Stable overexpression of p8 increases survival of INS-1E beta cells in response to streptozotocin (STZ)-induced beta cell damage in vitro

OBJECTIVE: N-(2-hydroxyethyl)-nicotinamide nitrate (nicorandil) is a unique anti-anginal agent, reported to act as both an ATP-sensitive K(+) channel opener (PCO) and a nitric oxide donor. It also has an anti-oxidant action. We examined the effects of nicorandil on streptozotocin (STZ)-induced islet beta-cell damage both in vivo and in vitro. DESIGN AND METHODS: STZ-induced diabetic Brown Norway rats (STZ-DM) were fed with nicorandil-containing chow from day 2 (STZ-DM-N48), 3 (STZ-DM-N72), and 4 (STZ-DM-N96) to day 30. Body weight, blood glucose, and plasma insulin were measured every week. For the in vitro assay, neonatal rat islet-rich cultures were performed and cells were treated with nicorandil from 1 h before to 2 h after exposure to STZ for 30 min. Insulin secretion from islet cells was assayed after an additional 24 h of culture. We also observed the effect of nicorandil on the generation of reactive oxygen species (ROS) from rat inslinoma cells (RINm5F). RESULTS: Body weight loss and blood glucose levels of STZ-DM-N48 rats were significantly lower than those of STZ-DM rats. Immunohistochemical staining of insulin showed preservation of insulin-secreting islet beta-cells in STZ-DM-N48 rats. Nicorandil also dose-dependently recovered the insulin release from neonatal rat islet cells treated with STZ in in vitro experiments. Nicorandil did not act as a PCO on neonatal rat islet beta-cells or RINm5F cells, and did not show an inhibitory effect on poly(ADP-ribose) polymerase-1. However, the drug inhibited the production of ROS stimulated by high glucose (22.0 mmol/l) in RINm5F cells. CONCLUSIONS: These results suggested that nicorandil improves diabetes and rat islet beta-cell damage induced by STZ in vivo and in vitro. It protects islet beta-cells, at least partly, via a radical scavenging effect.

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LncRNA LEGLTBC Functions as a ceRNA to Antagonize the Effects of miR-34a on the Downregulation of SIRT1 in Glucolipotoxicity-Induced INS-1 Beta Cell Oxidative Stress and Apoptosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4010764 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 2

Author(s):

Xiang Kong ◽

Chong-xiao Liu ◽

Guo-dong Wang ◽

Hui Yang ◽

Xin-ming Yao ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Cell Injury ◽

Cell Damage ◽

High Serum ◽

Cell Dysfunction ◽

Beta Cell Damage

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose and/or high serum free fatty acids. Chronic hyperlipidemia causes the dysfunction of pancreatic beta cells, which is aggravated in the presence of hyperglycemia (glucolipotoxicity). Long noncoding RNAs (lncRNAs) have been suggested to play key roles in type 1 diabetes mellitus development. However, their roles in glucolipotoxicity-induced beta cell dysfunction are not fully understood. In the present study, we identified the differentially expressed lncRNAs in INS-1 cells exposed to high glucose and palmitate (HG/PA). Among the dysregulated lncRNAs, NONRATT003679.2 (low expression in glucolipotoxicity-treated beta cells (LEGLTBC)) was involved in glucolipotoxicity-evoked rat islet beta cell damage. LEGLTBC functioned as a molecular sponge of miR-34a in INS-1 cells. Additionally, SIRT1 was identified as a target of miR-34a and LEGLTBC promoted SIRT1 expression by sponging miR-34a. The upregulation of LEGLTBC attenuated HG/PA-induced INS-1 cell injury through the promotion of SIRT1-mediated suppression of ROS accumulation and apoptosis. This is the first study to comprehensively identify the lncRNA expression profiling of HG/PA-treated INS-1 beta cells and to demonstrate that LEGLTBC functions as a competing endogenous RNA and regulates miR-34a/SIRT1-mediated oxidative stress and apoptosis in INS-1 cells undergoing glucolipotoxicity.

