Diabetes & Metabolism Journal

Original Articles

Basic Research
Hypoxia Increases β-Cell Death by Activating Pancreatic Stellate Cells within the Islet: Jong Jin Kim, Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song; Diabetes Metab J. 2020;44(6):919-927. Published online May 11, 2020; DOI: https://doi.org/10.4093/dmj.2019.0181

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Background

Hypoxia can occur in pancreatic islets in type 2 diabetes mellitus. Pancreatic stellate cells (PSCs) are activated during hypoxia. Here we aimed to investigate whether PSCs within the islet are also activated in hypoxia, causing β-cell injury.

Methods

Islet and primary PSCs were isolated from Sprague Dawley rats, and cultured in normoxia (21% O₂) or hypoxia (1% O₂). The expression of α-smooth muscle actin (α-SMA), as measured by immunostaining and Western blotting, was used as a marker of PSC activation. Conditioned media (hypoxia-CM) were obtained from PSCs cultured in hypoxia.

Results

Islets and PSCs cultured in hypoxia exhibited higher expressions of α-SMA than did those cultured in normoxia. Hypoxia increased the production of reactive oxygen species. The addition of N-acetyl-L-cysteine, an antioxidant, attenuated the hypoxia-induced PSC activation in islets and PSCs. Islets cultured in hypoxia-CM showed a decrease in cell viability and an increase in apoptosis.

Conclusion

PSCs within the islet are activated in hypoxia through oxidative stress and promote islet cell death, suggesting that hypoxia-induced PSC activation may contribute to β-cell loss in type 2 diabetes mellitus.

Citations

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Kai Duan, Mengyang Zhou, Yong Wang, Jose Oberholzer, Joe F. Lo
Microsystems & Nanoengineering.2023;[Epub] CrossRef
Pancreatic stellate cells promote pancreatic β-cell death through exosomal microRNA transfer in hypoxia
Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song
Molecular and Cellular Endocrinology.2023; 572: 111947. CrossRef
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Cellular Signalling.2022; 91: 110219. CrossRef
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Frontiers in Physiology.2022;[Epub] CrossRef
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Journal of Inflammation Research.2022; Volume 15: 4409. CrossRef
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Le Li, Xing-jia Yu, Lei Gao, Long Cheng, Bei Sun, Gang Wang
Antioxidants & Redox Signaling.2022; 37(16-18): 1206. CrossRef
Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia
Matias Estaras, Manuel R. Gonzalez-Portillo, Miguel Fernandez-Bermejo, Jose M. Mateos, Daniel Vara, Gerardo Blanco-Fernandez, Diego Lopez-Guerra, Vicente Roncero, Gines M. Salido, Antonio González
International Journal of Molecular Sciences.2021; 22(11): 5555. CrossRef
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Yuan Li, Bingwei Li, Bing Wang, Mingming Liu, Xiaoyan Zhang, Ailing Li, Jian Zhang, Honggang Zhang, Ruijuan Xiu
Microcirculation.2021;[Epub] CrossRef
Pancreatic stellate cells - rising stars in pancreatic pathologies
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Protective Effect of Heme Oxygenase-1 on High Glucose-Induced Pancreatic β-Cell Injury: Eun-Mi Lee, Young-Eun Lee, Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Sung-Dae Moon, Ki-Ho Song, Yu-Bae Ahn; Diabetes Metab J. 2011;35(5):469-479. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.469

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Abstract PDF PubReader

Background

Glucose toxicity that is caused by chronic exposure to a high glucose concentration leads to islet dysfunction and induces apoptosis in pancreatic β-cells. Heme oxygenase-1 (HO-1) has been identified as an anti-apoptotic and cytoprotective gene. The purpose of this study is to investigate whether HO-1 up-regulation when using metalloprotophyrin (cobalt protoporphyrin, CoPP) could protect pancreatic β-cells from high glucose-induced apoptosis.

