Diabetes & Metabolism Journal

Original Articles

The Effects of Glyburide on Apoptosis and Endoplasmic Reticulum Stress in INS-1 Cells in a Glucolipotoxic Condition: Min Jeong Kwon, Hye Suk Chung, Chang Shin Yoon, Jung Hae Ko, Hae Jung Jun, Tae Kyun Kim, Soon Hee Lee, Kyung Soo Ko, Byoung Doo Rhee, Mi Kyung Kim, Jeong Hyun Park; Diabetes Metab J. 2011;35(5):480-488. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.480

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Background

β-cell death due to endoplasmic reticulum (ER) stress has been regarded as an important pathogenic component of type 2 diabetes. The possibility has been suggested that sulfonylurea, currently being used as one of the main oral hypoglycemic agents of type 2 diabetes, increases ER stress, which could lead to sulfonylurea failure. The authors of the present study examined ER stress of β-cells in a glucolipotoxic condition using glyburide (GB) in an environment mimicking type 2 diabetes.

Methods

Apoptosis was induced by adding various concentrations of GB (0.001 to 200 µM) to a glucolipotoxic condition using 33 mM glucose, and the effects of varied concentrations of palmitate were evaluated via annexin V staining. The markers of ER stress and pro-apoptotic markers were assessed by Western blotting and semi-quantitative reverse transcription-polymerase chain reaction. Additionally, the anti-apoptotic markers were evaluated.

Results

Addition of any concentration of GB in 150 µM palmitate and 33 mM glucose did not increase apoptosis. The expression of phosphorylated eukaryotic initiation factor (eIF-2α) was increased and cleaved caspase 3 was decreased by adding GB to a glucolipotoxic condition. However, other ER stress-associated markers such as Bip-1, X-box binding protein-1, ATF-4 and C/EBP-homologous protein transcription factor and anti-apoptotic markers phosphor-p85 phosphatidylinositol 3-kinase and phosphorylation of Akt did not change significantly.

Conclusion

GB did not show further deleterious effects on the degree of apoptosis or ER stress of INS-1 cells in a glucolipotoxic condition. Increased phosphorylation of eIF-2α may attenuate ER stress for adaptation to increased ER protein load.

Citations

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The antagonistic atorvastatin-glibenclamide interactions suppressed the atorvastatin-induced Bax/cytochrome c/p53 mRNA expressions and increased Rho A mRNA expression in B16f10 melanoma cell culture
Maryam Malek, Nasim Dana, Ahmad Ghasemi, Maedeh Ghasemi
Gene Reports.2021; 23: 101156. CrossRef
Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism
Marcus Lundberg, Anton Stenwall, Angie Tegehall, Olle Korsgren, Oskar Skog
Islets.2018; 10(2): 69. CrossRef
Pharmacological Modulators of Endoplasmic Reticulum Stress in Metabolic Diseases
Tae Jung, Kyung Choi
International Journal of Molecular Sciences.2016; 17(2): 192. CrossRef
The TRPA1 channel and oral hypoglycemic agents
Carlos Manlio Diaz-Garcia
Channels.2013; 7(6): 420. CrossRef
Dimethyl sulfoxide reduces hepatocellular lipid accumulation through autophagy induction
Young Mi Song, Sun-Ok Song, Yong-Keun Jung, Eun-Seok Kang, Bong Soo Cha, Hyun Chul Lee, Byung-Wan Lee
Autophagy.2012; 8(7): 1085. CrossRef
The Duration of Sulfonylurea Treatment Is Associated withβ-Cell Dysfunction in Patients with Type 2 Diabetes Mellitus
Mi-Seon Shin, Jee Hee Yu, Chang Hee Jung, Jenie Yoonoo Hwang, Woo Je Lee, Min-Seon Kim, Joong-Yeol Park
Diabetes Technology & Therapeutics.2012; 14(11): 1033. CrossRef

The Effect of Glucose Fluctuation on Apoptosis and Function of INS-1 Pancreatic Beta Cells: Mi Kyung Kim, Hye Sook Jung, Chang Shin Yoon, Jung Hae Ko, Hae Jung Jun, Tae Kyun Kim, Min Jeong Kwon, Soon Hee Lee, Kyung Soo Ko, Byoung Doo Rhee, Jeong Hyun Park; Korean Diabetes J. 2010;34(1):47-54. Published online February 28, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.1.47

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Abstract PDF PubReader

Background

Blood glucose level continuously fluctuates within a certain range in the human body. In diabetes patients, the extent of such fluctuation is large, despite the strict control of blood glucose. Blood glucose fluctuation has been shown to mediate more adverse effects on vascular endothelial cells and diabetes complications than chronic hyperglycemia, which has been explained as due to oxidative stress. As few previous studies have reported the effects of chronic and intermittent hyperglycemia on the apoptosis and function of pancreatic beta cells, this study reported herein was performed to investigate such effects on these cells.

