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Generation of Insulin-Expressing Cells in Mouse Small Intestine by Pdx1, MafA, and BETA2/NeuroD
So-Hyun Lee, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
Diabetes Metab J. 2017;41(5):405-416.   Published online September 5, 2017
DOI: https://doi.org/10.4093/dmj.2017.41.5.405
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  • 5 Web of Science
  • 5 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

To develop surrogate insulin-producing cells for diabetes therapy, adult stem cells have been identified in various tissues and studied for their conversion into β-cells. Pancreatic progenitor cells are derived from the endodermal epithelium and formed in a manner similar to gut progenitor cells. Here, we generated insulin-producing cells from the intestinal epithelial cells that induced many of the specific pancreatic transcription factors using adenoviral vectors carrying three genes: PMB (pancreatic and duodenal homeobox 1 [Pdx1], V-maf musculoaponeurotic fibrosarcoma oncogene homolog A [MafA], and BETA2/NeuroD).

Methods

By direct injection into the intestine through the cranial mesenteric artery, adenoviruses (Ad) were successfully delivered to the entire intestine. After virus injection, we could confirm that the small intestine of the mouse was appropriately infected with the Ad-Pdx1 and triple Ad-PMB.

Results

Four weeks after the injection, insulin mRNA was expressed in the small intestine, and the insulin gene expression was induced in Ad-Pdx1 and Ad-PMB compared to control Ad-green fluorescent protein. In addition, the conversion of intestinal cells into insulin-expressing cells was detected in parts of the crypts and villi located in the small intestine.

Conclusion

These data indicated that PMB facilitate the differentiation of mouse intestinal cells into insulin-expressing cells. In conclusion, the small intestine is an accessible and abundant source of surrogate insulin-producing cells.

Citations

Citations to this article as recorded by  
  • Harnessing gut cells for functional insulin production: Strategies and challenges
    Kelvin Baafi, John C. March
    Biotechnology Notes.2023; 4: 7.     CrossRef
  • Differential Morphological Diagnosis of Various Forms of Congenital Hyperinsulinism in Children
    Lubov Borisovna Mitrofanova, Anastasia Arkadyevna Perminova, Daria Viktorovna Ryzhkova, Anna Andreyevna Sukhotskaya, Vladimir Gireyevich Bairov, Irina Leorovna Nikitina
    Frontiers in Endocrinology.2021;[Epub]     CrossRef
  • Generation of iPSC-derived insulin-producing cells from patients with type 1 and type 2 diabetes compared with healthy control
    Min Jung Kim, Eun Young Lee, Young-Hye You, Hae Kyung Yang, Kun-Ho Yoon, Ji-Won Kim
    Stem Cell Research.2020; 48: 101958.     CrossRef
  • ERK Regulates NeuroD1-mediated Neurite Outgrowth via Proteasomal Degradation
    Tae-young Lee, In-Su Cho, Narayan Bashyal, Francisco J Naya, Ming-Jer Tsai, Jeong Seon Yoon, Jung-Mi Choi, Chang-Hwan Park, Sung-Soo Kim, Haeyoung Suh-Kim
    Experimental Neurobiology.2020; 29(3): 189.     CrossRef
  • Generation of a PDX1–EGFP reporter human induced pluripotent stem cell line, KSCBi005-A-3, using the CRISPR/Cas9 system
    Youngsun Lee, Hye Young Choi, Ara Kwon, Hyeyeon Park, Mi-Hyun Park, Ji-Won Kim, Min Jung Kim, Yong-Ou Kim, Sungwook Kwak, Soo Kyung Koo
    Stem Cell Research.2019; 41: 101632.     CrossRef
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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AbstractAbstract PDFPubReader   
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

Citations to this article as recorded by  
  • 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
Review
Cell Replacement and Regeneration Therapy for Diabetes
Hee-Sook Jun
Korean Diabetes J. 2010;34(2):77-83.   Published online April 30, 2010
DOI: https://doi.org/10.4093/kdj.2010.34.2.77
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AbstractAbstract PDFPubReader   

Reduction of beta cell function and a beta cell mass is observed in both type 1 and type 2 diabetes. Therefore, restoration of this deficiency might be a therapeutic option for treatment of diabetes. Islet transplantation has benefits, such as reduced incidence of hypoglycemia and achievement of insulin independence. However, the major drawback is an insufficient supply of islet donors. Transplantation of cells differentiated in vitro or in vivo regeneration of insulin-producing cells are possible approaches for beta cell/islet regenerative therapy. Embryonic and adult stem cells, pancreatic ductal progenitor cells, acinar cells, and other endocrine cells have been shown to differentiate into pancreatic beta cells. Formation of fully functional beta cells and the safety of these cells are critical issues for successful clinical application.

