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Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea
Byung-Joon Kim, Jun-Seop Shin, Byoung-Hoon Min, Jong-Min Kim, Chung-Gyu Park, Hee-Jung Kang, Eung Soo Hwang, Won-Woo Lee, Jung-Sik Kim, Hyun Je Kim, Iov Kwon, Jae Sung Kim, Geun Soo Kim, Joonho Moon, Du Yeon Shin, Bumrae Cho, Heung-Mo Yang, Sung Joo Kim, Kwang-Won Kim
Received August 7, 2023  Accepted January 17, 2024  Published online May 21, 2024  
DOI:    [Epub ahead of print]
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans.
A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness.
A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.
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Association of Muscle Mass Loss with Diabetes Development in Liver Transplantation Recipients
Sejeong Lee, Minyoung Lee, Young-Eun Kim, Hae Kyung Kim, Sook Jung Lee, Jiwon Kim, Yurim Yang, Chul Hoon Kim, Hyangkyu Lee, Dong Jin Joo, Myoung Soo Kim, Eun Seok Kang
Diabetes Metab J. 2024;48(1):146-156.   Published online January 3, 2024
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Post-transplant diabetes mellitus (PTDM) is one of the most significant complications after transplantation. Patients with end-stage liver diseases requiring transplantation are prone to sarcopenia, but the association between sarcopenia and PTDM remains to be elucidated. We aimed to investigate the effect of postoperative muscle mass loss on PTDM development.
A total of 500 patients who underwent liver transplantation at a tertiary care hospital between 2005 and 2020 were included. Skeletal muscle area at the level of the L3–L5 vertebrae was measured using computed tomography scans performed before and 1 year after the transplantation. The associations between the change in the muscle area after the transplantation and the incidence of PTDM was investigated using a Cox proportional hazard model.
During the follow-up period (median, 4.9 years), PTDM occurred in 165 patients (33%). The muscle mass loss was greater in patients who developed PTDM than in those without PTDM. Muscle depletion significantly increased risk of developing PTDM after adjustment for other confounding factors (hazard ratio, 1.50; 95% confidence interval, 1.23 to 1.84; P=0.001). Of the 357 subjects who had muscle mass loss, 124 (34.7%) developed PTDM, whereas of the 143 patients in the muscle mass maintenance group, 41 (28.7%) developed PTDM. The cumulative incidence of PTDM was significantly higher in patients with muscle loss than in patients without muscle loss (P=0.034).
Muscle depletion after liver transplantation is associated with increased risk of PTDM development.
Basic Research
Differentiation of Microencapsulated Neonatal Porcine Pancreatic Cell Clusters in Vitro Improves Transplant Efficacy in Type 1 Diabetes Mellitus Mice
Gyeong-Jin Cheon, Heon-Seok Park, Eun-Young Lee, Min Jung Kim, Young-Hye You, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
Diabetes Metab J. 2022;46(5):677-688.   Published online February 7, 2022
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  • 256 Download
  • 2 Web of Science
  • 2 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Neonatal porcine pancreatic cell clusters (NPCCs) have been proposed as an alternative source of β cells for islet transplantation because of their low cost and growth potential after transplantation. However, the delayed glucose lowering effect due to the immaturity of NPCCs and immunologic rejection remain as a barrier to NPCC’s clinical application. Here, we demonstrate accelerated differentiation and immune-tolerant NPCCs by in vitro chemical treatment and microencapsulation.
NPCCs isolated from 3-day-old piglets were cultured in F-10 media and then microencapsulated with alginate on day 5. Differentiation of NPCCs is facilitated by media supplemented with activin receptor-like kinase 5 inhibitor II, triiodothyronine and exendin-4 for 2 weeks. Marginal number of microencapsulated NPCCs to cure diabetes with and without differentiation were transplanted into diabetic mice and observed for 8 weeks.
The proportion of insulin-positive cells and insulin mRNA levels of NPCCs were significantly increased in vitro in the differentiated group compared with the undifferentiated group. Blood glucose levels decreased eventually after transplantation of microencapsulated NPCCs in diabetic mice and normalized after 7 weeks in the differentiated group. In addition, the differentiated group showed nearly normal glucose tolerance at 8 weeks after transplantation. In contrast, neither blood glucose levels nor glucose tolerance were improved in the undifferentiated group. Retrieved graft in the differentiated group showed greater insulin response to high glucose compared with the undifferentiated group.
in vitro differentiation of microencapsulated immature NPCCs increased the proportion of insulin-positive cells and improved transplant efficacy in diabetic mice without immune rejection.


