- Effects of Islet Transplantation on Endogenous beta-cell Regeneration after Partial Pancreatectomy in Rodents.
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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
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Korean Diabetes J. 2007;31(2):113-122. Published online March 1, 2007
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DOI: https://doi.org/10.4093/jkda.2007.31.2.113
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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.
- Activin A and Glucose Derived Human Pancreatic Ductal Cells into Insulin-producing Cells.
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Seung Hyun Hong, Chul Han, Hyo Sup Kim, Mi Kyung Park, Young Jin Lee, Jae Hoon Jeong, Yong Ki Min, Myung Shik Lee, Kwang Won Kim, Moon Kyu Lee
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Korean Diabetes J. 2007;31(1):44-50. Published online January 1, 2007
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DOI: https://doi.org/10.4093/jkda.2007.31.1.44
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Cellular replacement therapy holds promise for the treatment of diabetes mellitus but donor tissue is severely limited. Human postnatal pancreatic ductal cells are a potential source of new beta cells. Therefore, we investigated the potential of human pancreatic ductal cells could be differentiated into endocrine cells that would be capable of secreting insulin in response to glucose. METHODS: Cell fractions enriched with pancreatic ductal cells after human islet isolation were treated with streptozotocin to remove residual beta cells, grown in monolayer culture, changed the media for differentiation in the presence of activin A and glucose, supplemented with 10% FCS. The differentiation markers, insulin secretion and cell proliferation were examined. RESULT: No insulin was detectable in cell preparations after 5 days of treatment with streptozotocin. In monolayer culture, 80% of the streptozotocin-treated pancreatic ductal cells expressed cytokeratin-19. Cell cultures with a high proportion of cytokeratin-19 cells had greater plasticity for differentiation into cells with phenotypic and functional markers of beta cells. This property were significantly enhanced by treatment of activin A and glucose. The differentiated human pancreatic ductal cells secreted insulin sensitively responded with high glucose. CONCLUSION: Human pancreatic ductal cells are a potential source of new glucose -induced insulin producing cells that may be developed further for clinical use. Therefore, the present data support a possible role for human adult pancreatic ductal cells, following expansion and differentiation, as a source of insulin by transplantation cells to type I diabetes patients.
- Thiazolidinediones on Insulin Resistance and Insulin Secretion in Obese Diabetic OLETF Rats.
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Jung hyun Noh, Seung hyun Hong, Kyoung hee Lee, Kyoung Min Min, Tae young Yang, Myung shik Lee, Kwang won Kim, Moon kyu Lee
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Korean Diabetes J. 2007;31(1):33-43. Published online January 1, 2007
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DOI: https://doi.org/10.4093/jkda.2007.31.1.33
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Thiazolidinediones are synthetic peroxisome proliferator-activated receptor-gamma agonists that decrease insulin resistance but, as in vitro and in vivo studies suggest, may have direct beneficial effects on pancreatic beta cells. Here, we investigated the effects of thiazolidinediones (TZDs) on the insulin resistance, beta-cell mass and insulin secretion in obese diabetic OLETF rats. METHODS: We studied insulin resistance (by hyperinsulinemic euglycemic clamp) and insulin secretion (by hyperglycemic clamp) in TZDs administered OLETF and LETO rats. Histologic alterations of the islets were observed and beta-cell mass was also measured by point counting method. RESULTS: Chronic administration of troglitazone (TGZ, 0.15%) or pioglitazone (PGZ, 0.02%) prevented the development of glucose intolerance in OLETF rats, as assessed by oral glucose tolerance test. There was significant difference in submaximal glucose infusion rate between TGZ-treated and untreated OLETF rats during euglycemic clamp studies at 24 weeks of age. At 16 and 24 weeks of ages, beta-cell mass significantly increased in TGZ-treated OLETF rats compared to untreated animals. At 19 weeks and 30 weeks of age, first-phase insulin secretion was not different in PGZ-treated OLETF rats from untreated OLETF rats during hyperglycemic clamp study. At 30 weeks of age, late-phase insulin secretion was decreased in PGZ-treated OLETF rats compared to untreated OLETF rats. The expression of alpha-smooth muscle actin, a marker of activated pancreatic stellate cells that are involved in the fibrosis of the pancreas, in the islets was suppressed by TGZ treatment at 24 weeks of age. CONCLUSION: The treatment of TGZ prevented the development of diabetes, and increased insulin sensitivity and pancreatic beta-cell mass in OLETF rats. These results might be related with the suppression of pancreatic stellate cells. Insulin secretion was not affected by PGZ treatment.
- Effective Glycemic Control Achieved by the Transplantation of VEGF-Transfected Islets in STZ-induced Diabetic Mice.
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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
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Korean Diabetes J. 2005;29(4):282-294. Published online July 1, 2005
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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 Tolerance to Complete Histocompatibility Mismatched Mice Islets through the Co-transplantation of Bone Marrow Cells in a Minimal Nonmyeloablative Condition.
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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
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Korean Diabetes J. 2005;29(2):103-111. Published online March 1, 2005
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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
- Maximal Oxygen Uptake (VO2max) and Metabolic Syndrome.
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Mira Kang, Ji Dong Sung, Byung Chul Yoo, Yoon Ho Choi, Sae Young Jae, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Kwang Won Kim, Moon Kyu Lee
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Korean Diabetes J. 2005;29(1):65-71. Published online January 1, 2005
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A number of studies have demonstrated an inverse relationship between cardiorespiratory fitness and metabolic syndrome. However, whether the maximal oxygen uptake (VO2max) is dependent on the number of metabolic components or on particular metabolic component remains to be assessed. METHODS: A total of 1,432 Korean subjects were studied. Each individual was assessed for the presence of metabolic syndrome using the modified NCEP-ATP III criteria. All subjects underwent a graded symptom-limited maximal exercise test to determine their VO2max, using a treadmill according to the Bruce protocol. RESULTS: The age-adjusted prevalence of metabolic syndrome in all subjects was 20.4%. The odds ratios for metabolic syndrome were higher in men, the elderly, the obese and those with a lower VO2max. The difference in the VO2max was dependent only on the presence of metabolic syndrome, not on the number of components. CONCLUSION: There were no significant differences in the VO2max according to the presence of particular metabolic components. These results suggest that the VO2max reflects the metabolic syndrome state, rather than the metabolic components, and might be a factor in determining metabolic syndrome
- Mitogenic Effects and Signaling Pathway of Insulin-Like Growth Factor-I (IGF-I) in the Rat Beta Cell Line (INS-1).