Citations

Citations to this article as recorded by  
  • The efficiency of stem cell differentiation into functional beta cells for treating insulin-requiring diabetes: Recent advances and current challenges
    Yunfei Luo, Peng Yu, Jianping Liu
    Endocrine.2024;[Epub]     CrossRef
  • Direct Reprogramming of Mice Skin Fibroblasts into Insulin-Producing CellsIn Vitro
    Israa S. Salman, Ahmed Majeed Al-Shammari, Mukhtar Khamis Haba
    Cellular Reprogramming.2022; 24(5): 271.     CrossRef
  • Effects of β-like cell autotransplantation through hepatic arterial intervention on diabetic dogs
    Yongxu Mu, Zhiming Hao, Junfeng He, Ruiqiang Yan, Haiyan Liu, Lei Zhang, Heming Liu, Xiaoyan Hu, Qiming Li
    Artificial Cells, Nanomedicine, and Biotechnology.2016; 44(5): 1333.     CrossRef
  • Meeting the Need for Regenerative Therapies I: Target-Based Incidence and Its Relationship to U.S. Spending, Productivity, and Innovation
    Nancy Parenteau, Janet Hardin-Young, William Shannon, Patrick Cantini, Alan Russell
    Tissue Engineering Part B: Reviews.2012; 18(2): 139.     CrossRef
  • Glucose-stimulated insulin secretion of various mesenchymal stem cells after insulin-producing cell differentiation
    Su-Jung Kim, Yong-Soo Choi, Eun-Sun Ko, Sang-Min Lim, Chang-Woo Lee, Dong-Il Kim
    Journal of Bioscience and Bioengineering.2012; 113(6): 771.     CrossRef
Original Articles
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
  • 4,041 View
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AbstractAbstract PDFPubReader   
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
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    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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    Eric Yuk Fai Wan, Colman Siu Cheung Fung, Daniel Yee Tak Fong, Cindy Lo Kuen Lam
    Journal of Diabetes and its Complications.2016; 30(7): 1240.     CrossRef
  • 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
  • Exercising for Metabolic Control: Is Timing Important
    Jonida Haxhi, Alessandro Scotto di Palumbo, Massimo Sacchetti
    Annals of Nutrition and Metabolism.2013; 62(1): 14.     CrossRef
  • Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats
    Yunli Yu, Xinting Wang, Can Liu, Dan Yao, Mengyue Hu, Jia Li, Nan Hu, Li Liu, Xiaodong Liu
    Toxicology and Applied Pharmacology.2013; 266(3): 375.     CrossRef
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    X. Ye, X. Cheng, L. Liu, D. Zhao, Y. Dang
    Clinical and Experimental Dermatology.2013; 38(5): 530.     CrossRef
  • 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
  • Overexpression of Insig-1 protects β cell against glucolipotoxicity via SREBP-1c
    Ke Chen, ping jin, Hong-hui He, Yan-hong Xie, Xiao-yun Xie, Zhao-hui Mo
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    Toxicology and Applied Pharmacology.2011; 252(1): 47.     CrossRef
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    Wang Yanjun, Xiao Yue, Li Shixing
    Regulatory Peptides.2011;[Epub]     CrossRef
Protective Effects of Glucagon Like Peptide-1 on HIT-T15 beta Cell Apoptosis via ER Stress Induced by 2-deoxy-D-glucose.
Ju Young Kim, Seong Kyu Lee, Haing Woon Baik, Ki Ho Lee, Hyun Jin Kim, Kang Seo Park, Byung Joon Kim
Korean Diabetes J. 2008;32(6):477-487.   Published online December 1, 2008
DOI: https://doi.org/10.4093/kdj.2008.32.6.477
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AbstractAbstract PDF
BACKGROUND
The characteristic feature of pancreatic beta cells is highly developed endoplasmic reticulum (ER) due to a heavy engagement in insulin secretion. The ER serves several important function, including post-translational modification, folding, and assembly of newly synthesized secretory proteins, and its proper function is essential to cell survival. Various stress conditions can interfere with ER function. Pancreatic beta cells may be particularly vulnerable to ER stress that causes to impair insulin biosynthesis and beta cell survival through apoptosis. Glucagon like peptide-1 (GLP-1) is a new drug for treatment of type 2 diabetes and has effects on stimulation of insulin secretion and beta cell preservation. Also, it may have an antiapoptotic effect on beta cells, but detailed mechanisms are not proven. Therefore, we investigated the protective mechanism of GLP-1 in beta cells through ER stress response induced by 2-deoxy-D-glucose (2DG). METHODS: For induction of the ER stress, HIT-T15 cells (hamster beta cell line) were treated with 2DG (10 mM). Apoptosis was evaluated with MTT assay, hoechst 33342 staining and Annexin/PI flow cytometry. Expression of ER stress-related molecules was determined by real-time PCR or western blot. For blocking ER stress, we pretreated HIT-T15 cells with exendin-4 (Ex-4; GLP-1 receptor agonist) for 1 hour before stress induction. RESULTS: After induction with ER stress (2DG), beta cells were lost by apoptosis. We found that Ex-4 had a protective effect through ER stress related molecules (GRP78, GRP94, XBP-1, eIF2alpha, CHOP) modulation. Also, Ex-4 recovered the expression of insulin2 mRNA in beta cells. CONCLUSION: These results suggest that GLP-1 may protect beta cells apoptosis through ER stress modulation.

