Diabetes & Metabolism Journal

Sung Joo Kim (Kim SJ)

5 Articles

Glucose-dependent Insulin Secretion from Genetically Engineered K-cells Using EBV-based Episomal Vector.: Ju Hee Kim, Sung Dae Moon, Seung Hyun Ko, Yu Bai Ahn, Ki Ho Song, Hyang Sook Lim, Sook Kyung Lee, Soon Jip Yoo, Hyun Shik Son, Kun Ho Yoon, Bong Yun Cha, Ho Young Son, Sung Joo Kim, Je Ho Han; Korean Diabetes J. 2007;31(1):9-21. Published online January 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.1.9

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BACKGROUND
Type 1 diabetes mellitus is an autoimmune disease resulting in destruction of the pancreatic beta cells. Insulin gene therapy for these patients has been vigorously researched. The strategy for achieving glucose-dependent insulin secretion in gene therapy relies on glucose-responsive transcription of insulin mRNA and the constitutive secretory pathway of target non-beta cells. We observed that genetically engineered K-cells using Epstein-Barr virus (EBV)-based episomal vector can produce glucose-regulated insulin production. METHODS: Green fluorescent protein (GFP) or rat-preproinsulin (PPI) expression cassette transcriptionally controlled by the promoter of glucose dependent insulinotropic peptide (GIPP) is fused to pCEP4 containing the origin of replication (oriP) and Epstein-Barr virus nuclear antigen 1 (EBNA-1). CMV promoter was replaced by subcloning the GIPP into pCEP4 to generate pGIPP/CEP4. Two recombinant EBV-based episomal vectors, pGIPP/GFP/CEP4 and pGIPP/PPI/CEP4, were constructed. pGIPP/GFP/CEP4 and pGIPP/PPI/CEP4 containing K-cell specific GIPP were co-transfected into STC-1. K-cell was isolated from the clonal expansion of the fluorescent cells selected by hygromycin treatment in STC-1, and were analyzed for the expression of glucokinase (GK) or transcription factors involved in pancreas development. K-cells concurrently transfected with pGIPP/PPI/CEP4 and pGIPP/GFP/CEP4 were analyzed for the transcripts of PPI by RT-PCR, and for the glucose dependent insulin expression by immunocytochemistry or insulin assay using ultra-sensitive rat-specific insulin ELISA kit. RESULT: STC-1 was stably-transfected with pGIPP/GFP/CEP4 along with pGIPP/PPI/CEP4. Genetically selected fluorescent K-cells expressed GK and transcription factors involved in pancreas development. And K-cells transfected with pGIPP/PPI/CEP4 contained detectable levels of PPI transcripts and showed glucose-dependent immunoreactive insulin secretion. CONCLUSION: We identified genetically engineered K-cells which exert a glucose-dependent insulin expression using EBV-based episomal vector. The similarities between K-cells and pancreatic beta cells support that K-cells may make effective and ideal targeting cells for insulin gene therapy or alternative cell therapy.

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Relationship of traditional and nontraditional cardiovascular risk factors to coronary artery calcium in type 2 diabetes
Ju-Yeon Sim, Ju-Hee Kim, Yu-Bae Ahn, Ki-Ho Song, Je-Ho Han, Bong-Yun Cha, Sook-Kyung Lee, Sung-Dae Moon
Korean Diabetes Journal.2009; 33(6): 466. 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

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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Abstract PDF: BACKGROUND
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

Re-transplantation of Pancreatic Islets in Insulin Dependent Diabetes Mellitus.: Tae Young Yang, Seung Hoon Oh, In Kyung Jeong, In Ah Seo, Eun Young Oh, Gun Young Cho, Sung Joo Kim, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim, Young Soo Do, Sung Wook Choo; Korean Diabetes J. 2000;24(4):457-466. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Over the past 20 years, significant advances have been made in human islet transplantaiton. However, cases of prolonged insulin independence after islet allotransplantation have rarely been reported and over time, a slight, gradual decrease in insulin secretion appears to occur, as suggested by the lower C-peptide. Although preliminary clinical success achieved over the past few years has been considerably higher with whole pancreatic transplant than with isolated islet grafts, both approaches remain experimental. Islet grafts might gain, over time, increasing credibility and might eventually provide an easier alternative in terms of grafting procedures and patient management, as compared with the more "traumatizing" whole-pancreas transplantation. Also, using islet, re-tran- splantation is possible. But it is not known whether re-transplantation of islet could be suitable for those patients who lost grafted islet function. The aim of the present study was to investigate the benefits of re-transplantation of islet in previously simultaneous islets-kidney transplant(SIK) patient who have lost graft function. METHODS: The recipient was a 32 year old male. First islet transplantation was underwent at December 25, 1999. However, the grafted islets lost function after 70 days. So we performed re-transplantation of islets. The isolation of islet was conducted sterilely on a laminar flow hood and isolated by a modified Recordi method. The islet was injected slowly into the liver via a cannular placed in the potal vein for 20 minutes. RESULTS: Transplanted islets were 90,000 IEq at first islet transplantation, 370,000 IEq at second islet transplantation. The insulin requirement was reduced from 75-85 to 35-40 U/day, the basal C-peptide level was 1.5 ng/mL at 7 days posttransplant Unfortunately, the grafted islets lost function after 70 days. After second transplantation, the insulin requirement was reduced to 26 U/day. CONCLUSIONS: Despite the continuous need for exogenous insulin therapy, islet transplantation can prevent wide glucose fluctuations, thus resulting in norma lization of glycemic control and improvement in HbA1c, and also, show that islets can be successfully and safely re-transplanted intraportally in patients who have lost previously grafted islet function (J Kor Diabetes Asso 457~466, 2000).