Citations to this article as recorded by  
  • Dual-targeted nano-encapsulation of neonatal porcine islet-like cell clusters with triiodothyronine-loaded bifunctional polymersomes
    Sang Hoon Lee, Minse Kim, Eun-Jin Lee, Sun Mi Ahn, Yu-Rim Ahn, Jaewon Choi, Jung-Taek Kang, Hyun-Ouk Kim
    Discover Nano.2024;[Epub]     CrossRef
  • Long‐term efficacy of encapsulated xenogeneic islet transplantation: Impact of encapsulation techniques and donor genetic traits
    Heon‐Seok Park, Eun Young Lee, Young‐Hye You, Marie Rhee, Jong‐Min Kim, Seong‐Soo Hwang, Poong‐Yeon Lee
    Journal of Diabetes Investigation.2024; 15(6): 693.     CrossRef
Short Communication
Islet Studies and Transplantation
Alginate-Catechol Cross-Linking Interferes with Insulin Secretion Capacity in Isolated Murine Islet Cells
Yu-Sik Kim, Seung-Woo Cho, Bomin Ko, Jisoo Shin, Chul Woo Ahn
Diabetes Metab J. 2018;42(2):164-168.   Published online March 28, 2018
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  • 6 Web of Science
  • 6 Crossref
AbstractAbstract PDFPubReader   

Over the past three decades, human pancreatic islet isolation and transplantation techniques have developed as a routine clinical procedure for selected patients with type 1 diabetes mellitus. However, due to the donor shortage and required chronic systemic immunosuppression, the widespread application of islet transplantation is limited. To overcome these limitations, providing a physical barrier to transplanted islet cells with encapsulating biomaterial has emerged as a promising approach to enhance engraftment and promote islet survival post-transplantation. Alginate has been considered to be a reliable biomaterial, as it enhances islet survival and does not hamper hormone secretion. Alginate-catechol (Al-CA) hydrogel was reported to provide high mechanical strength and chemical stability without deformation over a wide range of pH values. In this study, we, demonstrated, for the first time in the literature, that encapsulation of murine pancreatic islet cells with Al-CA hydrogel does not induce cytotoxicity ex vivo for an extended period; however, it does markedly abate glucose-stimulated insulin secretion. Catechol should not be considered as a constituent for alginate gelation for encapsulating islet cells in the application of islet transplantation.


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    Luca Szabó, Sandrine Gerber-Lemaire, Christine Wandrey
    Polymers.2020; 12(4): 919.     CrossRef
  • Catechol-Functionalized Alginate Nanoparticles as Mucoadhesive Carriers for Intravesical Chemotherapy
    Nitjawan Sahatsapan, Tanasait Ngawhirunpat, Theerasak Rojanarata, Praneet Opanasopit, Prasopchai Patrojanasophon
    AAPS PharmSciTech.2020;[Epub]     CrossRef
Sulwon Lecture 2011
Post-Renal Transplant Diabetes Mellitus in Korean Subjects: Superimposition of Transplant-Related Immunosuppressant Factors on Genetic and Type 2 Diabetic Risk Factors
Hyun Chul Lee
Diabetes Metab J. 2012;36(3):199-206.   Published online June 14, 2012
  • 3,756 View
  • 31 Download
  • 9 Crossref
AbstractAbstract PDFPubReader   

Postrenal transplantation diabetes mellitus (PTDM), or new-onset diabetes after organ transplantation, is an important chronic transplant-associated complication. Similar to type 2 diabetes, decreased insulin secretion and increased insulin resistance are important to the pathophysiologic mechanism behind the development of PTDM. However, β-cell dysfunction rather than insulin resistance seems to be a greater contributing factor in the development of PTDM. Increased age, family history of diabetes, ethnicity, genetic variation, obesity, and hepatitis C are partially accountable for an increased underlying risk of PTDM in renal allograft recipients. In addition, the use of and kinds of immunosuppressive agents are key transplant-associated risk factors. Recently, a number of genetic variants or polymorphisms susceptible to immunosuppressants have been reported to be associated with calcineurin inhibition-induced β-cell dysfunction. The identification of high risk factors of PTDM would help prevent PTDM and improve long-term patient outcomes by allowing for personalized immunosuppressant regimens and by managing cardiovascular risk factors.