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In Kyung Jeong, Ja Young Kim, Hyung Joon Yoo, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
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Korean Diabetes J. 2004;28(6):478-489. Published online December 1, 2004
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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.
- Effect of Pancreatic Islet Autotransplantation after Pacreatectomy in Patients with Benign Pancreatic Tumor.
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Jae Hwan Jee, Byung Wan Lee, Seung Hoon Oh, Ji Youn Kim, Hyun Jin Kim, Jung Hyun Noh, Sung Ho Choi, Jae Hoon Chung, Yong Ki Min, Myung Sik Lee, Moon Kyu Lee, Kwang Won Kim
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Korean Diabetes J. 2004;28(2):88-100. Published online April 1, 2004
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Previously, in patients suffering from insulin deficient DM after a partial or total pancreatectomy as treatment for a benign pancreatic tumor, insulin treatment has only led to severe fluctuation in the blood glucose level, and frequently to sudden hypoglycemia due to glucagon deficiency and lack of delicate insulin control. Several worldwide reports have suggested that autologous transplantation of islet cells isolated from an unaffected portion of a resected pancreas, mostly for the cure of chronic pancreatitis or a pancreatic tumor without immunosuppressive agent treatment, resulted in good glycemic control, and even in the prevention of DM. Attempts were made to evaluate the effect of islet autotrans-plantation for glycemic control in eight patients undergoing a pancreatectomy for a benign pancreatic tumor. METHOD: Between December 2001 and October 2003, an islet autotransplantation was performed in eight patients patholologically confirmed with benign pancreatic tumors following a pancreatectomy. There was no past medical history of DM in any of the patients, but impaired glucose tolerance(IGT) was detected in 2 patients on a 75g oral glucose tolerance test(oral GTT), and was also suspected in a pre-pancreatectomy state patient. Islets were isolated by ductal perfusion, using the cold collagenase P and semi-automated method, and purified on a density gradients using a COBE 2991 cell processor or tube system of Ficoll solution. After being confirmed as a benign pancreatic tumor, the cultured islet cells were transplanted to the liver through the portal vein. Each patient was transplanted with a mean islet mass of 3,190+/-896 islet equivalents per kilogram of body weight. The median follow-up period was 12 months, with the longest being 36 months. All patients underwent follow-up for oral GTT, HbA1c and complication of DM, pancreatectomy, or transplantation within this period. RESULTS: On the 75g oral GTT, a normal glucose tolerance(NGT) was maintained until the last follow-up month in five of the eight patients undergoing islet autotransplantation. DM recurred in three of the eight patients undergoing islet autotransplantation, with to cases in a state of IGT and 1 case of NGT at the initial stage. The HbA1c levels were not significantly changed between pre-pancreatectomy and post-islet transplantation period. The amplitude of the decrease in the postprandial 2 hour glucose level was larger than that of the fasting glucose level between the pre- and post-transplantation periods, but this was not statistically. Also, the elevation of the postprandial C-peptide level was larger than the fasting C-peptide during the post-transplantation period, but again, this was not significant. No complications occurred in relation with the islet transplantation, portography, DM and hypoglycemia. CONCLUSION: Islet transplantation could prevent and reverse the diabetic process in patients undergoing a pancreatectomy for a benign pancreatic tumor, with some exception such as those with a small transplanted islet mass or with initial insulin resistance. The 2 hour postprandial changes in the glucose and C- peptide levels on the oral GTT somewhat reflected insulin secretory function of the remaining and newly transplanted islet cells. Pancreatic islet autotransplantation is the most prospective method for the prevention or cure of insulin deficient DM following a pancreatectomy for a benign pancreatic tumor.
- Activin A Converts Pancreatic Ductal Cells into Insulin-Secreting Cells.
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Kyoung Hee Lee, Mi Kyung Park, Han Wook Kang, Hyun Jin Kim, In Kyung Jeong, Hyung Joon Yoo, Jae Hoon Jeong, Yong Ki Min, Myung Shik Lee, Kwang Won Kim, Moon Kyu Lee
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Korean Diabetes J. 2004;28(1):20-27. Published online February 1, 2004
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Islet transplantation as a potential treatment for diabetes has been investigated extensively over the past years. One of the major limitations to successful islet transplantation is shortage of insulin-producing tissue, which has stimulated the search for alternative sources, and recently, attention has been focused on the possible use of controlled differentiation of stem cells to obtain specialized cells useful in treating many diseases. It is currently believed that pancreatic progenitor or stem cells exist in the ductal cell population. Activin A is a member of the TGFbeta superfamily, which can block the exocrine pancreatic development and potentiate the endocrine development of the pancreas. In this study, whether activin A could expand and/or differentiate the ductal cells into insulin-producing cells was examined. METHODS: From a collagenase P digested pancreas, ductal tissue was cultured under conditions that allowed expansion as a monolayer, where the cells were overlaid with a rat tail collagen I-coated dish. Activin A cDNA was transfected into rat ductal cells by using Lipofectamine, and the insulin secretion, content and differentiation markers examined. RESULT: The clumps of ductal tissue adhered to the dish 24 hr later, and formed a complete monolayer after 3 days of culture. Activin A overexpression significantly increased both the insulin secretion and content from the ductal cells. The glucose(16.7mM)-induced insulin secretion was also significantly increased. Immunohistochemistry and RT-PCR analyses revealed expression of PDX-1, as well as insulin & GLUT2. CONCLUSION: Activin A overexpression could potentiate the differentiation of pancreatic ductal cells, which might provide a potential new source of cinsulin- producing cells for transplantation
- Insulin Secretory Dysfunction in the Pathogenesis of Type 2 Diabetes in Koreans: A Minimal Model Analysis.