Methods

Reverse transcription-polymerase chain reaction was performed to analyze the CoPP-induced mRNA expression of HO-1. Cell viability of INS-1 cells cultured in the presence of CoPP was examined by acridine orange/propidium iodide staining. The generation of intracellular reactive oxygen species (ROS) was measured using flow cytometry. Glucose stimulated insulin secretion (GSIS) was determined following incubation with CoPP in different glucose concentrations.

Results

CoPP increased HO-1 mRNA expression in both a dose- and time-dependent manner. Overexpression of HO-1 inhibited caspase-3, and the number of dead cells in the presence of CoPP was significantly decreased when exposed to high glucose conditions (HG). CoPP also decreased the generation of intracellular ROS by 50% during 72 hours of culture with HG. However, decreased GSIS was not recovered even in the presence of CoPP.

Conclusion

Our data suggest that CoPP-induced HO-1 up-regulation results in protection from high glucose-induced apoptosis in INS-1 cells; however, glucose stimulated insulin secretion is not restored.

Citations

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CYTOCHROMES OF MITOCHONDRIES AND ACTIVITY OF HEME METABOLISM ENZYMES IN THE LIVER UNDER DIFFERENT NUTRIENT REGIMES
G.P. Kopylchuk, Z.-M. I. Grynenkiv, O.M. Voloshchuk
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Xiang Ye, Wen Chen, Pengcheng Tu, Ruoyi Jia, Yangyang Liu, Yonglu Li, Qiong Tang, Xiaodong Zheng, Qiang Chu
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Telmisartan protects against high glucose/high lipid‐induced apoptosis and insulin secretion by reducing the oxidative and ER stress
Yan Wang, Jingjing Xue, Yan Li, Xin Zhou, Shun Qiao, Dewu Han
Cell Biochemistry and Function.2019; 37(3): 161. CrossRef
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Alyssa Ward, David K. Klassen, Kate M. Franz, Sebastian Giwa, Jedediah K. Lewis
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Chunyan Liu, Yanan Hao, Fei Yin, Yonglan Zhang, Jianhui Liu
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Eff ects of hemin, a heme oxygenase-1 inducer in L-arginine-induced acute pancreatitis and associated lung injury in adult male albino rats
N. M. Aziz, M. Y. Kamel, R. A. Rifaai
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Chronic Resveratrol Treatment Protects Pancreatic Islets against Oxidative Stress in db/db Mice
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Decreased Expression and Induced Nucleocytoplasmic Translocation of Pancreatic and Duodenal Homeobox 1 in INS-1 Cells Exposed to High Glucose and Palmitate: Gyeong Ryul Ryu, Jun Mo Yoo, Esder Lee, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song; Diabetes Metab J. 2011;35(1):65-71. Published online February 28, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.1.65

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36 Download
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Abstract PDF PubReader

Background

Type 2 diabetes mellitus (T2DM) is often accompanied by increased levels of circulating fatty acid. Elevations in fatty acids and glucose for prolonged periods of time have been suggested to cause progressive dysfunction or apoptosis of pancreatic beta cells in T2DM. However, the precise mechanism of this adverse effect is not well understood.

Methods

INS-1 rat-derived insulin-secreting cells were exposed to 30 mM glucose and 0.25 mM palmitate for 48 hours.

Results

The production of reactive oxygen species increased significantly. Pancreatic and duodenal homeobox 1 (Pdx1) expression was down-regulated, as assessed by reverse transcription-polymerase chain reaction and Western blot analyses. The promoter activities of insulin and Pdx1 were also diminished. Of note, there was nucleocytoplasmic translocation of Pdx1, which was partially prevented by treatment with an antioxidant, N-acetyl-L-cysteine.

Conclusion

Our data suggest that prolonged exposure of beta cells to elevated levels of glucose and palmitate negatively affects Pdx1 expression via oxidative stress.

