Liu ◽

Qing Zheng ◽

Min Zhu ◽

Xiaohong Liu ◽

Jingping Liu ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Secretion ◽

Metabolic Disorders ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Β Cells ◽

Pancreatic Β Cells ◽

Nonalcoholic Fatty Liver ◽

Wide Range ◽

Regulatory Effects

: The N-3 polyunsaturated fatty acids (PUFAs) have a wide range of health benefits, including anti-inflammatory effects, improvements in lipids metabolism and promoting insulin secretion, as well as reduction of cancer risk. Numerous studies support that N-3 PUFAs have the potentials to improve many metabolic diseases, such as diabetes, nonalcoholic fatty liver disease and obesity, which are attributable to N-3 PUFAs mediated enhancement of insulin secretion by pancreatic β-cells and improvements in insulin sensitivity and metabolic disorders in peripheral insulin-sensitive tissues such as liver, muscles, and adipose tissue. In this review, we summarized the up-to-date clinical and basic studies on the regulatory effects and molecular mechanisms of N-3 PUFAs mediated benefits on pancreatic β-cells, adipose tissue, liver, and muscles in the context of glucose and/or lipid metabolic disorders. We also discussed the potential factors involved in the inconsistent results from different clinical researches of N-3 PUFAs.

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Sfrp5 mediates glucose-induced proliferation in rat pancreatic β-cells

Journal of Endocrinology ◽

10.1530/joe-15-0535 ◽

2016 ◽

Vol 229 (2) ◽

pp. 73-83 ◽

Cited By ~ 5

Author(s):

Binbin Guan ◽

Wenyi Li ◽

Fengying Li ◽

Yun Xie ◽

Qicheng Ni ◽

...

Keyword(s):

Cell Proliferation ◽

Wnt Signaling ◽

Molecular Mechanisms ◽

Wnt Signaling Pathway ◽

Akt Pathway ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Promote Cell Proliferation

The cellular and molecular mechanisms of glucose-stimulated β-cell proliferation are poorly understood. Recently, secreted frizzled-related protein 5 (encoded by Sfrp5; a Wnt signaling inhibitor) has been demonstrated to be involved in β-cell proliferation in obesity. A previous study demonstrated that glucose enhanced Wnt signaling to promote cell proliferation. We hypothesized that inhibition of SFRP5 contributes to glucose-stimulated β-cell proliferation. In this study, we found that the Sfrp5 level was significantly reduced in high glucose-treated INS-1 cells, primary rat β-cells, and islets isolated from glucose-infused rats. Overexpression of SFRP5 diminished glucose-stimulated proliferation in both INS-1 cells and primary β-cells, with a concomitant inhibition of the Wnt signaling pathway and decreased cyclin D2 expression. In addition, we showed that glucose-induced Sfrp5 suppression was modulated by the PI3K/AKT pathway. Therefore, we conclude that glucose inhibits Sfrp5 expression via the PI3K/AKT pathway and hence promotes rat pancreatic β-cell proliferation.

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Signal integration at the level of ion channel and exocytotic function in pancreatic β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00426.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. E1065-E1069 ◽

Cited By ~ 23

Author(s):

Patrick E. MacDonald

Keyword(s):

Insulin Secretion ◽

Molecular Mechanisms ◽

Whole Body ◽

Signal Integration ◽

Β Cells ◽

Pancreatic Β Cells ◽

Precise Control ◽

The Past ◽

Associated Proteins ◽

Body Energy

Whole body energy balance is ensured by the exquisite control of insulin secretion, the dysregulation of which has serious consequences. Although a great deal has been learned about the control of insulin secretion from pancreatic β-cells in the past 30 years, there remains much to be understood about the molecular mechanisms and interactions that underlie the precise control of this process. Numerous molecular interactions at the plasma membrane mediate the excitatory and amplifying events involved in insulin secretion; this includes interactions between ion channels, signal transduction machinery, and exocytotic proteins. The present Perspectives article considers evidence that key membrane and membrane-associated proteins essential to insulin secretion are regulated in concert as a functional unit, ensuring an integrated excitatory and exocytotic response to the signals that control insulin secretion.