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Sung Hoon Kim, Dong Jun Kim, Byung Wan Lee, In Ah Seo, Jae Hoon Chung, Young Ki Min, Myung Shik Lee, Kwang Won Kim, Moon Kyu Lee
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Korean Diabetes J. 2003;27(5):414-419. Published online October 1, 2003
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Type 2 diabetes is a complex, heterogeneous disorder, characterized by impairments in both insulin secretion and insulin action. This study was done to examine the significance of alterations in insulin sensitivity and beta-cell function in the pathogenesis of type 2 diabetes in Korean subjects with varying degrees of glucose intolerance. METHODS: Forty Korean subjects were studied, 12 with normal glucose tolerance (NGT), 14 with impaired glucose tolerance (IGT) and 14 with type 2 diabetes. An oral glucose tolerance test (OGTT) was performed on each subject. Insulin sensitivity (SI), glucose effectiveness (Sg), acute insulin response after intravenous glucose (AIRg) and the disposition index (DI= SI x AIRg) were measured by the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: Neither fasting serum insulin level nor SI was significantly different among the NGT, lGT and diabetes groups. Sg was significantly lower in the type 2 diabetes group than in the NGT group. The mean AIRg was blunted in the IGT and diabetes groups when compared with the NGT group. DI was more powerful in differentiating between NGT and IGT, compared to AIRg alone. CONCLUSION: These findings suggest that a defect in the compensatory insulin secretion might be more important than insulin resistance in the development of type 2 diabetes in Korean subjects.
- Effects of Peroxisome Proliferator-activated Receptor-gamma(PPARgamma) on the Pancreatic beta Cell Proliferation.
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Jung Hyun Noh, Tae Young Yang, In Kyung Jeong, Jae Hun Chung, Yong Ki Min, Myung Shik Lee, Kwang Won Kim, Moon Kyu Lee
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Korean Diabetes J. 2003;27(3):241-252. Published online June 1, 2003
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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.
- Comparative Study about the Effects of Acarbose and Voglibose in Type 2 Diabetic Patients.
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In Kyung Jeong, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim, Yun Ey Chung, Joong Yeol Park, Sung Kwan Hong, Ki Up Lee
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Korean Diabetes J. 2002;26(2):134-145. Published online April 1, 2002
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Acarbose and voglibose are alpha-glucosidase inhibitors. Although different pharmacological effects and adverse abdominal events associated with the two drugs have been reported, no study directly compared acarbose and voglibose in diabetes has been undertaken. To compare the pharmacological effects and gastrointestinal adverse events between two drugs, a randomized, placebo-controlled, double-blind study was performed in type 2 diabetes patients. METHODS: The period of study was 12 weeks (observation period: 4 weeks; treatment period: 8 weeks). Fifty-three patients were randomized into two groups (the acarbose group: 24 patients; the voglibose group: 29 patients). The serum glucose, insulin, fructosamine, HbA1c, cholesterol, triglyceride and the incidence of adverse events were measured. RESULTS: 1) The reduction of glucose from before treatment to 4 weeks after treatment was significantly higher in the acarbose group, but the change before treatment and 8 weeks after treatment in the two groups was similar (p = 0.569). 2) The insulin significantly decreased after voglibose treatment (p = 0.040). 3) HbA1c level tended to decrease in voglibose group, and there was a significant decrease after acarbose treatment. However, the change in HbA1c level before and after treatment was similar between the two groups (p = 0.412). 4) The two drugs did not cause any other changes in the total, HDL-cholesterol and triglyceride. 5) The number of patients with gastrointestinal adverse events was significantly low 4 weeks after voglibose treatment (p = 0.049), but the incidence in the two groups was similar after 8 weeks (p = 0.215). CONCLUSIONS: Acarbose and voglibose significantly improved postprandial hyperglycemia in diabetes. The incidence of gastrointestinal adverse events was low 4 weeks after voglibose treatment.
- The Effect of Step-wised, Controlled Cooling Method for Islet Cryopreservation on the in vivo and in vitro Islet Function.
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In Kyung Jeong, Seung Hoon Oh, Byung Joon Kim, Tae Young Yang, Byung Wan Lee, Chang Young Ha, Jung Hyung Noh, Jae Hoon Chung, Young Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
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Korean Diabetes J. 2002;26(1):65-74. Published online February 1, 2002
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Although islet transplantation has been attempted to reverse the state of diabetes, achieving a critical number of islets and modulating the immune response limit the success ofl islet transplantation. Cryo-preservation of islets offers many important benefits for islet transplantation by collecting islets with a wide variety of HLA phenotypes and islet MHC expression. The aims of this study was to determine the optimal conditions for cryo-preservation by using a controlled cooling method and to evaluate in vitro and in vivo functional properties of the cryo-preserved islets. METHODS: Collagenase-isolated, Ficoll-purified islets were cultured for 48 hours. They were aliquoted into freezing tubes (1000 islets per tube), equilibrated with 2 M dimethyl sulfoxide (DMSO) in three steps, supercooled, nucleated, and controll- cooled at rate of 0.25 degrees C/min to - 40 degrees C prior to storage at - 196 degrees C. Rapid thawing and removal of DMSO with 0.75 M sucrose preceded 48 hour of culture and the morphology, viability, glucose-induced insulin secretion, and in vivo function of rats transplanted with cryopreserved islets was reexamined. RESULTS: 1) Recovery was 90.2+/-0.2%, 85.7+/-0.1% and 81.7+/-0.1% immediately after, 24 hours and 72 hours after thawing respectively. The viability was 60+/-5%, 80+/-5%, 90+/-5% immediately after, 24 hours and 72 hours after thawing respectively. 2) The glucose-stimulated-insulin secretion (GSIS) tended to decrease immediately after thawing, but GSIS increased to the level of pre-cryopreservation 72 hours after thawing. 3) The in dynamic GSIS, the first and the second phase of insulin secretion were well preserved in islets cultured for 72 hours after thawing. 4) The cryopreserved islets were cultured for 3 days and transplanted into renal sub-capsular space of streptozotocin (STZ) induced diabetic rats. The duration of normoglycemia in the STZ-induced diabetic rats transplanted with cryopreserved islets was significantly longer than that of the fresh islets. CONCLUSION: The optimal condition of cryopreservation using the controlled cooling method was established in rat pancreatic islets. This cryopreservation method can be a feasible approach for human islet transplantation.