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  • Risk Factors Related to New-Onset Diabetes after Renal Transplantation in Patients of a High Complexity University Hospital in Colombia, 20 Years of Experience
    Guillermo E. Guzmán, Angela M. Victoria, Isabella Ramos, Alejandro Maldonado, Eliana Manzi, Juan F. Contreras-Valero, Liliana Mesa, Johanna Schweineberg, Juan G. Posada, Jorge I. Villegas, Luis A. Caicedo, Carlos E. Durán
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    Alireza Heidari
    Advanced Science, Engineering and Medicine.2020; 12(8): 1002.     CrossRef
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    Hisao Shimada, Junji Uchida, Shunji Nishide, Kazuya Kabei, Akihiro Kosoku, Keiko Maeda, Tomoaki Iwai, Toshihide Naganuma, Yoshiaki Takemoto, Tatsuya Nakatani
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    Danièle Dubois-Laforgue
    Néphrologie & Thérapeutique.2017; 13: S137.     CrossRef
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    Eugene Han, Myoung Soo Kim, Yu Seun Kim, Eun Seok Kang
    Metabolism.2016; 65(10): 1559.     CrossRef
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    Ana Laura Pimentel, Andrea Carla Bauer, Joíza Lins Camargo
    Clinica Chimica Acta.2015; 450: 327.     CrossRef
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    Eun Yeong Choe, Hye Jin Wang, Obin Kwon, Yongin Cho, Kyu Ha Huh, Myoung Soo Kim, Yu Seun Kim, Chul Woo Ahn, Bong Soo Cha, Hyun Chul Lee, Eun Seok Kang
    Transplantation.2014; 97(4): 419.     CrossRef
  • Statin therapy is associated with the development of new-onset diabetes after transplantation in liver recipients with high fasting plasma glucose levels
    Yongin Cho, Min Jung Lee, Eun Yeong Choe, Chang Hee Jung, Dong Jin Joo, Myoung Soo Kim, Bong Soo Cha, Joong-Yeol Park, Eun Seok Kang
    Liver Transplantation.2014; 20(5): 557.     CrossRef
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    J.Y. Choi, O.J. Kwon
    Transplantation Proceedings.2013; 45(8): 2892.     CrossRef
Clinical Allogeneic and Autologous Islet Cell Transplantation: Update
Shinichi Matsumoto
Diabetes Metab J. 2011;35(3):199-206.   Published online June 30, 2011
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  • 44 Download
  • 17 Crossref
AbstractAbstract PDFPubReader   

Islet cell transplantation is categorized as a β-cell replacement therapy for diabetic patients who lack the ability to secrete insulin. Allogeneic islet cell transplantation is for the treatment of type 1 diabetes, and autologous islet cell transplantation is for the prevention of surgical diabetes after a total pancreatectomy. The issues of allogeneic islet cell transplantation include poor efficacy of islet isolation, the need for multiple donor pancreata, difficulty maintaining insulin independence and undesirable side effects of immunosuppressive drugs. Those issues have been solved step by step and allogeneic islet cell transplantation is almost ready to be the standard therapy. The donor shortage will be the next issue and marginal and/or living donor islet cell transplantation might alleviate the issue. Xeno-islet cell transplantation, β-cell regeneration from human stem cells and gene induction of the naïve pancreas represent the next generation of β-cell replacement therapy. Autologous islet cell transplantation after total pancreatectomy for the treatment of chronic pancreatitis with severe abdominal pain is the standard therapy, even though only limited centers are able to perform this treatment. Remote center autologous islet cell transplantation is an attractive option for hospitals performing total pancreatectomies without the proper islet isolation facilities.


