Honokiol protects pancreatic β cell against high glucose and intermittent hypoxia-induced injury by activating Nrf2/ARE pathway in vitro and in vivo

Background/Aims: Intermittent hypoxia (IH) causes apoptosis in pancreatic β-cells, but the potential mechanisms remain unclear. Endoplasmic reticulum (ER) stress, autophagy, and apoptosis are interlocked in an extensive crosstalk. Thus, this study aimed to investigate the contributions of ER stress and autophagy to IH-induced pancreatic β-cell apoptosis. Methods: We established animal and cell models of IH, and then inhibited autophagy and ER stress by pharmacology and small interfering RNA (siRNA) in INS-1 cells and rats. The levels of biomarkers for autophagy, ER stress, and apoptosis were evaluated by immunoblotting and immunofluorescence. The number of autophagic vacuoles was observed by transmission electron microscopy. Results: IH induced autophagy activation both in vivo and in vitro, as evidenced by increased autophagic vacuole formation and LC3 turnover, and decreased SQSTM1 level. The levels of ER-stress-related proteins, including GRP78, CHOP, caspase 12, phosphorylated (p)-protein kinase RNA-like ER kinase (PERK), p-eIF2α, and activating transcription factor 4 (ATF4) were increased under IH conditions. Inhibition of ER stress with tauroursodeoxycholic acid or 4-phenylbutyrate partially blocked IH-induced autophagy in INS-1 cells. Furthermore, inhibition of PERK with GSK2606414 or siRNA blocked the ERstress-related PERK/eIF2α/ATF4 signaling pathway and inhibited autophagy induced by IH, which indicates that IH-induced autophagy activation is dependent on this signaling pathway. Promoting autophagy with rapamycin alleviated IH-induced apoptosis, whereas inhibition of autophagy with chloroquine or autophagy-related gene (Atg5 and Atg7) siRNA aggravated pancreatic β-cell apoptosis caused by IH. Conclusion: IH induces autophagy activation through the ER-stress-related PERK/eIF2α/ATF4 signaling pathway, which is a protective response to pancreatic β-cell apoptosis caused by IH.

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The anti-inflammatory protein NUPR1 (p8) is a novel intracellular mediator of pancreatic β-cell protection during diabetogenic stress in vitro and in vivo

Diabetologie und Stoffwechsel ◽

10.1055/s-0034-1374962 ◽

2014 ◽

Vol 9 (S 01) ◽

Author(s):

AE Mehana ◽

I Pilz ◽

B Dufner ◽

C Jäger ◽

S Sojka ◽

...

Keyword(s):

Pancreatic Β Cell ◽

Cell Protection ◽

Β Cell ◽

Inflammatory Protein ◽

Anti Inflammatory

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Preptin, another peptide product of the pancreatic β-cell, is osteogenic in vitro and in vivo

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00642.2005 ◽

2007 ◽

Vol 292 (1) ◽

pp. E117-E122 ◽

Cited By ~ 51

Author(s):

J. Cornish ◽

K. E. Callon ◽

U. Bava ◽

M. Watson ◽

X. Xu ◽

...

Keyword(s):

Bone Mass ◽

Map Kinases ◽

Cell Number ◽

Dependent Manner ◽

Pancreatic Β Cell ◽

Hepatitis C Infection ◽

Β Cell ◽

High Bone Mass

Several hormones that regulate nutritional status also impact on bone metabolism. Preptin is a recently isolated 34-amino acid peptide hormone that is cosecreted with insulin and amylin from the pancreatic β-cells. Preptin corresponds to Asp69-Leu102 of pro-IGF-II. Increased circulating levels of a pro-IGF-II peptide complexed with IGF-binding protein-2 have been implicated in the high bone mass phenotype observed in patients with chronic hepatitis C infection. We have assessed preptin's activities on bone. Preptin dose-dependently stimulated the proliferation (cell number and DNA synthesis) of primary fetal rat osteoblasts and osteoblast-like cell lines at periphysiological concentrations (>10−11 M). In addition, thymidine incorporation was stimulated in murine neonatal calvarial organ culture, likely reflecting the proliferation of cells from the osteoblast lineage. Preptin did not affect bone resorption in this model. Preptin induced phosphorylation of p42/p44 MAP kinases in osteoblastic cells in a dose-dependent manner (10−8-10−10 M), and its proliferative effects on primary osteoblasts were blocked by MAP kinase kinase inhibitors. Preptin also reduced osteoblast apoptosis induced by serum deprivation, reducing the number of apoptotic cells by >20%. In vivo administration of preptin increased bone area and mineralizing surface in adult mice. These data demonstrate that preptin, which is cosecreted from the pancreatic β-cell with amylin and insulin, is anabolic to bone and may contribute to the preservation of bone mass observed in hyperinsulinemic states such as obesity.