- The Prevalence of Islet Cell Cytoplasmic Antibody in Korean Type 1 Diabetes: Possible Replacement with Combined Measurement of Anti-GAD, Anti-ICA512, and Anti-phogrin Antibodies.
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Kyoung Ah Kim, Dong Jun Kim, Jae Hoon Chung, Yong Ki Min, Moon Kyu Lee, Kwang Won Kim, Dong Kyu Jin, Kyung Soo Ko, Sang Jin Kim, Myung Shik Lee
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Korean Diabetes J. 2001;25(6):430-445. Published online December 1, 2001
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Type 1 diabetes includes all forms of autoimmune-mediated and idiopathic beta-cell destruction leading to an absolute insulin deficiency. Evidence of an autoimmune pathogenesis was assessed by studying cytoplasmic islet cell antibodies (ICA), antibodies to glutamic acid decarboxylase (GADA), antibodies reacting with an islet tyrosine phosphatase-related molecule referred to as ICA512 (ICA512A), or its homologue phogrin (phogrin-A). In comparison with ICA, the best validation to assess the risk of type 1 diabetes, shows that a combination of antibodies to GADA with ICA512A has the power to detect a majority of ICA and 97~100% of subjects who progressed to overt diabetes. These findings suggest the possibility of replacing the laborious ICA test in the screening programs to identify subjects at risk of progressing to type 1 diabetes or forclassifying the stage of diabetes at the time of diagnosis. Up to now, it is unclear whether these results are applicable to the slowly progressive type 1 diabetes that appears to be more prevalent in Asian than in western countries. The prevalence of combined autoantibody testing (1 of GADA, ICA512A, or phogrin-A) was investigated in the patients with type 1 diabetes (typical and slowly progressive) and type 2 diabetes, and compared with that of ICA which is a more laborious and insensitive test. METHODS: The ICA assay was performed using immunoenzymatic staining of frozen human (blood group O) pancreatic sections with serial dilutions of serum samples with peroxidase-labeled protein A. For the GADA determination, commercially available GADA radioimmunoassay kits utilizing the 125I-labeled recombinant GAD65 (RSR , United Kingdom) as an antigen was used. Either ICA512A or phogrin-A were detected by a radioligand-binding assay after in vitro transcription and translation using the clone ICA512bdc or phogrin cDNA. Serum was obtainedfrom 76 patients with type 1 diabetes (mean age 22.8+/-14.0 years), 22 patients with slowly progressive type 1 diabetes (mean age 37.9+/-13.9 years) and 39 patients with type 2 diabetes (mean age 45.3+/-12.3 years). Typical and slowly progressive type 1 diabetes patients had the disease for between 4.0+/-4.6 and 10.1+/-9.5 years, respectively at the earliest serum sampling. RESULTS: 1) In typical type 1 diabetes, 30% of patients tested positive for ICA and 57% for the combined autoantibody test (1 of GADA, ICA512A, or phogrin-A). In the slowly progressive type 1 diabetes group, 18% of patients tested positive for ICA and 50% for the combined autoantibody test. In type 2 diabetes, 7.7% and 5.1% tested positive, respectively. 2) Ninety-six percent of ICA-positive patients expressed one or more of the 3 auto-antibody specificities in typical type 1 diabetes. Among the 53 ICA-negative patients with typical type 1 diabetes, 40% had one or more of these auto-antibodies. In the slowly progressive type 1 diabetes, 100% of the ICA-positive and 39% of the ICA- negative patients expressed one or more of the 3 autoantibody specificities. 3) Of the 23 patients with ICA-positive typical type 1 diabetes patients, 87% had a positive result for GADA, 48% for ICA512A, 44% for phogrin-A, and 96% for GADA or ICA512A. Of the 4 patients with ICA-positive slowly progressive type 1 diabetes, three had a positive result for GADA, and 1 for ICA512A. 4) When the prevalence of combined autoantibody testing was analyzed according to the duration of diabetes, the prevalence in patients tested within 4 years after the diagnosis and more than 4 years after the diagnosis was 61% and 52%, respectively in typical type 1 diabetes. Furthermore, that for the ICA was 37% and 21%, respectively. In the slowly progressive type 1 diabetes, the prevalence of combined auto-antibody testing was 88% and 25%, respectively (p<0.05), while that of ICA was 25% and 13%, respectively. 5) In typical type 1 diabetes, ICA were detected more frequently in patients younger than 15 years of age (48%) than in older patients (23%) (p<0.05), while the prevalence of combined auto-antibody testing -was not different according to the onset age (65% vs 53%). CONCLUSION: Combined autoantibody testing for GADA and ICA512A is more sensitive that ICA in type 1 diabetes. Therefore, it could replace the laborious ICA measurement and may be useful for discriminating the etiology of adult onset atypical diabetes.
- Prevalence of Diabetes Mellitus in Pancreatic Cancer Patients.