Methods

For chronic hyperglycemia, INS-1 cells were cultured for 5 days with changes of RPMI 1640 medium containing 33 mM glucose every 12 hours. For intermittent hyperglycemia, the medium containing 11 mM glucose was exchanged with the medium containing 33 mM glucose every 12 hours. Apoptosis was assessed by TUNEL assay Hoechst staining and cleaved caspase 3. Insulin secretory capacity was assessed, and the expression of Mn-SOD and Bcl-2 was measured by Western blotting.

Results

In comparison to the control group, INS-1 cells exposed to chronic hyperglycemia and intermittent hyperglycemia showed an increase in apoptosis. The apoptosis of INS-1 cells exposed to intermittent hyperglycemia increased significantly more than the apoptosis of INS-1 cells exposed to chronic hyperglycemia. In comparison to the control group, the insulin secretory capacity in the two hyperglycemic states was decreased, and more with intermittent hyperglycemia than with chronic hyperglycemia. The expression of Mn-SOD and Bcl-2 increased more with chronic hyperglycemia than with intermittent hyperglycemia.

Conclusion

Intermittent hyperglycemia induced a higher degree of apoptosis and decreased the insulin secretory capacity more in pancreatic beta cells than chronic hyperglycemia. This activity may be mediated by the anti-oxidative enzyme Mn-SOD and the anti-apoptotic signal Bcl-2.

Citations

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Association between hemoglobin glycation index and diabetic kidney disease in type 2 diabetes mellitus in China: A cross- sectional inpatient study
Sixu Xin, Xin Zhao, Jiaxiang Ding, Xiaomei Zhang
Frontiers in Endocrinology.2023;[Epub] CrossRef
Plant polyphenols mechanisms of action on insulin resistance and against the loss of pancreatic beta cells
Camelia Papuc, Gheorghe V. Goran, Corina N. Predescu, Liliana Tudoreanu, Georgeta Ștefan
Critical Reviews in Food Science and Nutrition.2022; 62(2): 325. CrossRef
Correlation between HbA1c and Triglyceride Level with Coronary Stenosis Degree in Type 2 Diabetes Mellitus with Coronary Heart Disease
Laily Adninta, Indranila Samsuria, Edward Kurnia Setiawan Limijadi
Open Access Macedonian Journal of Medical Sciences.2022; 10(B): 944. CrossRef
Age‐specific associations of glycated haemoglobin variability with cardiovascular disease and mortality in patients with type 2 diabetes mellitus: A 10‐ year cohort study
Eric Yuk Fai Wan, Esther Yee Tak Yu, Weng Yee Chin, Florence Ting Yan Ng, Shu Ming Cheryl Chia, Ian Chi Kei Wong, Esther Wai Yin Chan, Cindy Lo Kuen Lam
Diabetes, Obesity and Metabolism.2020; 22(8): 1316. CrossRef
Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications
Zhen-Ye Zhang, Ling-Feng Miao, Ling-Ling Qian, Ning Wang, Miao-Miao Qi, Yu-Min Zhang, Shi-Peng Dang, Ying Wu, Ru-Xing Wang
Frontiers in Endocrinology.2019;[Epub] CrossRef
Resolution on the results of the first working meeting of the scientific advisory board «Actual problems of glycemic variability as a new criterion of glycemic control and safety of diabetes therapy»
Mikhail B. Antsiferov, Gagik R. Galstyan, Alexey V. Zilov, Alexander Y. Mayorov, Tatyana N. Markova, Nikolay A. Demidov, Olga M. Koteshkova, Dmitry N. Laptev, Alisa V. Vitebskaya
Diabetes mellitus.2019; 22(3): 281. CrossRef
Intermittent High Glucose Enhances the Proliferation of Rat Aortic Vascular Smooth Muscle Cells More Than Constant High Glucose via the Mitogen-Activated Protein Kinase Pathway
Sung Hoon Yu, Hyung Joon Yoo, Dong Hyun Kang, Shin Je Moon, Jae Myung Yu
Annals of Geriatric Medicine and Research.2017; 21(3): 131. CrossRef
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Ginsenoside Rg3 prevents INS-1 cell death from intermittent high glucose stress
You Jeong Kim, Su Min Park, Hye Sook Jung, Eun Ju Lee, Tae Kyoon Kim, Tae-Nyun Kim, Min Jeong Kwon, Soon Hee Lee, Byoung Doo Rhee, Mi-kyung Kim, Jeong Hyun Park
Islets.2016; 8(3): 57. CrossRef
Different antihyperglycaemic drug effects on glycaemic variability in Type 2 diabetic patients
Alina Babenko, Elena Ivanovna Krasilnikova, Nikolay Pavlovich Likhonosov, Anna Pavlovna Likhonosova, Elena Nikolaevna Grineva
Diabetes mellitus.2014; 17(4): 72. CrossRef
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Jonida Haxhi, Alessandro Scotto di Palumbo, Massimo Sacchetti
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Toxicology and Applied Pharmacology.2013; 266(3): 375. CrossRef
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Glucose exposure pattern determines glucagon-like peptide 1 receptor expression and signaling through endoplasmic reticulum stress in rat insulinoma cells
Ye-Hwang Cheong, Mi-Kyung Kim, Moon-Ho Son, Bong-Kiun Kaang
Biochemical and Biophysical Research Communications.2011; 414(1): 220. CrossRef
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Ke Chen, ping jin, Hong-hui He, Yan-hong Xie, Xiao-yun Xie, Zhao-hui Mo
Journal of Biomedical Science.2011;[Epub] CrossRef
Association of glycemic variability and the presence and severity of coronary artery disease in patients with type 2 diabetes
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Cardiovascular Diabetology.2011;[Epub] CrossRef
Lithospermic acid B protects beta-cells from cytokine-induced apoptosis by alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2–HO-1 and Sirt1
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Regulatory Peptides.2011;[Epub] CrossRef