Citations

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  • Exendin-4 Protects Against Sulfonylurea-Induced β-Cell Apoptosis
    Ju-Young Kim, Dong-Mee Lim, Hyung-Seo Park, Chan-Il Moon, Kyung-Jin Choi, Seong-Kyu Lee, Haing-Woon Baik, Keun-Young Park, Byung-Joon Kim
    Journal of Pharmacological Sciences.2012; 118(1): 65.     CrossRef
  • GLP-1 Can Protect Proinflammatory Cytokines Induced Beta Cell Apoptosis through the Ubiquitination
    Dong Mee Lim, Ju Young Kim, Kang Woo Lee, Keun Young Park, Byung Joon Kim
    Endocrinology and Metabolism.2011; 26(2): 142.     CrossRef
  • Exendin-4 Protects Oxidative Stress-Induced β-Cell Apoptosis through Reduced JNK and GSK3β Activity
    Ju-Young Kim, Dong-Mee Lim, Chan Il Moon, Kyung-Jin Jo, Seong-Kyu Lee, Haing-Woon Baik, Ki-Ho Lee, Kang-Woo Lee, Keun-Young Park, Byung-Joon Kim
    Journal of Korean Medical Science.2010; 25(11): 1626.     CrossRef
Review
Glucose Toxicity and Pancreatic Beta Cell Dysfunction in Type 2 Diabetes.
Kyu Chang Won, Ji Sung Yoon
Korean Diabetes J. 2008;32(3):175-181.   Published online June 1, 2008
DOI: https://doi.org/10.4093/kdj.2008.32.3.175
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AbstractAbstract PDF
The adverse effects of prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations (i.e. glucose toxicity) is mediated at least in part by glucose oxidation and the subsequent generation of reactive oxygen species (ROS) that can impair insulin gene expression and beta cell function. Multiple biochemical pathways and mechanisms of action for glucose toxicity have been suggested. These include glucose autoxidation, protein kinase C activation, methylglyoxal formation and glycation, hexosamine metabolism, sorbitol formation, and oxidative phosphorylation. There are many potential mechanisms whereby excess glucose metabolites traveling along these pathways might cause beta cell damage. However, all these pathways have in common the formation of reactive oxygen species that, in excess and over time, cause chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. The intracellular peroxide levels of the pancreatic islets (INS-1 cells, rat islets) by flow cytometry were increased in the high glucose media compared to 5.6 mM glucose media. The insulin, MafA, PDX-1 mRNA levels and glucose stimulated insulin secretion (GSIS) were decreased in high glucose media compared to 5.6 mM glucose media. The HO-1 seems to mediate the protective response of pancreatic islets against the oxidative stress that is due to high glucose conditions. Also, we observed decreased glutathione level, gamma-GCS expression and increased oxidized LDL, malondialdehyde level at leukocytes and mesothelial cells from patients with Korean Type 2 Diabetes (esp, poorly controlled patients). In conclusion, this pathophysiologic sequence sets the scene for considering antioxidant therapy as an adjunct in the management of diabetes, especially type 2 Diabetes.