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Yu Jeong Park, Kwang Won Kim, Eun Young Oh, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Jong Kyun Lee, Kyu Taek Lee, Yong Il Kim, Yoon Ho Choi
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Korean Diabetes J. 2001;25(4):316-322. Published online August 1, 2001
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Pancreatic cancer is a highly malignant tumor and its incidence has been significantly increased. It has well been known that pancreatic cancer patients had high prevalence of diabetes mellitus. But it is still controversial if diabetes predispose pancreatic cancer or it is an epiphenomenon of pancreatic cancer. Thus, the aims of this study was to investigate the prevalence of diabetes mellitus in pancreatic cancer patients in Korea, to characterize the diabetes mellitus in this situation, and to observe an association between the two conditions. METHOD: 275 pancreatic cancer patients admitted in Samsung Medical Center from January 1998 to December 2000 were selected for this study. We reviewed patients medical record and recorded diabetic history. Subjects who visited our Health Promotion Center in 1999 was used to evaluate the prevalence of diabetes mellitus. RESULT: 30% of pancreatic cancer patients had diabetes mellitus. 60% of diabetic pancreatic cancer patients had detected diabetes within recent two years. 25.6% of them had been known their diabetic state when they detected pancreatic cancer. There were no differences in smoking history, percent of distant metastasis, frequency of curative resection, and BMI between diabetic and nondiabetic pancreatic cancer patients. Significant weight loss was noted in pancreatic cancer patients with diabetes (p<0.01). CONCLUSION: The prevalence rate of diabetes in pancreatic cancer patient was significantly high. Pancreatic cancer patients with diabetes presented with much profound weight loss. Furthermore, more than half of the pancreatic cancer patients with diabetes had recent onset diabetes. Further investigations would be necessary to elucidate causal relation in the pathogenesis of diabetes and pancreatic cancer.
- Re-transplantation of Pancreatic Islets in Insulin Dependent Diabetes Mellitus.
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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
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Korean Diabetes J. 2000;24(4):457-466. Published online January 1, 2001
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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).
- The Stimulatory Effect of IL-1on The Insulin Secretion and Its Relating Factors.
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In Kyung Jeong, Seung Hoon Oh, Tong Mook Kang, Jae Hoon Jeong, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
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Korean Diabetes J. 2000;24(4):431-443. Published online January 1, 2001
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The inhibitory effect of IL-1 on the insulin secretion has been validated in pathogenesis of type 1 diabetes, but complex results about the stimulatory effect of IL-1 have been reported. The aims of this study are to clarify the effects of IL-1 on insulin secretion of pancreatic islets and to investigate the mechanisms in terms of preproinsulin synthesis, inducible NOS expression, and calcium channel activity. METHODS: Islets were isolated from male Sprague-Dawley (SD) rat by modified Lacy-Kostianovsky's method. After islets were treated with different concentrations (0, 0.5, 5, 50, 500 pmol/L) and exposure time (2, 6, 24 hours) of IL-1 , morphology, viability, static stimulation of insulin to glucose, insulin content, preproinsulin mRNA expression, iNOS mRNA expression and calcium channel activity were measured. RESULTS: 1) Viability of islets was reduced in high concentrations of long term exposure of IL-1 . 2) Insulin secretion was stimulated in islets treated with 5, 50, and 500 pmol/L of IL-1 for 2 hours and 0.5 pmol/L for 6 hours. It was inhibited in 5, 50, and 500 pmol/L for 6 and 24 hours. 3) Insulin content was not significantly different regardless of concentration and exposure time of IL-1 . 4) Preproinsulin mRNA expression increased in islets treated with 50, 500 pmol/L of IL-1 for 2 hours. After 24 hours, it decreased in dose dependent manner. 5) iNOS mRNA expression was detectable after 2 hours in the presence of IL-1 , peaks at 6 hour and decreased after 24hours. It was increased above 5 pmol/L of IL-1 in dose dependent manner. 6) Activities of the voltage-dependent Ca2+ channels were not different among groups. CONCLUSION: IL-1 plays a positive role in terms of insulin secretion and insulin synthesis in high concentration of short term or low concentration of long term. These effects of IL-1 might be neither dependent of iNOS pathway nor Ca2+ channel activity.
- Insulin Secretion and Insulin Sensitivity in Korean Subjects with Impaired Glucose Intolerance.
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Dong Jun Kim, Jong Ryul Hahm, In Kyoung Jeong, Tae Young Yang, Eun Young Oh, Yoon Ho Choi, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
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Korean Diabetes J. 2000;24(3):356-364. Published online January 1, 2001
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Although insulin resistance has been known to be a primary defect causing type 2 diabetes in Pima Indians and Caucasians. However, insulin secretory defect rather than insulin resistance has been speculated and demonstrated to be a more important factor in the development of type 2 diabetes in other ethnic groups. Thus, we undertook this study to investigate the initial abnormality of glucose intolerance in Korean subjects. METHODS: 374 Korean subjects were stratified according to the World Health Organization criteria (normal glucose tolerance [NGT], n = 128; impaired glucose tolerance [IGT], n=128; diabetes, n=118) and subdivided further into the two groups; non-obese (BMI < 25 kg/m2) and obese group (BMI 25 kg/m2). Insulinogenic index (the ratio of the increment of insulin to that of plasma glucose 30 min after glucose load) was used as an index of early-phase insulin secretion. AUC insulin (area under the insulin curve during OGTT) was used as an index of total insulin secretion. Insulin resistance was assessed by HOMA (R), the R value of the Homeostasis model. RESULTS: Insulinogenic index decreased significantly in IGT compared with that in NGT in both non-obese and obese groups, respectively. There was no significant difference in AUC insulin and HOMA (R) between NGT and IGT group. WhereasAUC insulin showed its peak level in the range of IGT (7.7~9.9 mmol/L), insulinogenic index showed the peak level in the range of NGT (5.6~7.7 mmol/lL and decreased progressively with increase of plasma glucose 120 min value. CONCLUSION: Early-phase insulin secretory defect might be the initial abnormality in the development of IGT from NGT in both non-obese and obese Korean subjects.
- The Effects of Troglitazone on Vascular Smooth Muscle Cell Proliferation.
