The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion

The glucotoxicity caused by long-term exposure of β-cells to high glucose (HG) conditions may lead to the generation of more reactive oxygen species (ROS), reduce the activity of antioxidant enzymes, cause cell damage and apoptosis, and induce insulin secretion dysfunction. Siegesbeckia orientalis linne is a traditional folk herbal medicine used to treat snake bites, rheumatoid arthritis, allergies, and immune deficiencies. In this study, we evaluated the protective effect of S. orientalis ethanol extract (SOE) on cell death and oxidative stress in RIN-m5f pancreatic β-cells stimulated by two HG concentrations (50–100 mM). In the cell viability assay, SOE could significantly increase the survival rate of pancreatic β-cells under HG-induced conditions. For the oxidative stress induced by HG condition, the treatment of SOE effectively reduced the ROS formation, increased the content of intracellular glutathione, and up-regulated the expression of antioxidant enzymes, catalase, superoxide dismutase, and glutathione peroxidase. As a result, the SOE treatment could decrease the glucotoxicity-mediated oxidative damage on RIN-m5F β-cells. Moreover, SOE had the function of regulating insulin secretion in pancreatic β-cells under different HG-mediated conditions. It could decrease the increasing intracellular insulin secretion under the low glucose concentration to normal level; while increase the decreasing intracellular insulin secretion under the relatively high glucose concentration to normal level. Taken together, this study suggests that SOE has a protective effect on pancreatic β-cells under the HG-stimulated glucotoxic environment.

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Diacylglycerol Signaling Pathway in Pancreatic β-Cells: An Essential Role of Diacylglycerol Kinase in the Regulation of Insulin Secretion

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b15-00060 ◽

2015 ◽

Vol 38 (5) ◽

pp. 669-673 ◽

Cited By ~ 12

Author(s):

Yukiko K. Kaneko ◽

Tomohisa Ishikawa

Keyword(s):

Insulin Secretion ◽

Signaling Pathway ◽

Essential Role ◽

Diacylglycerol Kinase ◽

Β Cells ◽

Pancreatic Β Cells

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The Role of the Glucose-Sensing Receptor in Glucose-Induced Insulin Secretion in Pancreatic β-Cells

Glucose-sensing Receptor in Pancreatic Beta-cells ◽

10.1007/978-981-13-0002-8_5 ◽

2018 ◽

pp. 61-71

Author(s):

Yuko Nakagawa ◽

Johan Medina

Keyword(s):

Insulin Secretion ◽

Glucose Sensing ◽

Β Cells ◽

Pancreatic Β Cells

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Regulatory role of adenosine in insulin secretion from pancreatic β-cells—Action via adenosine A1 receptor and beyond

Journal of Physiology and Biochemistry ◽

10.1007/s13105-014-0371-y ◽

2014 ◽

Vol 71 (1) ◽

pp. 133-140 ◽

Cited By ~ 6

Author(s):

Tomasz Szkudelski ◽

Katarzyna Szkudelska

Keyword(s):

Insulin Secretion ◽

Adenosine A1 Receptor ◽

Regulatory Role ◽

Β Cells ◽

Pancreatic Β Cells ◽

Adenosine A1 ◽

A1 Receptor

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CFTR silencing in pancreatic β-cells reveals a functional impact on glucose-stimulated insulin secretion and oxidative stress response

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00333.2015 ◽

2016 ◽

Vol 310 (3) ◽

pp. E200-E212 ◽

Cited By ~ 22

Author(s):

Thierry Ntimbane ◽

Geneviève Mailhot ◽

Schohraya Spahis ◽

Remi Rabasa-Lhoret ◽

Marie-Laure Kleme ◽

...

Keyword(s):

Oxidative Stress ◽

Cystic Fibrosis ◽

Insulin Secretion ◽

Inflammatory Responses ◽

Lipid Peroxides ◽

Β Cells ◽

Pancreatic Β Cells ◽

Min6 Cells ◽

Atp Production

Cystic fibrosis (CF)-related diabetes (CFRD) has become a critical complication that seriously affects the clinical outcomes of CF patients. Although CFRD has emerged as the most common nonpulmonary complication of CF, little is known about its etiopathogenesis. Additionally, whether oxidative stress (OxS), a common feature of CF and diabetes, influences CFRD pathophysiology requires clarification. The main objective of this study was to shed light on the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in combination with OxS in insulin secretion from pancreatic β-cells. CFTR silencing was accomplished in MIN6 cells by stable expression of small hairpin RNAs (shRNA), and glucose-induced insulin secretion was evaluated in the presence and absence of the valuable prooxidant system iron/ascorbate (Fe/Asc; 0.075/0.75 mM) along with or without the antioxidant Trolox (1 mM). Insulin output from CFTR-silenced MIN6 cells was significantly reduced (∼70%) at basal and at different glucose concentrations compared with control Mock cells. Furthermore, CFTR silencing rendered MIN6 cells more sensitive to OxS as evidenced by both increased lipid peroxides and weakened antioxidant defense, especially following incubation with Fe/Asc. The decreased insulin secretion in CFTR-silenced MIN6 cells was associated with high levels of NF-κB (the major participant in inflammatory responses), raised apoptosis, and diminished ATP production in response to the Fe/Asc challenge. However, these defects were alleviated by the addition of Trolox, thereby pointing out the role of OxS in aggravating the effects of CFTR deficiency. Our findings indicate that CFTR deficiency in combination with OxS may contribute to endocrine cell dysfunction and insulin secretion, which at least in part may explain the development of CFRD.

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Nuclear Factor Y in Male Mouse pancreatic β-cells Plays a Crucial Role in Glucose Homeostasis by Regulating β-Cell Mass and Insulin Secretion

10.2337/figshare.14547255 ◽

2021 ◽

Author(s):

Yin Liu ◽

Siyuan He ◽

Ruixue Zhou ◽

Xueping Zhang ◽

Shanshan Yang ◽

...

Keyword(s):

Cell Proliferation ◽

Insulin Secretion ◽

Cell Mass ◽

Physiological Role ◽

Nuclear Factor ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells ◽

Nuclear Factor Y

Pancreatic β-cell mass and insulin secretion are determined by the dynamic change of transcription factor expression levels in response to altered metabolic demand. Nuclear factor-Y (NF-Y) is an evolutionarily conserved transcription factor playing critical roles in multiple cellular processes. However, the physiological role of NF-Y in pancreatic β-cells is poorly understood. The present study was undertaken in a conditional knockout of Nf-ya specifically in pancreatic β-cells (Nf-ya βKO) to define the essential physiological role of NF-Y in β-cells. Nf-ya βKO mice exhibited glucose intolerance without changes in insulin sensitivity. Reduced β-cell proliferation resulting in decreased β-cell mass was observed in these mice, which was associated with disturbed actin cytoskeleton. NF-Y-deficient β-cells also exhibited impaired insulin secretion with a reduced Ca2+ influx in response to glucose, which was associated an inefficient glucose uptake into β-cells due to a decreased expression of glucose transporter 2 and a reduction in ATP production resulting from the disruption of mitochondrial integrity. This study is the first to show that NF-Y is critical for pancreatic islets homeostasis and function through regulation in β-cell proliferation, glucose uptake into β-cells, and mitochondrial energy metabolism. Modulating NF-Y expression in β-cells may therefore offer an attractive approach for therapeutic intervention.

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