Citations

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  • Factors That Influence Pancreatic Beta Cell Function and Insulin Resistance in Newly Diagnosed Type 2 Diabetes Patients: A Sub-Analysis of the MARCH Trial
    Yan Duan, Jia Liu, Yuan Xu, Ning Yang, Wenying Yang, Guang Wang
    Diabetes Therapy.2018; 9(2): 743.     CrossRef
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    Min-Ki Lee, Jin-Hwan Yoon
    The Korean Journal of Physical Education.2017; 56(3): 551.     CrossRef
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    Jin Ook Chung, Dong Hyeok Cho, Dong Jin Chung, Min Young Chung
    Endocrinology and Metabolism.2010; 25(2): 110.     CrossRef
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    Journal of Life Science.2009; 19(4): 492.     CrossRef
Original Articles
Differentiation of Pancreatic beta Cells from Human Pancreatic Duct Cells Derived from a Partial Pancreas Tissue.
Ki Ho Song, Myung Mee Kim, Min Kyung Lee, Gyeong Ryul Ryu, Seung Hyun Ko, Sung Dae Moon, Yu Bae Ahn, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Hyung Min Chin
Korean Diabetes J. 2007;31(3):236-242.   Published online May 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.3.236
  • 2,075 View
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  • 1 Crossref
AbstractAbstract PDF
BACKGROUND
Despite a recent breakthrough in human islet transplantation for treating diabetes mellitus, the limited availability of insulin-producing tissue is still a major obstacle. This has led to a search for alternative sources of transplantable insulin-producing cells including pancreatic duct cells. We aimed to establish in vitro culture of pancreatic duct cells from a partial pancreas tissue in human, which could be harnessed to differentiate into pancreatic beta cells. METHODS: We isolated pancreatic duct cells from small pieces of pancreas tissue (1~3 g) derived from non-diabetic humans (n = 8) undergoing pancreatic surgery due to cancer. Pancreas tissue was finely minced after injection of collagenase P into the parenchyma. The mince was incubated in a shaking water bath at 37degrees C for 25 min and passed through a 150 micrometer mesh. The released cells were recovered, washed, and plated in a dish containing CMRL culture medium with serum. RESULTS: Isolated pancreatic cells grew in monolayer and became confluent in 1~2 wks showing typical epithelial cobblestone morphology. Immunochemistry demonstrated that ~90% of the cultured cells were cytokeratin7-positive duct cells. To induce beta cell differentiation, the cells were incubated in DMEM/F12 culture medium without serum. In addition, treatment with Matrigel overlay, exendin-4, cholera toxin or forskolin was done. Though beta cell differentiation was found by immunostaining and RT-PCR, the differentiation efficiency was very low. Over-expression of neurogenin-3 by recombinant adenovirus did not increase beta cell differentiation of the cultured duct cells significantly. CONCLUSION: We established in vitro culture of pancreatic duct cells from a partial pancreas tissue in human, which differentiate into pancreatic cells. However, a strategy to optimize beta cell differentiation in this model is needed.