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Yun Jae Chung, Kyeong Min Min, Eun Young Oh, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
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Korean Diabetes J. 2000;24(3):348-355. Published online January 1, 2001
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Elevated fasting and postprandial insulin levels are frequently observed in patients with obesity and hypertension as well as type 2 diabetes mellitus. This phenomenon has been suggested as an independent risk factors for atherosclerotic cardiovascular diseases. Troglitazone, an insulin-sensitizing antidiabetic agent, has been shown to inhibit atherosclerotic process, but its mechanism of action is not yet elucidated. This study was undertaken to examine the effects of troglitazone, a peroxisome proliferator- activated receptor- (PPAR ) ligand, on vascular smooth muscle cell proliferation. METHODS: Aortic smooth muscle cells were isolated from Sprague-Dawley rats and the effects of several different agonists (insulin, ET-I, IGF-I) on cellular DNA synthesis were measured and compared with the effects of troglitazone. In addition, the mRNA of PPARgamma gene in rat aortic smooth muscle cells(RASMCs) was detected by RT-PCR methods. RESULTS:1. Insulin, endothelin-I and IGF-I significantly stimulated DNA synthesis in RASMCs (p<0.05). 2. Insulin-induced DNA synthesis was not significantly inhibited by coincubation with wortmannin or LY294002 but inhibited by PD98059. 3. Troglitazone significantly inhibited insulin, endothelin-I and IGF-I-induced DNA synthesis in RASMCs (p<0.05, respectively). 4. PPAR mRNA was detected in RASMCs by RT-PCR and its expression did not significantly increase by troglitazone treatment. CONCLUSION: Troglitazone could inhibit agonist-induced proliferation of vascular smooth muscle cells and might be a useful agent for treatment as well as prevention of atherosclerosis.
- Distension and Collagenase Digestion Time of The Pancreas are Critical Factors in Islet Isolation of Canine Pancreas.
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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
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Korean Diabetes J. 2000;24(2):180-190. Published online January 1, 2001
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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.
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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
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Korean Diabetes J. 2000;24(2):170-179. Published online January 1, 2001
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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.
- Mutations in Hepatocyte Nuclear Factor-la in Early-Onset Type 2 Diabetes Mellitus in Korea.
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Kyoung Ah Kim, Myung Shik Lee, Kyu Jeung Ahn, Jae Hoon Chung, Yong Ki Min, Moon Kyu Lee, Ki Up Lee, Ghi Su Kim, Kyoung Ho Suk, Dae Yeun Hwang, Kwang Won Kim
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Korean Diabetes J. 1999;23(6):793-802. Published online January 1, 2001
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Type 2 diabetes mellitus is a heterogeneous disorder caused by the unfavorable combination of genetic and environmental factors. Maturity-onset diabetes of the young (MODY) is a rare form of familial type 2 diabetes mellitus characterized by an early onset, and it is appearance in at least three consecutive generations, consistent with an autosomal dominant mode of inheritance. It accounts for 1~3% of type 2 diabetes mellitus cases. As of today, five different MODY genes have been identified. In 1996, Yamagata et al. reported that MODY3 and MODY 1 were caused by mutations in hepatocyte nuclear factor (HNF) la and 4a, respectively. Furthermore, there have been reports that HNF-la gene mutation could be a cause of early-onset type 2 diabetes mellitus with familial history, although these patients do not fulfill the clinical criteria of MODY. Therefore, the purpose of this study was to examine the mutation of HNF-la gene in early-onset type 2 diabetes mellitus in Korean subjects. METHODS: Sixteen cases of early-onset type 2 diabetes mellitus with familial history were included in the study. Five of these subjects were MODY patients according to our revised criteria. DNA was isolated from peripheral blood. The 10 exons and flanking introns of the HNF-1 a gene were amplified by polymerase chain reaction (PCR). The PCR products were sequenced using an AmpliTaq FS Dye Terminator Cycle Sequencing Kit (Perkin-Elmer Applied Biosystems). RESULT: Mutation in the HNF-la gene was identified in 1 of the 16 patients. It was a hitherto unreported novel missense mutation, R263L. This mutation co-segregated with type 2 diabetes mellitus or impaired glucose tolerance in his family and was not found in family members with normal glucose tolerance. CONCLUSION: Findings from this study suggests that MODY3 caused by mutation of HNF-la gene is also present in early onset type 2 diabetic of Korean subjects. This is the first time that HNF-la mutation causing MODY was identified in Korea.
- The Appropriteness of New ADA Diagnostin Criteria for Diabetes Mellitus in Korean Population.
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Moon kyu Lee, Myung Shik Lee, Young Ki Min, Sung Hoon Kim, Byoung Joon Kim, Dong Jun Kim, Jong Ryeal Hahm, Eun Young Oh, Yun Jae Chung, Kyoung Ah Kim, Jae Hoon Chung, Kwang Won Kim
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Korean Diabetes J. 1999;23(3):336-351. Published online January 1, 2001
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The ADA has proposed a new diagnostic criteria for diabetes based on fasting plasma glucose, redefining diabetes as fasting plasma glucose 7.0 mmol/L. Since only a few studies for the appropriateness of tbis new ADA criteria were undertaken in the Korean population, we examined the appropriateness of the new ADA criteria by analyzing the results of oral glucose tolerance tests done in our hospital. METHODS: 507 oral glucose tolerance tests were conducted. Cases with diabetes and diseases that could affect the glucose tolerance were excluded. Plasma glucose was measured by the hexokinase method. Three groups of NGT, IGT, and DM by the WHO criteria of 2 hour-plasma glucose were redivided at each level of fasting plasma glucose. We calculated the sensitivity and specificity of each level of fasting plasma glucose (FPG), and the FPG value of maximum accuracy to diagnose diabetes with reference to the WHO criteria of 2 hour-plasma glucose. RESULTS: Correlation between the levels of fasting plasma glucose and 2 hour-plasma glucose was relatively low (r=0.676). FPG of 7.0 mmol/L for diagnosing diabetes was relatively specific (specificity=0.934), but not sensitive (sensitivity= 0.552). FPG value of maximum accuracy for diagnosing diabetes was 6.8 mmol/L. 39 % of IFG (> 6.1mmol/L and < 7.0mmol/L) was reclassified as diabetes by the criteria of 2 hour plasma glucose 11.1 mmol/L and 34 % of NFG (<6.1mmol/L) was reclassified as impaired glucose tolerance by the criteria of 2 hour plasma glucose > 7.8 mmol/L. CONCLUSION: The fasting plasma glucose of 7.0 mmol/L was relatively specific for diagnosing diabetes. However, the new ADA criteria tended to underestimate the prevalence of diabetes and impaired glucose tolerance in the Korean population. Therefore, oral glucose tolerance test may be needed to diagnose diabetes in high risk subjects. Large-scale cross-sectional and prospective studies will be needed to clarify these points.