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    T.R. Lansberry, C.L. Stabler
    Advanced Drug Delivery Reviews.2024; 206: 115179.     CrossRef
  • Efficacy and safety of total pancreatectomy with islet autotransplantation: A clinical study in Japan
    Masayuki Shimoda, Daisuke Chujo, Toshiaki Kurokawa, Akitsu Kawabe, Nobuyuki Takahashi, Kyoji Ito, Koji Maruyama, Koya Shinohara, Kumiko Ajima, Yzumi Sugahara, Tadashi Takaki, Hiroshi Kajio, Mikio Yanase, Chihaya Hinohara, Makoto Tokuhara, Yukari Uemura, Y
    Journal of Diabetes.2021; 13(11): 940.     CrossRef
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    Appakalai N. Balamurugan, Deborah A. Elder, Maisam Abu-El-Haija, Jaimie D. Nathan
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    Sang-Man Jin, Kwang-Won Kim
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  • Feasibility of islet magnetic resonance imaging using ferumoxytol in intraportal islet transplantation
    Sang-Man Jin, Seung-Hoon Oh, Bae Jun Oh, Wooyoung Shim, Jin Myung Choi, Dongkyeom Yoo, Yong Hwa Hwang, Jung Hee Lee, Dong Yun Lee, Jae Hyeon Kim
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    Thomas C. Schulz, Holly Y. Young, Alan D. Agulnick, M. Josephine Babin, Emmanuel E. Baetge, Anne G. Bang, Anindita Bhoumik, Igor Cepa, Rosemary M. Cesario, Carl Haakmeester, Kuniko Kadoya, Jonathan R. Kelly, Justin Kerr, Laura A. Martinson, Amanda B. McLe
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Original Articles
Adenoviruses Expressing PDX-1, BETA2/NeuroD and MafA Induces the Transdifferentiation of Porcine Neonatal Pancreas Cell Clusters and Adult Pig Pancreatic Cells into Beta-Cells
Young-Hye You, Dong-Sik Ham, Heon-Seok Park, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
Diabetes Metab J. 2011;35(2):119-129.   Published online April 30, 2011
  • 3,659 View
  • 36 Download
  • 9 Crossref
AbstractAbstract PDFPubReader   

A limitation in the number of insulin-producing pancreatic beta-cells is a special feature of diabetes. The identification of alternative sources for the induction of insulin-producing surrogate beta-cells is a matter of profound importance. PDX-1/VP16, BETA2/NeuroD, and MafA overexpression have been shown to influence the differentiation and proliferation of pancreatic stem cells. However, few studies have been conducted using adult animal pancreatic stem cells.


Adult pig pancreatic cells were prepared from the non-endocrine fraction of adult pig pancreata. Porcine neonatal pancreas cell clusters (NPCCs) were prepared from neonatal pigs aged 1-2 days. The dispersed pancreatic cells were infected with PDX-1/VP16, BETA2/NeuroD, and MafA adenoviruses. After infection, these cells were transplanted under the kidney capsules of normoglycemic nude mice.


The adenovirus-mediated overexpression of PDX-1, BETA2/NeuroD and MafA induced insulin gene expression in NPCCs, but not in adult pig pancreatic cells. Immunocytochemistry revealed that the number of insulin-positive cells in NPCCs and adult pig pancreatic cells was approximately 2.6- and 1.1-fold greater than those in the green fluorescent protein control group, respectively. At four weeks after transplantation, the relative volume of insulin-positive cells in the grafts increased in the NPCCs, but not in the adult porcine pancreatic cells.


These data indicate that PDX-1, BETA2/NeuroD, and MafA facilitate the beta-cell differentiation of NPCCs, but not adult pig pancreatic cells. Therefore PDX-1, BETA2/NeuroD, and MafA-induced NPCCs can be considered good sources for the induction of pancreatic beta-cells, and may also have some utility in the treatment of diabetes.


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    Zhengcao Li, Xiaohong Liu, Chen Wang, Zhenyang Li, Bo Jiang, Ruifeng Zhang, Lu Tong, Youping Qu, Sheng He, Haifan Chen, Yafei Mao, Qingnan Li, Torsten Pook, Yu Wu, Yanjun Zan, Hui Zhang, Lu Li, Keying Wen, Yaosheng Chen
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    Yu Na Lee, Hye-Jin Yi, Eun Hye Seo, Jooyun Oh, Song Lee, Sarah Ferber, Teruo Okano, In Kyong Shim, Song Cheol Kim
    Stem Cell Research & Therapy.2021;[Epub]     CrossRef
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    Stem Cell Research.2020; 48: 101958.     CrossRef
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    Yaqin He, Xiaoliang Xie, Xiaoyan Li, Shikuo Rong, Yukui Li, Zhenhui Lu
    Journal of Biosciences.2019;[Epub]     CrossRef
  • 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
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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
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AbstractAbstract PDF
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 to this article as recorded by  
  • 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
Effects of Islet Transplantation on Endogenous beta-cell Regeneration after Partial Pancreatectomy in Rodents.