Citations

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  • 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 Journal.2009; 33(6): 475.     CrossRef
Proliferation and Differentiation of Pancreatic beta Cells in L-type Calcium Channel alpha(1D) Subunit (Ca(v)1.3) Heterozygous Knock Out Mice After Partial Pancreatectomy.
Yoon Hee Choi, Il Hee Yun, Sun Hee Suh, Dong Jun Lim, Jae Hyuung Cho, Hyuk Sang Kwon, Bong Yun Cha, Ho Young Son, Chung Gyu Park, Kun Ho Yoon
Korean Diabetes J. 2007;31(3):208-219.   Published online May 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.3.208
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AbstractAbstract PDF
BACKGROUND
S: L-type voltage-dependent calcium channel (LTCC) plays a crucial role in insulin secretion from pancreatic beta cells through Ca2+ influx. In the recent report, LTCC Ca(v)1.3 subtype homozygous knock out mice showed impairment of postnatal pancreatic beta cell development as well as insulin secretion. METHODS: We performed 90% partial pancreatectomy in heterozygous Ca(v)1.3 knock out mice to investigate the effect of partial deficiency of Ca(v)1.3 gene on beta cell regeneration in the adult. Glucose homeostasis, metabolic profiles including serum insulin and lipid levels and morphologic changes of pancreatic islets were studied. RESULTS: 90% Partial pancreatectomy induced glucose intolerance only in the heterozygous knock out mice at 8 weeks after surgery. Distribution of islet size was significantly different between two groups after partial pancreatectomy; median value of islet size of heterozygote was larger than that of wild type (642.8 micrometer2 vs 1459.8 micrometer2, P < 0.01). The frequency of single beta cell unit, considered as a unit of beta cell neogenesis, was much lower in heterozygote than that of wild type (41% vs 23.3%, P < 0.05). CONCLUSION: These data suggest that Ca(v)1.3 gene deficiency is specifically associated with impairment of beta cell regeneration, especially neogensis and eventual glucose intolerance in the 90% partial pancreatectomized mice.
Review
The Roles of Clusterin on Morphogenesis of Beta Cells During Pancreas Regeneration.
Seok Woo Hong, KC Ranjan, Song Lee, Yong Jae Shin, Bon Hong Min, In Sun Park
Korean Diabetes J. 2007;31(1):1-8.   Published online January 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.1.1
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AbstractAbstract PDF
Clusterin is a highly glycosylated heterodimeric glycoprotein that plays diverse biological roles in various organs. The secreted clusterin has been established as a major form of the protein that exerts diverse tissue effects. For instance, clusterin is known to act in cell protection through the actions of extra-cellular molecular chaperones. In the extracellular milieu, clusterin participates in specific interactions with a diverse array of native biological molecules including LRP-2 (Lipoprotein receptor-related protein 2, also known as gp330 or megalin), which is involved in ligand endocytosis at the surfaces of certain epithelia. Clusterin is expressed transiently in developing and differentiating endocrine pancreatic cells and might be involved in pancreas development. This transient expression of clusterin at specific time points of pancreas development and cell differentiation during pancreas regeneration implies that the protein is a regulatory factor for cytodifferentiation as well as for replication. A specific action of the clusterin in the reconstruction and remodeling of the endocrine pancreas has been demonstrated. It also strongly stimulates duct cell differentiation into insulin-secreting cells under in vitro culture conditions. Clusterin appears thus as a potent regulator of insulin cell morphogenesis.