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In vivo evaluation of GG2–GG1/A2 element activity in the insulin promoter region using the CRISPR–Cas9 system

Scientific Reports ◽

10.1038/s41598-021-99808-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hirofumi Noguchi ◽

Chika Miyagi-Shiohira ◽

Takao Kinjo ◽

Issei Saitoh ◽

Masami Watanabe

Keyword(s):

Promoter Region ◽

In Vivo Studies ◽

Pancreatic Β Cell ◽

Β Cell ◽

In Vivo Evaluation ◽

Specific Expression ◽

Insulin Promoter ◽

Element Activity

AbstractThe insulin promoter is regulated by ubiquitous as well as pancreatic β-cell-specific transcription factors. In the insulin promoter, GG2–GG1/A2–C1 (bases − 149 to − 116 in the human insulin promoter) play important roles in regulating β-cell-specific expression of the insulin gene. However, these events were identified through in vitro studies, and we are unaware of comparable in vivo studies. In this study, we evaluated the activity of GG2–GG1/A2 elements in the insulin promoter region in vivo. We generated homozygous mice with mutations in the GG2–GG1/A2 elements in each of the Ins1 and Ins2 promoters by CRISPR–Cas9 technology. The mice with homozygous mutations in the GG2–GG1/A2 elements in both Ins1 and Ins2 were diabetic. These data suggest that the GG2–GG1/A2 element in mice is important for Ins transcription in vivo.

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The Angiotensin-(1–7)/Mas Axis Improves Pancreatic β-Cell Function in Vitro and in Vivo

Endocrinology ◽

10.1210/en.2016-1247 ◽

2016 ◽

Vol 157 (12) ◽

pp. 4677-4690 ◽

Cited By ~ 16

Author(s):

Anika Sahr ◽

Carmen Wolke ◽

Jonas Maczewsky ◽

Peter Krippeit-Drews ◽

Anja Tetzner ◽

...

Keyword(s):

Cell Function ◽

Pancreatic Β Cell ◽

Β Cell ◽

Β Cell Function

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Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00416.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. E255-E262 ◽

Cited By ~ 133

Author(s):

Adria Giacca ◽

Changting Xiao ◽

Andrei I. Oprescu ◽

Andre C. Carpentier ◽

Gary F. Lewis

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Cell Function ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Dysfunction ◽

Β Cell Function

The phenomenon of lipid-induced pancreatic β-cell dysfunction (“lipotoxicity”) has been very well documented in numerous in vitro experimental systems and has become widely accepted. In vivo demonstration of β-cell lipotoxicity, on the other hand, has not been consistently demonstrated, and there remains a lack of consensus regarding the in vivo effects of chronically elevated free fatty acids (FFA) on β-cell function. Much of the disagreement relates to how insulin secretion is quantified in vivo and in particular whether insulin secretion is assessed in relation to whole body insulin sensitivity, which is clearly reduced by elevated FFA. By correcting for changes in in vivo insulin sensitivity, we and others have shown that prolonged elevation of FFA impairs β-cell secretory function. Prediabetic animal models and humans with a positive family history of type 2 diabetes are more susceptible to this impairment, whereas those with severe impairment of β-cell function (such as individuals with type 2 diabetes) demonstrate no additional impairment of β-cell function when FFA are experimentally raised. Glucolipotoxicity (i.e., the combined β-cell toxicity of elevated glucose and FFA) has been amply demonstrated in vitro and in some animal studies but not in humans, perhaps because there are limitations in experimentally raising plasma glucose to sufficiently high levels for prolonged periods of time. We and others have shown that therapies directed toward diminishing oxidative stress and ER stress have the potential to reduce lipid-induced β-cell dysfunction in animals and humans. In conclusion, lipid-induced pancreatic β-cell dysfunction is likely to be one contributor to the complex array of genetic and metabolic insults that result in the relentless decline in pancreatic β-cell function in those destined to develop type 2 diabetes, and mechanisms involved in this lipotoxicity are promising therapeutic targets.