Hye Seung Jung, You Ran Ahn, Seung Hoon Oh, Jung Hwa Jung, Tae Hyun Kim, You Cheol Hwang, Mira Kang, Yongsuk Bae, Young seok Kim, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
Korean Diabetes J. 2007;31(2):113-122.   Published online March 1, 2007
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AbstractAbstract PDF
Islet transplantation is one of regimens supplying the deficient insulin in diabetes patients, but the effects of islet grafts on the changes of endogenous beta-cells are not clear. In the present study, we examined the changes of endogenous beta-cell mass after islet transplantation in partially pancreatectomized mice. METHODS: Balb/c mice were 70% pancreatectomized, transplanted with syngeneic islets (group IV), and were compared with pancreatectomized mice treated with insulin (group III) or no insulin (group II). Blood glucose levels and body weight were monitored. Remnant pancreas was obtained at 6 or 10 days after pancreatectomy, and immunohistochemical staining was done for the evaluation of beta-cell mass changes. RESULTS: Hyperglycemia and weight loss were induced after pancreatectomy. After islet transplantation or insulin treatment, blood glucose levels recovered to normal, and body weight started to increase. Plasma insulin levels were higher and beta-cell mass was larger in group IV than in group II (P < 0.05). Especially, the difference of beta-cell mass between them was more evident at 7 days as compared to at 3 day after transplantation. When compared to group III, group IV showed larger individual beta-cell area after 7 days and larger beta-cell mass after 3 days of islet transplantation (P < 0.05). CONCLUSION: These observations indicate that islet transplantation plays a role in enhancing remnant beta-cell regeneration after partial pancreatectomy in rodents.
PDX-1/VP16 Overexpression Induce the Transdifferentiation of Canine Adult Pancreatic Cells into Beta-cells.
Young Hye You, Sun Cheol Park, Seung Hwan Lee, Heon Seok Park, Dong Sik Ham, Marie Rhee, Ji Won Kim, Ki Ho Song, Kun Ho Yoon
Korean Diabetes J. 2007;31(1):51-62.   Published online January 1, 2007
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AbstractAbstract PDF
A major obstacle of islet transplantation is an inadequate supply of insulin-producing tissue. Ad-PDX-1/VP16 overexpression and Exendin-4 treatment have been proved the effects on differentiation and proliferation of pancreatic stem cells. But, the study is insufficient using adult animal pancreatic stem cells. METHODS: Pancreatic cells were prepared from the non-endocrine fraction of canine pancreases. This cells were cultivated free floating state and monolayer culture after dispersion. The floating pancreatic cells were transplanted under the kidney capsule of normoglycaemic nude mice. The dispersed pancreatic cells were infected with Ad-PDX-1/VP16 or Ad-GFP. After infection, those cells were transplanted of nude mice. After transplantation, mice were treated with either 1 nmol/kg exendin-4 or saline solution by intraperitoneal injection for 10 days. RESULTS: The relative volume of the beta-cells in the grafts of the free floating cultured pancreatic cells were 23.4 +/- 13.1% at two weeks and 5.2 +/- 2.0% at eight weeks. At two weeks after transplantation, the relative volume of insulin-positive cells in the grafts of dispersed pancreatic cells were 28 +/- 5.7%, 20.5 +/- 0.7% and 31 +/- 1.4% in control, GFP and PDX-1/VP16 treated groups respectively. At eight weeks after transplantation, the relative volume of insulin-positive cells in the grafts were 11.8 +/- 5.9%, 8 +/- 7.3% and 16.6 +/- 7.4% in control, GFP and PDX-1/VP16 treated groups respectively. Exendin-4 treatment didn't show any additive effects on transdifferentiation of pancreas stem cell into beta-cells. CONCLUSION: The expansion and transdifferentiation were not observed after the transplantation of the free floating cultured pancreatic cells. PDX-1/VP16 overexpression induces the transdifferentiation of adult pancreatic cells into beta-cells. However Exendin-4 treatment hasn't any effects on the expansion and transdifferentiation of the cells in the grafts.