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Abnormal cannabidiol ameliorates inflammation preserving pancreatic beta cells in mouse models of experimental type 1 diabetes and beta cell damage

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.112361 ◽

2021 ◽

pp. 112361

Author(s):

Isabel González-Mariscal ◽

Macarena Pozo Morales ◽

Silvana Y. Romero-Zerbo ◽

Vanesa Espinosa-Jimenez ◽

Alejandro Escamilla-Sánchez ◽

...

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Beta Cells ◽

Mouse Models ◽

Pancreatic Beta Cells ◽

Cell Damage ◽

Experimental Type ◽

Beta Cell Damage

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Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway

Antioxidants ◽

10.3390/antiox9050406 ◽

2020 ◽

Vol 9 (5) ◽

pp. 406 ◽

Cited By ~ 1

Author(s):

Hyo-Jin Kim ◽

Donghee Kim ◽

Haelim Yoon ◽

Cheol Soo Choi ◽

Yoon Sin Oh ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Cell Damage ◽

Beta Cell Death ◽

Min6 Cells ◽

Erk Phosphorylation ◽

Beta Cell Damage

Pancreatic beta cells are vulnerable to oxidative stress, which causes beta cell death and dysfunction in diabetes mellitus. Broussonetia kazinoki Siebold (BK) is a widely used herbal medicine, but its potential effects against beta cell death-induced diabetes have not been studied. Therefore, we investigated the protective effect of an ethanolic extract of BK fruit (BKFE) against streptozotocin (STZ)-induced toxicity in pancreatic beta cells. Intraperitoneal injection of STZ in mice induced hyperglycemia; however, oral administration of BKFE significantly decreased the blood glucose level as well as HbA1c levels. BKFE treatment improved glucose tolerance and increased body weight in diabetic mice. Moreover, BKFE treatment resulted in increased serum insulin levels and insulin expression in the pancreas as well as decreased 4-hydroxynonenal levels induced by oxidative stress. Treatment with STZ decreased cell viability of mouse insulinoma cells (MIN6), which was blocked by BKFE pretreatment. BKFE significantly inhibited apoptotic cells and decreased the expression levels of cleaved-caspase-3 and cleaved-poly (ADP-ribose) polymerase (PARP) induced by STZ treatment. Production of reactive oxygen species in STZ-treated MIN6 cells was also significantly decreased by treatment with BKFE. Erk phosphorylation and Nox4 levels increased in STZ-treated MIN6 cells and the pancreas of mice injected with STZ and this increase was inhibited by treatment with BKFE. Inhibition of Erk phosphorylation by treatment with the PD98059 inhibitor or siRNA Erk also blocked the expression of Nox4 induced by STZ treatment. In conclusion, BKFE inhibits Erk phosphorylation, which in turn prevents STZ-induced oxidative stress and beta cell apoptosis. These results suggested that BKFE can be used to prevent or treat beta cell damage in diabetes.

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Beneficial Effect ofLespedeza cuneata(G. Don) Water Extract on Streptozotocin-induced Type 1 Diabetes and Cytokine-induced Beta-cell Damage

Natural Product Sciences ◽

10.20307/nps.2016.22.3.175 ◽

2016 ◽

Vol 22 (3) ◽

pp. 175 ◽

Cited By ~ 5

Author(s):

Min Suk Kim ◽

Bhesh Raj Sharma ◽

Dong Young Rhyu

Keyword(s):

Type 1 Diabetes ◽

Beta Cell ◽

Beneficial Effect ◽

Cell Damage ◽

Water Extract ◽

Beta Cell Damage

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Pax4 Expression does not Transduce Pancreatic Alpha Cells to Beta Cells

Cellular Physiology and Biochemistry ◽

10.1159/000430146 ◽

2015 ◽

Vol 36 (5) ◽

pp. 1735-1742 ◽

Cited By ~ 4

Author(s):

Ling Chen ◽

Jing Zhang ◽

Zhuo Zhang ◽

Yaping Chu ◽

Bing Song ◽

...