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FMK, an Inhibitor of p90RSK, Inhibits High Glucose-Induced TXNIP Expression via Regulation of ChREBP in Pancreatic β Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20184424 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4424

Author(s):

Jung-Hwa Han ◽

Suji Kim ◽

Heejung Lee ◽

So-Young Park ◽

...

Keyword(s):

High Glucose ◽

Molecular Mechanisms ◽

Cell Function ◽

Nuclear Translocation ◽

Ros Generation ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Interacting Protein ◽

Cell Dysfunction

Hyperglycemia is the major characteristic of diabetes mellitus, and a chronically high glucose (HG) level causes β-cell glucolipotoxicity, which is characterized by lipid accumulation, impaired β-cell function, and apoptosis. TXNIP (Thioredoxin-interacting protein) is a key mediator of diabetic β-cell apoptosis and dysfunction in diabetes, and thus, its regulation represents a therapeutic target. Recent studies have reported that p90RSK is implicated in the pathogenesis of diabetic cardiomyopathy and nephropathy. In this study, we used FMK (a p90RSK inhibitor) to determine whether inhibition of p90RSK protects β-cells from chronic HG-induced TXNIP expression and to investigate the molecular mechanisms underlying the effect of FMK on its expression. In INS-1 pancreatic β-cells, HG-induced β-cell dysfunction, apoptosis, and ROS generation were significantly diminished by FMK. In contrast BI-D1870 (another p90RSK inhibitor) did not attenuate HG-induced TXNIP promoter activity or TXNIP expression. In addition, HG-induced nuclear translocation of ChREBP and its transcriptional target molecules were found to be regulated by FMK. These results demonstrate that HG-induced pancreatic β-cell dysfunction resulting in HG conditions is associated with TXNIP expression, and that FMK is responsible for HG-stimulated TXNIP gene expression by inactivating the regulation of ChREBP in pancreatic β-cells. Taken together, these findings suggest FMK may protect against HG-induced β-cell dysfunction and TXNIP expression by ChREBP regulation in pancreatic β-cells, and that FMK is a potential therapeutic reagent for the drug development of diabetes and its complications.

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Extracellular Vesicles in Immune System Regulation and Type 1 Diabetes: Cell-to-Cell Communication Mediators, Disease Biomarkers, and Promising Therapeutic Tools

Frontiers in Immunology ◽

10.3389/fimmu.2021.682948 ◽

2021 ◽

Vol 12 ◽

Author(s):

Giuseppina Emanuela Grieco ◽

Daniela Fignani ◽

Caterina Formichi ◽

Laura Nigi ◽

Giada Licata ◽

...

Keyword(s):

Type 1 Diabetes ◽

Immune System ◽

Autoimmune Diseases ◽

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Biological Fluids ◽

Β Cells ◽

Pancreatic Β Cells ◽

Disease Biomarkers

Extracellular vesicles (EVs) are generated by cells of origin through complex molecular mechanisms and released into extracellular environment. Hence, the presence of EVs has been described in multiple biological fluids and in most cases their molecular cargo, which includes non-coding RNAs (ncRNA), messenger RNAs (mRNA), and proteins, has been reported to modulate distinct biological processes. EVs release and their molecular cargo have been demonstrated to be altered in multiple diseases, including autoimmune diseases. Notably, numerous evidence showed a relevant crosstalk between immune system and interacting cells through specific EVs release. The crosstalk between insulin-producing pancreatic β cells and immune system through EVs bidirectional trafficking has yet started to be deciphered, thus uncovering an intricate communication network underlying type 1 diabetes (T1D) pathogenesis. EVs can also be found in blood plasma or serum. Indeed, the assessment of circulating EVs cargo has been shown as a promising advance in the detection of reliable biomarkers of disease progression. Of note, multiple studies showed several specific cargo alterations of EVs collected from plasma/serum of subjects affected by autoimmune diseases, including T1D subjects. In this review, we discuss the recent literature reporting evidence of EVs role in autoimmune diseases, specifically focusing on the bidirectional crosstalk between pancreatic β cells and immune system in T1D and highlight the relevant promising role of circulating EVs as disease biomarkers.

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