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  • Generation of Functional Insulin-Producing Cells from Neonatal Porcine Liver-Derived Cells by PDX1/VP16, BETA2/NeuroD and MafA
    Dong-Sik Ham, Juyoung Shin, Ji-Won Kim, Heon-Seok Park, Jae-Hyoung Cho, Kun-Ho Yoon, Kathrin Maedler
    PLoS ONE.2013; 8(11): e79076.     CrossRef
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    Young-Hye You, Dong-Sik Ham, Heon-Seok Park, Marie Rhee, Ji-Won Kim, Kun-Ho Yoon
    Diabetes & Metabolism Journal.2011; 35(2): 119.     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 Journal.2009; 33(6): 475.     CrossRef
Inducible Nitric Oxide Synthase (iNOS) Expression in the Hypoxic Injury to Pancreatic Beta (MIN6) Cells.
Seung Hyun Ko, Seung Bum Kim, Kyung Ryul Ryu, Ji Won Kim, Yu Bai Ahn, Sung Dae Moon, Sung Rae Kim, Jung Min Lee, Hyuk Snag Kwon, Kun Ho Yoon, Ki Ho Song
Korean Diabetes J. 2006;30(5):336-346.   Published online September 1, 2006
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Islet transplantation is an alternative potential strategy to cure type 1 diabetes mellitus. However, two or more donors are usually needed for one recipient because a substantial part of the graft becomes nonfunctional due to several factors including hypoxia. Though hypoxic exposure of pancreatic beta cells has been reported to induce apoptotic cell death, the molecular processes involved in hypoxia-induced cell death are poorly understood. In type I diabetes, Nitric Oxide (NO) is known as an important cytokine, involved in the pathogenesis of beta cell dysfunction. Pancreatic beta cells are sensitive to the induction of inducible nitric oxide synthase (iNOS) when stimulated by TNF-a or IL-1beta. But contribution of iNOS in response to hypoxia is not yet fully understood. METHODS: Mouse insulinoma cells (MIN6) were incubated in an anaerobic chamber (75% N2/15% CO2/5% H2) for up to 12 hours. Cell viability was measured after AO/PI staining. Caspase-3 activation was also determined using Western blot analysis. Nitric Oxide (NO) release into culture medium was measured using a Griess reagent. The expression of iNOS and PDX-1 mRNA and iNOS protein was examined using real time PCR and Western blot analysis. RESULTS: Marked cell death was observed within 6 hours after hypoxic exposure of MIN6 cells (control, < 5%; 2 hr, 11.0+/-7.6%; 6 hr, 46.2+/-12.8%, P < 0.05). Immunoreactivity to activated caspase-3 was observed at 2, 4 and 6 hrs. NO production was increased in a time dependent manner. Expression of iNOS mRNA and protein was significantly increased at 4 and 6 hour after hypoxia. iNOS expression was confirmed by immunostaining. Of note, Pdx-1 mRNA expression was markedly attenuated by hypoxic treatment. Pretreatment with a selective iNOS inhibitor, 1400 W, significantly prevented beta cell death induced by hypoxic injury. CONCLUSION: Our data suggest that iNOS-NO play an important role in hypoxic injury to MIN6 cells. Therefore, iNOS-NO might be a potential therapeutic target for improving engraftment of the transplanted islets and suppression of iNOS would be helpful for prevention of beta cells damage to hypoxic injury.
The effects of mixed chimerism conducted by natural killer cell depletion with non myeloablation on islet allograft rejection.
Heon Seok Park, Seok Goo Cho, Chung Gyu Park, Oak Kee Hong, Ji Won Kim, Bo Ryung Kim, Kun Ho Yoon
Korean Diabetes J. 2006;30(1):54-63.   Published online January 1, 2006
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AbstractAbstract PDF
Because of the shortage of human pancreas and immunorejection, very small fraction of patients with type 1 diabetes can be treated with islet transplantation. The immune tolerance induction for overcoming the immume rejectin of trausplamted islets could be conducted by hematopoietic mixed chimerims with various invasive methods. The purpose of this study is to investigate the effect of mixed chimerims conducted by newly developed minimally invasive methods on islet allografts rejection in streptozotocin induced diabetic mice. METHODS: Recipient, Balb/c(H-2Kd) mice were injected intraperitoneally with anti- asialoGM1 antibody at one day before bone marrow transplantation. There were received total body irradiation at a dose of 500 cGy and followed by tail vein injection of the 2 x 10(7) T-cell depleted bone marrow cells from C57BL/6(H-2Kb). Mixed chimerism mice were determined by gDNA PCR of lymphocyte MHC class I gene (H-2K) on 21st day. Streptozotocin induced diabetic mixed chimera mice were received islet transplantation from bone marrow donors. Grafts, spleen and peripheral blood were obtained from the mixed chimera mice, and there were used by Immunohistochimeical staining, flow cytometric analysis and gDNA PCR on 21st day. RESULTS: The blood glucose levels of streptozotocin induced diabetic mice were normalized by transplantation of bone marrow donor islets and maintained during 30 days. After removal of first islet allografts, hyperglycemia was re-established. We could re-confirmed donor specific tolerance of transplanted islets by second transplantation of bone marrow donor islets. Normoglycemia was maintained during 21 days after second islet transplantation. Furthermore islet grafts from MHC-mismatched third party mice were immediately rejected. Flow cytometric analysis results suggest that the mixed chimerism mice were maintain during the whole study period. CONCLUSION: The mixed chimerism model conducted by newly developed and minimally invasive method effectively prevents the islet allo grafts rejection in STZ-induced mixed chimerism mice.