Citations

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Nrf2 Activation Protects Mouse Beta Cells from Glucolipotoxicity by Restoring Mitochondrial Function and Physiological Redox Balance
Johanna Schultheis, Dirk Beckmann, Dennis Mulac, Lena Müller, Melanie Esselen, Martina Düfer
Oxidative Medicine and Cellular Longevity.2019; 2019: 1. CrossRef
Early overnutrition reduces Pdx1 expression and induces β cell failure in Swiss Webster mice
Maria M. Glavas, Queenie Hui, Eva Tudurí, Suheda Erener, Naomi L. Kasteel, James D. Johnson, Timothy J. Kieffer
Scientific Reports.2019;[Epub] CrossRef
Anti-diabetic effect of mulberry leaf polysaccharide by inhibiting pancreatic islet cell apoptosis and ameliorating insulin secretory capacity in diabetic rats
Yao Zhang, Chunjiu Ren, Guobing Lu, Zhimei Mu, Weizheng Cui, Huiju Gao, Yanwen Wang
International Immunopharmacology.2014; 22(1): 248. CrossRef
The Furan Fatty Acid Metabolite CMPF Is Elevated in Diabetes and Induces β Cell Dysfunction
Kacey J. Prentice, Lemieux Luu, Emma M. Allister, Ying Liu, Lucy S. Jun, Kyle W. Sloop, Alexandre B. Hardy, Li Wei, Weiping Jia, I. George Fantus, Douglas H. Sweet, Gary Sweeney, Ravi Retnakaran, Feihan F. Dai, Michael B. Wheeler
Cell Metabolism.2014; 19(4): 653. CrossRef

Transdifferentiation of Enteroendocrine K-cells into Insulin-expressing Cells.: Esder Lee, Jun Mo Yu, Min Kyung Lee, Gyeong Ryul Ryu, Seung Hyun Ko, Yu Bae Ahn, Sung Dae Moon, Ki Ho Song; Korean Diabetes J. 2009;33(6):475-484. Published online December 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.6.475

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Abstract PDF

BACKGROUND
Despite a recent breakthough in human islet transplantation for treating type 1 diabetes mellitus, the limited availability of donor pancreases remains a major obstacle. Endocrine cells within the gut epithelium (enteroendocrine cells) and pancreatic beta cells share similar pathways of differentiation during embryonic development. In particular, K-cells that secrete glucose-dependent insulinotropic polypeptide (GIP) have been shown to express many of the key proteins found in beta cells. Therefore, we hypothesize that K-cells can be transdifferentiated into beta cells because both cells have remarkable similarities in their embryonic development and cellular phenotypes. METHODS: K-cells were purified from heterogeneous STC-1 cells originating from an endocrine tumor of a mouse intestine. In addition, a K-cell subclone expressing stable Nkx6.1, called "Kn4-cells," was successfully obtained. In vitro differentiation of K-cells or Kn4-cells into beta cells was completed after exendin-4 treatment and serum deprivation. The expressions of insulin mRNA and protein were examined by RT-PCR and immunocytochemistry. The interacellular insulin content was also measured. RESULTS: K-cells were found to express glucokinase and GIP as assessed by RT-PCR and Western blot analysis. RT-PCR showed that K-cells also expressed Pdx-1, NeuroD1/Beta2, and MafA, but not Nkx6.1. After exendin-4 treatment and serum deprivation, insulin mRNA and insulin or C-peptide were clearly detected in Kn4-cells. The intracellular insulin content was also increased significantly in these cells. CONCLUSION: K-cells are an attractive potential source of insulin-producing cells for treatment of type 1 diabetes mellitus. However, more experiments are necessary to optimize a strategy for converting K-cells into beta cells.

Citations

Citations to this article as recorded by

Reprogramming of enteroendocrine K cells to pancreatic β-cells through the combined expression of Nkx6.1 and Neurogenin3, and reaggregation in suspension culture
Esder Lee, Gyeong Ryul Ryu, Sung-Dae Moon, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song
Biochemical and Biophysical Research Communications.2014; 443(3): 1021. CrossRef

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