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  • Effect of African Mango (Irvingia gabonesis, IGOB 131TM) Extract on Glucose Regulation in STZ-Induced Diabetes
    Yejin Ha, Minhee Lee, Han Ol Kwon, Yoo-Hyun Lee
    Journal of the Korean Society of Food Science and Nutrition.2015; 44(11): 1607.     CrossRef
Original Articles
Role of Glucocorticoid Receptor on Insulin Secretion and Synthesis in INS-1 Cells.
Ju Yeon Yang, Myong Su Kang, Tak Ho Song, In Kook Jeong, Pyong Ju Seo, Hee Jin Kim
Korean Diabetes J. 2006;30(6):428-434.   Published online November 1, 2006
DOI: https://doi.org/10.4093/jkda.2006.30.6.428
  • 1,657 View
  • 25 Download
AbstractAbstract PDF
BACKGROUND
Glucocorticoids play important roles in the regulation of glucose homeostasis. It is well known that glucocorticoids reduce hepatic and peripheral tissue sensitivity to insulin, but the roles of glucocorticoids on insulin secretion and synthesis in pancreatic beta cells are still unclear. We have investigated the direct effects of glucocorticoids on insulin secretion and synthesis in rat insulinoma (INS-1) cells. METHODS: Insulin content and 11.2 mM glucose-stimulated insulin secretion (GSIS) were measured in INS-1 cells after culture with or without 1 micrometer dexamethasone (DEX). Preproinsulin mRNA levels were analyzed by real-time RT-PCR and normalized to the internal control. Effect of RU486 on DEX-induced inhibition of GSIS and preproinsulin mRNA synthesis was evaluated. RESULTS: Insulin content of INS-1 cells cultured in RPMI containing 11.2 mM glucose in the presence of DEX was not different from that of control cells. After 1-h preincubation in 2.8 mM glucose, basal insulin secretion from cells treated with DEX did not differ from that of controls, but GSIS was significantly reduced in the cells treated with DEX in comparison to control cells. The expression of preproinsulin mRNA relative to beta-actin mRNA was also lower in the cells treated with DEX. Glucocorticoid receptor antagonist improved DEX-induced inhibition of GSIS and preproinsulin mRNA synthesis. CONCLUSION: DEX inhibited GSIS and preproinsulin mRNA synthesis in INS-1 cells. Glucocorticoid receptor antagonist ameliorated the reduced GSIS and preproinsulin mRNA synthesis induced by DEX.
Taurine-Mediated Restoration of Glucose Sensitivity of Pancreatic Beta Cells in OLETF Rats.
So Yeon Kim, Keun Gyu Park, In Kyu Lee, Seong Il Nam, Dae Kyu Song
Korean Diabetes J. 2005;29(3):198-205.   Published online May 1, 2005
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BACKGROUND
An OLETF(Otsuka Long-Evans Tokushima Fatty) rat is a model of type 2 diabetes that is characterized by obesity-induced insulin resistance. Taurine has been known to be beneficial for type 2 diabetes. This study evaluated the potential taurine effect on the insulin response to high glucose in the islets of OLETF rats. METHODS: One percent of taurine was put in the drinking water for the taurine group of OLETF rats at the time of their being 20 to 39 weeks of age. At 40 weeks, the pancreatic islets and beta cells were obtained to measure the glucose-stimulated insulin secretion(GSIS) and the ATP-sensitive K+(KATP) channel current. RESULTS: Taurine supplementation had no effect on the weight change of the rats when this was measured weekly from 20 to 39 weeks(mean+/-SE: 702+/-19g in the control group vs. 688+/-18g in the taurine group at the 39th week). However, the GSIS was significantly potentiated in the taurine-treated rats(8.9+/-1.3% vs. 13.2+/-3.2% of the total secreted at 15 mM glucose for 1h). The glucose-induced KATP channel inhibition in the beta cells was also greater in the taurine group. CONCLUSION: Taurine supplementation is a beneficial tool for the restoration of GSIS in the pancreatic islet of the OLETF rats. Maintenance of blood taurine level may be important in treating type 2 diabetic patients, who are subject to a low blood level of taurine
Mitogenic Effects and Signaling Pathway of Insulin-Like Growth Factor-I (IGF-I) in the Rat Beta Cell Line (INS-1).
In Kyung Jeong, Ja Young Kim, Hyung Joon Yoo, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
Korean Diabetes J. 2004;28(6):478-489.   Published online December 1, 2004
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BACKGROUND