Effective Glycemic Control Achieved by the Transplantation of VEGF-Transfected Islets in STZ-induced Diabetic Mice.
Byung Wan Lee, Hee Young Chae, You Ran Ahn, Seung Hoon Oh, Ji Youn Kim, Yun Jae Chung, Sang Young Kim, Kyun Yung Cho, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
Korean Diabetes J. 2005;29(4):282-294.   Published online July 1, 2005
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AbstractAbstract PDF
Hypoxic damage is one of the major causes of early islet graft failure, and VEGF is known to play a crucial role in revascularization. We tried to evaluate whether the VEGF transgene in an islet graft can increase islet revascularization and; therefore, increase the survival rate of transplanted islets in order to achieve effective glycemic control in diabetic mice models using a non-viral cationic lipid reagent for gene delivery into non- dividing islet cells. METHODS: Human VEGF165 cDNA was transfected into Balb/c mice islets using Effectene, and the vascular neogenesis and glucose levels examined in the recipient syngeneic Balb/c mice. A minimal number of VEGF-transfected islets(100 IEQ/animal) were transplanted into STZ-induced diabetic mice. The recipient mice were classified into three groups: islet transplantation(IT) without intervention(IT-alone group, n=8), IT with an islets transduced rhoJDK-control vector(IT-rhoJDK group, n=8), and IT with an islets transduced rhoJDK-VEGF vector(IT-rhoJDK-VEGF group, n=8). RESULTS: The transfection efficiency was highest with 4microgram/microliter cDNA and 25microliter Effectene(1: 6 weight ratio), with satisfactory cell viability under these conditions. The overproductions of VEGF mRNA and proteins from the conditioned cells were confirmed. A minimal number of the VEGF-transfected islets(100 IEQ/animal) were transplanted into STZ-induced diabetic mice. The control of hyperglycemia in the IT-alone(0/8) and IT-rhoJDK groups(0/8) failed. However, complete abrogation of hyperglycemia and viable islets, and an increased vascularization of the VEGF-transfected grafts were identified in the renal capsules of the IT-rhoJDK-VEGF group(8/8). CONCLUSION: These studies support the utility of VEGF-transfected islet delivery using a cationic lipid reagent to achieve euglycemia with minimal islets via neovascularization.
Induction of Immune Tolerance by Macrochimerism: Preliminary Study for Overcome of Islet Allograft Rejection.