Cloning of Novel Epidermal Growth Factor (EGF) Plasmid for Gene Therapy on Diabetic Foot Ulcer.: Hye Sook Chung, Chang Shin Yoon, Min Jeong Kwon, Mi Kyung Kim, Soon Hee Lee, Kyung Soo Ko, Byung Doo Rhee, Jeong Hyun Park; Korean Diabetes J. 2008;32(2):131-140. Published online April 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.2.131

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Abstract PDF

BACKGROUND
Epidermal Growth Factor (EGF) is one of the important growth factors involved in the epithelialization during cutaneous wound healing. Peptide EGF has been used for the treatment of diabetic foot ulcer. But the inferiority of cost-effectiveness and the inconvenience of daily application might have restricted its wide clinical usage. EGF gene therapy could dramatically improve the efficacy and inconvenience through long-term expression and bypassing the EGF degradation by hostile non-specific proteinases expressed in the wound bed. METHODS: EGF DNAs were amplified via PCR. For the more effective secretion from the transfected cell, we inserted furin cleavage site into EGF plasmids. The efficacy of novel plasmid pbeta-EGF was verified by transfection into the various animal cell lines, and the biologic potency of expressed EGF was confirmed via phosphorylation of PI3K and GSK3beta by Western blotting. RESULTS: We tested various kinds of human EGFs. One of the human EGF isoforms, EGF(828) including a membrane-anchoring domain was successfully released as the mature EGF protein in the cell culture media. Also EGF plasmid including furin cleavage site showed more than 2-fold increased EGF expression compared with the sequence without furin cleavage site. CONCLUSION: In conclusion, these findings suggest that mature EGF could be released easily out of cells by modifying EGF DNA sequence. Our novel EGF plasmid DNA could markedly increase the efficiency of non-viral gene therapy for diabetic foot ulcer.

Citations

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Effective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle vascular endothelial growth factor DNA and a cationic dendrimer
Min J. Kwon, Songhie An, Sunghyun Choi, Kihoon Nam, Hye S. Jung, Chang S. Yoon, Jung H. Ko, Hye J. Jun, Tae K. Kim, Soo J. Jung, Jeong H. Park, Yan Lee, Jong‐Sang Park
The Journal of Gene Medicine.2012; 14(4): 272. CrossRef

The Protective Effect of EGCG on INS-1 Cell in the Oxidative Stress and Mechanism.: Mi Kyung Kim, Hye Sook Jung, Chang Shin Yoon, Min Jeong Kwon, Kyung Soo Koh, Byung Doo Rhee, Jeong Hyun Park; Korean Diabetes J. 2008;32(2):121-130. Published online April 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.2.121

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Abstract PDF

BACKGROUND
Oxidative stress is important in both diabetic complications and the development and the progression of type 2 diabetes via the effects on the pancreatic beta-cells. EGCG (epigallocatechin galleate), a major constituent of green tea, has been known to have beneficial effects on various diseases through the mechanisms of antioxidant and cell signaling modulation. But, very small numbers of studies were published about the direct effects of EGCG on the pancreatic beta cell lines. We performed this study to see the protective effect of EGCG on pancreatic beta cell line under H2O2 and the mechanisms of this phenomenon. METHODS: We used INS-1 cells and hydrogen peroxide as an oxidative stressor. Their viabilities were verified by MTT assay and FACS. The activity of glutathione peroxidase was assessed by total glutathione quantification kit. Western blot and semi-quantitative RT-PCR for the catalase, SOD (superoxide dismutase), PI3K and Akt were performed. Functional status of INS-1 cells was tested by GSIS (glucose stimulated insulin secretion). RESULTS: The biological effects of EGCG were different according to its concentrations. 10 micrometer EGCG effectively protected hydrogen peroxide induced damage in INS-1 cells. The expression and the activity of SOD, catalase and the glutathione peroxidase were significantly increased by EGCG. EGCG significantly increased PI3K and Akt activity and its effect was inhibited partially by wortmannin. GSIS was well preserved by EGCG. CONCLUSION: EGCG in low concentration effectively protected INS-1 cells from the oxidative stress through the activation of both antioxidant systems and anti-apoptosis signaling. Further studies will be necessary for the more detailed mechanisms and the clinical implications.