- Measurement of Anti-Phogrin Antibody in Korean Autoimmune Deabetes; Comparison to Anti-IA-2 Antibody.
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Moon kyu Lee, Yong Ki Min, Myung Shik Lee, Sung Hoon Kim, Byoung Joon Kim, Dong Jun Kim, Jong Ryeal Hahm, Dong Kyu Jin, Kyoung Ah Kim, Kwang Won Kim
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Korean Diabetes J. 1999;23(3):269-277. Published online January 1, 2001
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Since the discovery of IA-2 as a major autoantigen in type 1 diabetes, the question arose as to whether other PTPs (protein tyrosine phosphatases) could act as diabetic autoantigens as well. A novel PTP, designated IA-2 B (phogrin; phosphatase homologue in granules of insulinoma) was isolated that has a high sequence similarity to IA-2. Since some studies suggested that auto- immunity to phogrin, rather than IA-2 may be more closely associated with the development of type 1 diabetes, we measured the frequency of anti-phogrin antibody in Korean patients with type 1 diabetes and compared it with that of anti-IA-2 antibody/ anti-GAD antibody. METHODS: The anti-phogrin antibody and the anti-IA-2 antibody were measured by radioligand binding assays using in vitro transcribed and translated S-labeled phogrin and IA-2, respectively. Anti-GAD antibody was measured using a commercial radioimmunoassay kit (RSR, Cardiff, U.K.). The subjects in this study consisted of 41 patients with classical type 1 diabetes, 22 with slowly progressive type 1 diabetes, and 39 with type 2 diabetes. Their average mean age was 16.9 years, 37.9 years and 45.3 years respectively. RESULTS: The prevalence of anti-phogrin antibody, anti-IA-2 antibody and anti-GAD antibody in classical type 1 diabetes was 24.4%, 26.8% and 51.2% respectively. That, in slowly progressive type 1 diabetes was 0%, 9.1% and 40.9% respectively. When the anti-GAD antibody assay and the anti-IA-2 antibody assay were combined, the prevalence of autoantibodies was 58.5% in classical type 1 diabetes and 50% in slowly progressive type I diabetes. However, the addition of the anti-phogrin antibody to the anti-GAD antibody/anti-IA-2 antibody measurement did not significantly increase the prevalence of autoantibody. The level of the antiphogrin antibody was positively correlated with that of the anti-IA-2 antibody. The presence of the anti-phogrin antibody and the anti-IA-2 antibody was negatively correlated with the age at diagnosis. One patient with type 1 diabetes had the anti-phogrin antibody without the anti-IA-2 antibody. CONCLUSION: Combined measurement of the anti-phogrin antibody with the anti-IA-2 antibody/ anti-GAD antibody did not significantly increase the prevalence of autoantibodies in Korean patients with type 1 diabetes. In the majority of Korean type 1 diabetes patients, the anti-phogrin antibody appears to share epitopes with the anti-IA-2 antibody. However, a small proportion of type 1 diabetes patients may have a specific autoimmune response to phogrin.
- Efficacy and Safety of Glimepiride: A Novel Sulfonylurea Drug compared with Gliclazide in the Treatment of Type 2 Diabetes Mellitus: an Open , Randomized Comparative Multi - Center Clinical Study.
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Sung Kwan Hong, Ki Up Lee, Yeon Sang Oh, Ho Young Son, Kwang Won Kim, Hyun Chul Lee, Kyung Rae Kim, Dong Seop Choi, Ie Byung Park, Young Seol Kim, Kwan Woo Lee, Hong Kyu Lee, Soon Hyun Shin
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Korean Diabetes J. 1999;23(1):87-97. Published online January 1, 2001
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Glimepiride (HOE490, Amaryl (R)) is a new, third generation sulfonylurea, which binds to a different protein of the sulfonylurea receptor than other sulfonylureas. Although there have been many studies proving the efficacy of glimepiride on Caucasian diabetic patients, only a few studies are available on Asian diabetic patients. We performed an open, randomized, comparative multicenter clinical trial to assess the efficacy and safety of glimepiride in Korean type 2 diabetic patients. METHOD: We recruited 262 type 2 cliabetic patients at 12 different university hospitals whose blood glucose was not controlled effectively with diet alone. Patients were randomized to 1~2mg glimepiride or 40~80mg gliclazide depending on the fasting blood glucose level. Doses were increased stepwise, up to 8mg for glimepiride (once-daily) and 320mg for gliclazide (>80 mg as dividedose) respectively, until metabolic control (fasting blood glucose < 7.9 mmol/L) or maximum dose was achieved. The quality of rnetabolic control was assessed by fasting blood glucose and HbA 1c as primary variables. Insulin, C-peptide and weight were monitored as secondary variables. Safety was assessed by obtaining patient history and laboratory values of relevant variables. RESULTS: Of the 262 patients randomized to treatment, 160(61%) patients completed the 18-week study. The rate of successful blood glucose control (3.9
- Plasma leptin Concentrations in Korean Type 2 Diabetic Patients.