Oak Kee Hong, Sung Joo Kim, Chung Gyu Park, Chul Woo Chung, Hyuk Sang Kwon, Yoon Hee Choi, Bong Yun Cha, Ho Yong Son, Kun Ho Yoon
Korean Diabetes J. 2005;29(2):112-121.   Published online March 1, 2005
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AbstractAbstract PDF
Recently islet transplantation(TPx) has achieved remarkable results while it is not the ultimate solution yet because of a serious shortage of human pancreases, immune rejection and recurrence of autoimmunity. Immune tolerance induction is one of the ideal way for overcome the immune rejection and recurrence of autoimmunity after islet TPx. In this study, we tested the efficacy of the mixed chimerism conducted by minimally invasive regimens on induction of immune tolerance in allogenic skin transplantation model. METHODS: Busulfan(600microgram/mouse) was administered on day -1, and 0.1 mg monoclonal antibody against CD45RB and 0.5 mg monoclonal antibody against CD154 were administered intraperitoneally on days 0, 2, 4, and 6. We gave the C57BL/6 recipients either a standard-dose(2x107 bone marrow cells/mouse; SBMT-Ig) or a high-dose(20x107 bone marrow cells/mouse; HBMT-Ig) of bone marrow from BALB/c donors. After transplantation the, C57BL/ 6 recipients received BALB/c donor skin grafting on day 0. Untreated control animals in each group, both the SBMT and HBMT mice(without busulfan) were treated with marrow cells only, and they received transplanted skin grafts from the BALB/c donor on day 0. We monitored chimerism by flow cytometry and we monitored tolerance by skin grafting. RESULTS: Chimerism was significantly increased in all the groups and it peaked on day 56 after bone marrow transplantation. On day 56, chimerism in the peripheral blood did not significantly differ between the SBMT(15.0+/-3.6%) mice and the HBMT+Ig(15.3+/-6.5%) mice. Allogenic skin transplanted on the untreated mice was invariably lost within 20 days, with a mean survival time of 10.0+/-2.5 days for the SBMT mice and 13.3+/-4.9 days for HBMT mice. The skin survival rates were significantly greater for the SBMT+Ig mice(39.0+/-36.6days) and for the HBMT+Ig mice(79.9+/-43.6 days)(HBMT+Ig vs. SBMT P=0.006: HBMT+Ig vs. SBMT+Ig P=0.0087: HBMT+Ig vs. HBMT P=0.0093). Although three of the eight(37.5%) HBMT+Ig mice showed a high skin graft survival rate >120 days, the chimerism was 3.4+/-1.3% in the peripheral blood. In the HBMT+Ig mice, chimerism was higher in the thymus(8.05+/-9.7%) than in the peripheral blood and it was significantly higher than in the thymus of the HBMT mice(0.36+/-0.5%)(P< 0.05). CONCLUSIONS: These data shows that chimerism created by minimally invasive method with high-dose bone marrow and anti-CD45RB/CD154 antibody seems promissing way for prolongation of islet allograft survival
Induction of Tolerance to Complete Histocompatibility Mismatched Mice Islets through the Co-transplantation of Bone Marrow Cells in a Minimal Nonmyeloablative Condition.
Ji In Lee, Seung Hoon Oh, You Ran Ahn, Hee Young Chae, Byung Wan Lee, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
Korean Diabetes J. 2005;29(2):103-111.   Published online March 1, 2005
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AbstractAbstract PDF
Islet transplantation(IT) is a therapeutic approach that is used to prevent the dreaded diabetes complications that occur in those patients having an insulin deficient state. However, the requirement of undergoing a lifelong immunosuppressive regimen, along with the related side effects, to prevent rejection of the graft restricts this from being the preferred treatment for type 1 diabetes. One of the strategies to overcome these limitations is to induce tolerance induction and graft acceptance through the process of hematopoietic chimerism. In this study we investigated whether tolerance to MHC-disparate and minor-disparate islet allografts could be induced by the simultaneous transplantation of islets and bone marrow cells(BMCs) under a minimal nonmyeloablative conditioning state. METHODS: The donor and recipient mice are BALB/c(H-2b) and C57BL/6(H-2d) mice, respectively. The streptozotocin induced diabetic C57BL/6(H-2d) mice received only 500 islets from the BALB/c(H-2b) mice in group 1. The group 2 recipients were conditioned with anti- lymphocyte serum(ALS), and 100cGy total body irradiation(TBI), and they were given islet cells of the BALB/c(H-2b) mice, but the group 3 mice were simultaneously given 30x106 BALB/c(H-2b) mice BMCs and islet cells in same condition as group 2. The chimerism of donor derived cells was analyzed by flow cytometry(FACS). Daily monitoring of blood glucose and immunohistochemical staining of the transplanted islets were used to assess the islet graft rejection and the islets' function. RESULTS: We obtained 5~6% allogeneic donor chimerism and 60% of the grafts survived at 80 days after islet transplantation, Additionally, we found infiltration of lymphocytes around the islet without destruction of the endocrine cells, and the presence of vivid insulin/ glucagon stained-cells was detected in group 3. CONCLUSION: This minimal nonmyeloablative conditioning therapy induced the donor's chimerism and immune tolerance between the MHC- and minor-disparate(BALB/c-->C57BL/6) mice. Long-term islet graft survival was obtained through the co-transplantation of BMCs in the mouse model

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