Citations

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Suppressive Effects of Epigallocatechin Gallate Pretreatment on the Expression of Inflammatory Cytokines in RAW264.7 Cells Activated by Lipopolysaccharide
Eun Ji Seo, Jun Go, Ji Eun Kim, Eun Kyoung Koh, Sung Hwa Song, Ji Eun Sung, Chan Kyu Park, Hyun Ah Lee, Dong Seob Kim, Hong Joo Son, Cung Yeoul Lee, Hee Seob Lee, Dae Youn Hwang
Journal of Life Science.2015; 25(9): 961. CrossRef
The Protective Effects of Chrysanthemum cornarium L. var. spatiosum Extract on HIT-T15 Pancreatic β-Cells against Alloxan-induced Oxidative Stress
In-Hye Kim, Kang-Jin Cho, Jeong-Sook Ko, Jae-Hyun Kim, Ae-Son Om
The Korean Journal of Food And Nutrition.2012; 25(1): 123. CrossRef
Protective Effects of Sasa Borealis Leaves Extract on High Glucose-Induced Oxidative Stress in Human Umbilical Vein Endothelial Cells
Ji-Young Hwang, Ji-Sook Han
Journal of the Korean Society of Food Science and Nutrition.2010; 39(12): 1753. CrossRef

Cytoprotective Effect by Antioxidant Activity of Quercetin in INS-1 Cell Line.: Min Jeong Kwon, Hye Sook Jung, Mi Kyung Kim, Seong Hoon Kang, Gwang Wook Seo, Jae Kwang Song, Tae Yeon Yoon, Min Kyeong Jeon, Tae Hwan Ha, Chang Shin Yoon, Mi Kyung Kim, Woo Je Lee, Jeong Hyun Noh, Soo Kyung Kwon, Dong Joon Kim, Kyung Soo Koh, Byung Doo Rhee, Kyung Ho Lim, Soon Hee Lee, Jeong Hyun Park; Korean Diabetes J. 2007;31(5):383-390. Published online September 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.5.383

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Abstract PDF

BACKGROUND
Oxidative stress is induced under diabetic conditions and causes various forms of tissue damages in the patients with diabetes. Recently, pancreatic beta cells are regarded as a putative target of oxidative stress-induced tissue damage, and this seems to explain in part the progressive deterioration of beta cell function in type 2 diabetes. The aim of this study was to examine the potential of Quercetin (QE) to protect INS-1 cells from the H2O2-induced oxidative stress and the effects of QE on the glucose-stimulated insulin secretion in INS-1 cells. METHODS: To study the cell viability, cells were incubated with H2O2 and/or QE at the various concentrations. To confirm the protective effect by QE in response to H2O2, the levels of antioxidant enzymes were assessed by RT-PCR and Western blot, and glutathione peroxidase activities were quantified by spectrophotometrical method. Glucose-stimulated insulin secretion (GSIS) was measured by ELISA. RESULTS: Cell incubations were performed with 80 microM of H2O2 for 5 hours to induce 40 - 50% of cell death. QE gradually showed protective effect (IC50 = 50 microM) in dose-dependent manner. Superoxide dismutase (SOD) mRNA level in H2O2 + QE group was increased as compared to H2O2 group, but catalase did not changed. And the QE recruited glutathione peroxidase activity against H2O2-induced oxidative injuries in INS-1 cells. CONCLUSION: In conclusion, these findings suggest that QE might have protective effect on beta cells by ameliorating oxidative stress and preserving insulin secretory function.

Citations

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Anti-diabetic effects of Allium tuberosum rottler extracts and lactic acid bacteria fermented extracts in type 2 diabetic mice model
Bae Jin Kim, Seung Kyeung Jo, Yoo Seok Jeong, Hee Kyoung Jung
Korean Journal of Food Preservation.2015; 22(1): 134. CrossRef
Protective Effects of Sasa Borealis Leaves Extract on High Glucose-Induced Oxidative Stress in Human Umbilical Vein Endothelial Cells
Ji-Young Hwang, Ji-Sook Han
Journal of the Korean Society of Food Science and Nutrition.2010; 39(12): 1753. CrossRef

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