Distension and Collagenase Digestion Time of The Pancreas are Critical Factors in Islet Isolation of Canine Pancreas.: Tae Young Yang, In Kyung Jeong, Seung Hoon Oh, Sang Hoon Lee, Dong Jun Kim, Jong Ryul Hahm, Jung Hwan Park, Jong Sung Kim, Jin Soo Han, Sung Joo Kim, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; Korean Diabetes J. 2000;24(2):180-190. Published online January 1, 2001

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Abstract PDF: BACKGROUND
S: One of the main problems conditioning the outcome of islet transplantation is the ability to separate a sufficient number of viable islets with preserved function. Islet purification is critically affected by all of the isolation stages, Thus, it is necessary to set up the standard isolation method that islets are separate well from acinar without compromising islet yield and viability. METHODS: Twenty three adult mongrel dogs were used for the experiment of total pancreatectomy with islet isolation. The islets were properly isolated by a modified Recordi method. The obtained islets were further purified by centrifugation on discontinuous gradients using cell separation system (Model 2991, Cobe, Lakewood Colo). We evaluatad islet number (islet equivalent number, 150 gm equivalents/kg of recipient body weight, lEq/kg), purity. cell volume, viabilty, recovery rate, and comparison of outcome according to the isolation conditions. RESULTS: 1) The mean of islet numbers before purification were 13543+/-943 lEq/kg, digestion times were 13.8+/-2.6 min. digestion tamperature was b was 59,7+/-7.0%, viability was 90.0+/-2.1%, cell volume was 4.7+/-1.1 mL, islet number after purification were 4064+/-361 lEq/kg, and recovery rate was 29+2.9. 2) Isolated islet numbers were different according to the degree of pancreas distension with collagenase, digestion temperature, and digestion time. 3) The best conditions for islet isolation were above 37.5 degree C in temperature at recirculation of collagenase, within 12min in digestion time and well distended pancreas with collagenase. 4) According to multiple regression adjusted by variable factors, the degree of pancreas distension with collagenase and digestion time were independently associated factors for successful islet isolation. CONCLUSIONS: In this study, we concluded that the degree of pancreas distension with collagenase and digestion time were independent factors for successful islet isolation and the best conditions for islet isolation were above 37.5 degree C in temperature at recirculation of collagenase, within 12 min in digestion time and well distended pancreas with collagenase.

Critical Factors Determined Islet Graft Function In Canine Islet Autotransplantation.: Tae Young Yang, In Kyung Jeong, Seung Hoon Oh, Sang Hoon Lee, Dong Jun Kim, Jong Ryul Hahm, Byung Joon Kim, Kyu Jeung Ahn, Sung Joo Kim, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; Korean Diabetes J. 2000;24(2):170-179. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Islet cell transplantation is an attractive alternative to whole organ pancreas transplantation, since it is clearly safer and simpler surgical procedure for the reciplents. However, several obstacles still remain, because the free islets appear to be more susceptible to non-specific inflammatory damage or immune mediated destruction than islets in an intact pancreas. Therefore, the purpose of this study is to examine the functional outcome of islet autograft and the factors related to the islets graft survival in mongrel dogs. METHODS: Twelve adult mongrel dogs weighting 12~16 kg were used for the experiment of total pancratectomy and islet autotransplantation. The islets were properly isolated by a modified Recordi method. The obtained islets were further purified by centrifugation on discontinuous gradients using cell separation system (Model 2991, Cobe, Lakewood Colo). After the heparization(50U/kg), the islets were injected slowly into the liver through the portal vain for 30 minutes. The post-transplantation intravenous glucose tolerence test (IVGTT) with glucose disappearance rate (K), liver function test (LFT), fasting plasma glucose (FPG) ware measured periodically. RESULTS: I) The median of Ks were 1.3%/min (range 0.3~2.1) and the lEq/kg (150 m equivalents/kg of recipient body weight) was 3520 (range 1350-6550). The Ks in recipients with high lEq/kg (> or =5,000) were significantly higher than those in recipients with low lEq/kg (<5,000)(r=0.78, p<0.05). 2) The islet cell viability were estimated to be 95% and the median of the required insulin dosage for the maintenance of normal FPG were 0.7 (range 0~1.6) U/kg/day, The insulin requirement correlated well with the level of lEq/kg (r=-0.90, p<0.01). 3) The median of the volume of the transplanted pancreatic islet cell were 2.1 mL (range 0.7~5.0) and the purity was 60k (range 10~95), The portal pressure gradients of during the transplant procedure were 4.0(range 0.5~12.0) cmH20. The portal pressure gradients in recipients with high purity were significantly lower than those in recipients with low purity (r=-0,80, p<0,05). CONCLUSIONS: In this study, we confirmed that autotransplantation of islet cell on the pancreatectomized dogs can render nearly normoglycemia, and transplanted islet mass was most critical factor to successful autotransplantation in canine model.

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