Nutrients and growth factors are known to stimulate pancreatic beta cell mitogenesis. IGF-I acts as a survival factor by limiting apoptosis and stimulating proliferation in many cell types. However, the appropriate mitogenic signaling pathways have not been defined. The aim of this study is to elucidate the mitogenic effect and signaling pathways of IGF-I in the rat beta cell line (INS-I). METHODS: The studies were performed using the rat pancreatic beta cell line, INS-1. INS-1 cells were cultured in RPMI 1640 containing serum-free, 0.2% BSA and 11.1 mmol/L glucose media for 24 hours, and the cells were then treated with IGF-I and different concentrations of glucose or tyrosine phosphorylation inhibitors, or insulin. The cell proliferation was measured by the [3H]thymidine uptake and MTT assay. The cell cycle was analyzed by a flow cytometer by using propidium iodide staining. Western blot analyses were performed using antibodies against PY20 and phospho-MAPK. RESULTS: 1) MTT assay and the [3H]thymidine uptake showed that IGF-I stimulated the INS-1 cell proliferation in a dose dependent manner. Glucose was noted to independently increase the INS-1 cell proliferation. A combination of IGF-I and glucose has a synergistic effect on the proliferation of INS-I cells. Insulin did not influence on the mitogenic effect of IGF-I. 2) The S fraction of INS-1 cells treated with IGF-I was increased in a dose dependent manner. IGF-I stimulated the exit from G1 into the S phase of the cell cycle. 3) Investigation of the role of the PI3K and MAPK, by using of the inhibitors LY294002, wortmannin, and PD98059, demonstrated that the activation of MAPK, but not PI3K, required to stimulate the proliferation of INS-1 cells. 4) IGF-I stimulated the phosphorylation activation of pp60 and phospho-MAPK in the INS-1 cells. IGF-I induced the beta cell proliferation, and this was mediated via a signaling mechanism that was facilitated by MAPK. CONCLUSION: The proliferative effect of IGF-I on pancreatic beta cell seems to be mediated through MAPK signaling pathway.
Effects of Peroxisome Proliferator-activated Receptor-gamma(PPARgamma) on the Pancreatic beta Cell Proliferation.
Jung Hyun Noh, Tae Young Yang, In Kyung Jeong, Jae Hun Chung, Yong Ki Min, Myung Shik Lee, Kwang Won Kim, Moon Kyu Lee
Korean Diabetes J. 2003;27(3):241-252.   Published online June 1, 2003
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BACKGROUND
The effects and mechanisms of PPARgamma ligands on the cell proliferation in pancreatic beta cells were examined. METHODS: PPARgamma 1 cDNA was overexpressed in INS-1 cells using an adenoviral vector. The cell proliferations were measured by the MTT assay method, following the treatments with troglitazone (TGZ), rosiglitazone (RGZ), 15d-prostaglandin J2 (15d-PGJ2) or retinoic acid (RA), at increasing doses, in INS-1 and PPARgamma overexpressed INS-1 cells. The apoptosis, telomere length and cell cycles were determined after the PPARgamma ligand treatment. RESULTS: The long-term incubation, with PPARgamma ligands over 24 hr, inhibited the INS-1 cell proliferation rate. Apoptosis was not observed with the PPARgamma ligand treatment. G1 cell cycle arrest was observed with the troglitazone treatment. The telomere length remained unchanged following the TGZ treatment. The basal cell proliferation rate was unaffected by the overexpression of PPARgamma . After 48 h of TGZ treatment, the proliferation of the INS-1 cells was inhibited, in a dose- dependent manner, both with and without the overexpression. Moreover, the degree of inhibition was exaggerated in the PPARgamma overexpressed cells compared to beta gal overexpressed cells. CONCLUSION: PPARgamma ligands have direct inhibitory effects on the proliferation of INS-1 cells. Although the basal cell proliferation rate was not affected by PPARgamma overexpression, the PPARgamma overexpression and PPARgamma ligands have a synergistic inhibitory effect on the cell proliferation rate in pancreatic beta cells. G1 cell cycle arrest may be involved in the reduction of cell proliferation due to PPARgamma ligands.
Effect of Leptin on Alteration of beta-cell Mass in Rat Pancreas.
Seong Bin Hong, Yu Mi Han, Young Ju Park, Yun Joo Oe, Sung Ki Kim, Yoe Joo Kim, Moon Suk Nam, Yong Seong Kim, In Sun Park
Korean Diabetes J. 2002;26(4):253-264.   Published online August 1, 2002
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BACKGROUND