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Cyclocarya paliurus tea leaves enhances pancreatic β cell preservation through inhibition of apoptosis

Scientific Reports ◽

10.1038/s41598-017-09641-z ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 22

Author(s):

Hai-tao Xiao ◽

Bo Wen ◽

Zi-wan Ning ◽

Li-xiang Zhai ◽

Cheng-hui Liao ◽

...

Keyword(s):

Cell Apoptosis ◽

Pancreatic Β Cell ◽

Diabetic Mice ◽

Tea Leaves ◽

Β Cell ◽

Cyclocarya Paliurus ◽

Obesity And Diabetes ◽

Cell Preservation

Abstract Leaves of Cyclocarya paliurus are a sweet tea traditionally used to treat obesity and diabetes in China. However, its protective mechanisms against hyperglycemia remains unclear. Here, we demonstrate that the extract of C. paliurus leaves significantly decreased body loss, food intake and blood glucose level, and increased blood insulin level, β-cell number and insulin-producing β cells in high-fat diet-low dose STZ-induced diabetic mice. In vivo and in vitro studies also showed the extract of C. paliurus leaves significantly inhibited pancreatic β cell apoptosis by suppressing the expression of caspase 8, caspase 9 and cleaved caspase-3, as well as Bax/Bcl-2 ratio, down-regulating p38, ERK and JNK phosphorylation, and up-regulating Akt phosphorylation. These effects were significantly enhanced by inhibitor p-38 or ERK or JNK, and counteracted by inhibitor of PI3K. In addition, the extract of C. paliurus leaves also significantly improved hepatic steatosis, nephropathy and cardiac hypertrophy of diabetic mice. Taken together, these results provide the insight into the effects of C. paliurus leaves on pancreatic β cell preservation in standing glucolipotoxicity. Therefore, C. paliurus tea leaves may be used as a new remedy for diabetes through enhancing pancreatic β cell preservation by inhibiting β cell apoptosis.

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Potential of Protein Phosphatase Inhibitor 1 As Biomarker of Pancreatic β-Cell Injury In Vitro and In Vivo

Diabetes ◽

10.2337/db12-1507 ◽

2013 ◽

Vol 62 (8) ◽

pp. 2683-2688 ◽

Cited By ~ 23

Author(s):

Lei Jiang ◽

Benedicte Brackeva ◽

Zhidong Ling ◽

Gertjan Kramer ◽

Johannes M. Aerts ◽

...

Keyword(s):

Protein Phosphatase ◽

Cell Injury ◽

Pancreatic Β Cell ◽

Β Cell ◽

Phosphatase Inhibitor ◽

Protein Phosphatase Inhibitor

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Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic β-cell dysfunction and death in vitro

Clinical Science ◽

10.1042/cs20130678 ◽

2014 ◽

Vol 126 (10) ◽

pp. 739-752 ◽

Cited By ~ 44

Author(s):

Mauricio Krause ◽

Kevin Keane ◽

Josianne Rodrigues-Krause ◽

Domenico Crognale ◽

Brendan Egan ◽

...

Keyword(s):

Insulin Resistance ◽

Heat Shock ◽

Chronic Exposure ◽

Pancreatic Β Cell ◽

Β Cells ◽

Β Cell ◽

Cell Dysfunction ◽

Important Mediator

We have demonstrated a positive correlation between eHSP72 and insulin resistance, and that chronic exposure of β-cells to eHSP72 may provoke β-cell dysfunction and thus is potentially an important mediator of β-cell failure.

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