Keyword(s):

Blood Glucose ◽

Beta Cell ◽

Beta Cells ◽

Cell Number ◽

Diabetic Patients ◽

Alpha Cells ◽

Diabetic Mice ◽

Glucose Response ◽

Pancreatic Alpha Cells

Background/Aims: The lack of available beta cells greatly limits the use of beta cell transplantation as a therapy for diabetes. Thus, generation of beta cells from other sources is substantially required. Pax4 has been shown to induce reprograming of alpha cells into beta cells during embryogenesis. Nevertheless, whether expression of Pax4 in adult alpha cells could trigger this alpha-to-beta cell reprogramming is unknown. Methods: Here we generated an adeno-associated virus carrying Pax4 and GFP under a CMV promoter (AAV-Pax4). We used AAV-Pax4 to transduce a mouse alpha cell line in vitro, and to transduce primary alpha cells in diabetic mice. Reprogramming was examined by double immunostaining and by changes in beta cell number. The effects on blood glucose were evaluated by fasting blood glucose and glucose response. Results: In vitro, Pax4 overexpression neither induced insulin expression, nor suppressed glucagon expression in alpha cells. In vivo, Pax4 overexpression failed to increase beta cell number, and did not alter hyperglycemia and glucose response in diabetic mice. Conclusion: Pax4 expression is not sufficient to transduce pancreatic alpha cells into beta cells. Overexpression of Pax4 in alpha cells may not increase functional beta cell number in diabetic patients.

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Glucokinase mediates coupling of glycolysis to mitochondrial metabolism but not to beta cell damage at high glucose exposure levels

Diabetologia ◽

10.1007/s00125-011-2133-5 ◽

2011 ◽

Vol 54 (7) ◽

pp. 1744-1755 ◽

Cited By ~ 9

Author(s):

H. Schmitt ◽

S. Lenzen ◽

S. Baltrusch

Keyword(s):

Beta Cell ◽

High Glucose ◽

Cell Damage ◽

Mitochondrial Metabolism ◽

Glucose Exposure ◽

Exposure Levels ◽

Beta Cell Damage

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Comparative toxicity of alloxan, N-alkylalloxans and ninhydrin to isolated pancreatic islets in vitro

Journal of Endocrinology ◽

10.1677/joe.0.1550283 ◽

1997 ◽

Vol 155 (2) ◽

pp. 283-293 ◽

Cited By ~ 31

Author(s):

A Jorns ◽

R Munday ◽

M Tiedge ◽

S Lenzen

Keyword(s):

Beta Cell ◽

Pancreatic Islets ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Ultrastructural Changes ◽

Cell Necrosis ◽

High Concentrations ◽

Beta Cell Necrosis

The in vitro toxicity of the diabetogenic agent alloxan as documented by the induction of beta cell necrosis was studied in isolated ob/ob mouse pancreatic islets. The effect of alloxan has been compared with that of a number of N-alkyl alloxan derivatives and with that of the structurally related compound, ninhydrin. Alloxan and its derivatives were selectively toxic to pancreatic beta cells, with other endocrine cells and exocrine parenchymal cells being well preserved, even at high concentration. In contrast, ninhydrin was selectively toxic to pancreatic beta cells only at comparatively low concentration, destroying all islet cell types at high concentrations. The ultrastructural changes induced by all the test compounds in pancreatic beta cells in vitro were very similar to those observed during the development of alloxan diabetes in vivo. The relative toxicity of the various compounds to pancreatic beta cells in vitro was not, however, related to their ability to cause diabetes in vivo. Indeed, the non-diabetogenic substances ninhydrin, N-butylalloxan and N-isobutylalloxan were very much more toxic to isolated islets than the diabetogenic compounds alloxan and N-methylalloxan. These results suggest that the differences in diabetogenicity among alloxan derivatives are not due to intrinsic differences in the susceptibility of the pancreatic beta cells to their toxicity, but may reflect differences in distribution or metabolism. High concentrations of glucose protected islets against the harmful effects of alloxan and its derivatives, but not those of ninhydrin. Low levels of glucose, and non-carbohydrate nutrients, afforded little protection, indicating that the effect of glucose is not due to the production of reducing equivalents within the cell, 3-O-Methylglucose, which protects against alloan diabetes in vivo, did not protect against alloxan toxicity in vitro. Since 3-O-methylglucose is known to prevent uptake of alloxan by pancreatic beta cells, it appears that uptake of alloxan by the cell is not a prerequisite for the induction of beta cell necrosis.

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