Diabetes mellitus can occur when insulin secretion and action are inadequate in relation to blood glucose level. Several experiments recently reported that leptin and pancreatic beta-cells have functional axis to interact each other. The present study was aimed to investigate the role of leptin on regulation of beta-cell mass during neonatal period when they show a dynamic growth. METHOD: Leptin was injected intraperitoneally to rat neonates for 7 days from the second day after birth. Using the pancreas of the rat pups, immunohistochemical stain, in-situ hybridization and northern blot for insulin were done for analysis of beta-cell mass as well as for insulin synthesis and secretion. In addition, PCNA (proliferating cell nuclear antigen) was examined to assess the effect of leptin on islet cell proliferation. RESULT: 1) The weight gain and blood glucose levels showed no significant difference between leptin injected groups (0.1 mg/kg, 0.5 mg/kg) and control one. 2) The weights of pancreas were not different between both group. 3) Pancreatic islets of rat who received leptin 0.5 mg/kg were reduced in area and number than those of normal pups. They also showed the decreased beta-cell number per islet compared with control as well as leptin 0.1 mg/kg injected groups (59+/-49 vs 47+/-31 vs 31+/-21 per islet, p<0.05). 4) The beta-cell mass of rat who received leptin 0.5 mg/kg decreased but there was no significant difference. 5) The mRNA expressions of insulin were not different among control, leptin 0.1 mg/kg and leptin 0.5 mg/kg group. 6) The expression of PCNA as a proliferation marker showed no difference between control and leptin injected group. CONCLUSION: These results reflected that leptin negatively regulated neonatal islet cell growth occurring in normal rat pups, and resulted to relative decrease of beta-cell number compared to the untreated control. We, therefore, suggest that leptin may play the important role in beta-cell mass during neonatal period.
The Effect of Long-term Treatment of Ramipril on Glucose Tolerance and Pancreatic Islets in Type 2 Diabetes Animal Model (OLETF Rats).
Seung Hyun Ko, Kun Ho Yoon, Myung Mi Kim, Yu Bae Ahn, Ki Ho Song, Soon Jib Yoo, Hyun Shik Son, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang
Korean Diabetes J. 2001;25(6):469-482.   Published online December 1, 2001
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BACKGROUND
In a Heart Outcomes Prevention Evaluation HOPE study, ramipril, a long- acting angiotensin-converting enzyme (ACE) inhibitor, significantly reduced the death rates the number of myocardial infarctions, strokes, heart failure as well as the risk of complications related to diabetes and of diabetes itself. However, it is known that ACE inhibitors improve glucose tolerance or insulin sensitivity or reduce the incidence of diabetes. METHODS: 24 week-old OLETF (Otsuka Long Evans Tokushima Fatty) rats weighing 400~450 g were used in this study. 4 groups of rats were examined in parallel for 40 weeks. The OLETF rats were randomized for treatment with an aqueous solution of ramipril ( 5mg/Kg) daily [OL (RMP), n=10)] and with saline [OL(CON), n=10)]. The LETO rats were also randomized in the same was as the OLETF rats (LT (RMP), n=10, LT (CON), n=10). The blood glucose level, body weight, systolic and diastolic blood pressure was assessed every month. At 3 and 6 months, the 24hrs urinary protein concentration was measured, and as insulin tolerance test and oral glucose tolerance test were conducted in all experimental groups. After 6 months, the body weight was matched for 2 months in each corresponding group. Subsequently, a 15% sucrose loading was done for 2 months. After the glucose tolerance test, the pancreas was excised and immunohistochemical staining was conducted for insulin to quantify the beta cell mass by a point-counting method. In addition, the islet morphology was evaluated in the pancreas. RESULTS: Ramipril treatment for a period of 6 months improved the 2hr blood glucose level, the area under the glucose curve in the oral glucose tolerance test, insulin sensitivity in addition to lowering significantly systolic and diastolic blood pressure and 24hrs urinary protein level significantly in OLETF rats. Of note, a lower weight gain was observed in both the ramipril-treated animals at 6 months. After weight matching, the AUCg and 2hr blood glucose level values were similar between the corresponding groups, but a 15% sucrose loading worsened the AUCg value. Histologically, the islets were less disorganized and the extent of fibrosis was lower in the ramipril- treated OLETF rats in the trichrome stain. CONCLUSION: Long-term treatment of ramipril, a long acting angiotensin-converting enzyme inhibitor may be useful for suppressing weight gain and proteinuria in addition to having aprotective effect on the islet to harmful stimuli such as hyperglycemia.

Diabetes Metab J : Diabetes & Metabolism Journal
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