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Eun Young Oh, Yun Jae Chung, Yoon Ho Choi, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
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Korean Diabetes J. 1998;22(4):531-537. Published online January 1, 2001
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Obesity is a well-established risk factor for a number of chronic diseases, including type 2 diabetes mellitus, hypertension, cardiovascular disease, and hyperlipidemia. Leptin, the protein procluct of the ob gene, is increased in obese individuals, suggesting resistance to its effect. We investigated whether the subjects with type 2 diabetes have an altered regulation of serum leptin levels METHODS: 205 Korean type 2 diabetic patients and 174 normal contro1 subjects participated in this study. We evaluated a difference between leptin level of diabetic patients and that of normal controls. In diabetic patients, correlations among plasma leptin concentration and other factors such as serum insulin concentration, percentage body fat, BMI, gender, total cholesterol, triglyceride, and fasting serum glucose level were evaluated. RESULTS: Fasting plasma leptin concentrations were correlated to BMI, percentage body fat, gender and serum insulin concentration. Plasma leptin concentrations are not significantly different in diabetic subjects compared to controls. CONCLUSIONS: We conclude that there was no significant difference in semm leptin level between type 2 diabetic and normal subjects and that body fat, sex, and the fasting insulin level are independently associated with plasma leptin level in type 2 diabetic patients.
- Combined Measurements of Anti-ICA512 and Anti-GAD Antibodies in Insulin-dependent Diabetes Mellitus and Slowly Progressive Insulin-dependent Diabetes Mellitus in Korea.
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Kyoung Ah Kim, Kyu Jung Ahn, Jae Hoon Chung, Yong Ki Min, Moon Kyu Lee, Phil Soo Oh, Dong Kyu Jin, Byung Tae Kim, Hae Joon Park, Kwang Won Kim, Myung Shik Lee
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Korean Diabetes J. 1998;22(4):482-490. Published online January 1, 2001
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Type 1 diabetes mellitus is a chronic autoimmune disease in which circulating antibodies to various islet-specific antigens including autoantibodies to glutamic acid decarboxylase (GADAb), antibodies reacting with an islet tyrosine phosphatase-related molecule termed as ICA512 (ICA512Ab), and insulin autoantibodies are frequently detected. These autoantibodies could be useful for presymptomatic diagnosis of type 1 diabetes mellitus, and tbeir presence suggest some patients with atypical diabetes mellitus that appears to be more prevalent in Asian than in western countries have autoimmune characteristics. ICA512Ab was discovered in 1992 and, when combined with GADAb, may increase the diagnostic sensitivity in autoimmune diabetes. In an attempt to study the autoimmune feature of atypical diabetes mellitus, we studied the prevalence of ICA512Ab using an in vitro transcription and translation method in the patients with insulin-dependent diabetes mellitus (IDDM), slowly progressive insulin-dependent diabetes mellitus (SPIDDM) and non-msulin-dependent diabetes mellitus (NIDDM), and compared it with that of GADAb. METHODS: ICA512Ab were measured by a radioimmunoprecipitation method using in vitro transcribed and translated S-methionine-labeled ICA512. GADAb were measured using a commercial radioimmunoassay kit (RSR, United Kingdom). The subjects in this study consisted of 43 patients with IDDM, 32 with SPIDDM, and 40 witb NIDDM. Their mean age was 21.2+14.5 years, 50.1+17.1 years, 52.5+13.4 years, respectively. RESULTS: The prevalence of ICA512Ab and GADAb in IDDM was 29 % and 51 %, respectively. That in SPIDDM was 9 % and 29 %; in NIDDM, 0 % and 2.5 %, respectively. When two antibodies were combined, 60 % of IDDM and 50 % of SPIDDM had the autoantibodies. When we analyzed the prevalence of autoantibodies according to the duration of diabetes, the prevalence of ICA 512Ab in patients tested within 4 years after the rliagnosis and more than 4 years after the diagnosis was 35 % and 19 %, respectively in IDDM. And also that of GADAb was 59 % and 38 %, respectively. In SPlDDM, the prevalence of ICA512Ab was 13 % and 7 %, respectively, while that of GADAb was 67 % and 14 % (p<0.05), respectively. In IDDM, ICA512Ab were more frequently detected in patients younger than 15 years ot age (45 %) than in older ones (14%) (p<0.05) while the prevalence of GADAb was not different according to the age (55 % vs 44 %). CONCLUSION: ICA512Ab are detected in some patients with autoimmune diabetes, while their prevalence is lower than that of GADAb. However, ICA512Ab, in combination with GADAb, increases the sensitivity ot autoantibody tests in autoimmune diabetes. Some of SPIDDM have an autoimmune etiology.
- The Significance of thebeta3 Adrenergic Receptor Gene Polymorphism in Obese Koreans.
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Byoung Joon Kim, Sung Hoon Kim, Dong Jun Kim, Jong Ryeal Hahm, Jin Seok Kim, Kyu Jeung Ahn, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim
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Korean Diabetes J. 1998;22(4):450-456. Published online January 1, 2001
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The b3 adrenergic receptor (b3-AR), expressed mainly in visceral fat of human, is involved in regulation of lipolysis and thermogenesis. The missense mutation of b3-AR gene, resulting in the replacement of tryptophan by arginine at position 64 (Trp64Arg), is associated with decreased resting metabolic rate, weight gain and development of obesity. The purpose of this study was to investigate the frequency of the b3-AR gene polymorphism in obese Koreans. Subjects and METHODS: b3-AR genotype was determined in 87 healthy Koreans who visited SMC for the purpose of health checking from Dec/1996 to Feb/1997. Oral glucose tolerance test was performed with 75 g glucose. Lipid profiles, insulin, C-peptide were measured. Anthropometric data was obtained from physical examination and medical records. The subjects with previously diagnosed diabetes mellitus, other endocrine diseases or chronic illness were excluded. To determine the polymorphism, genomic DNA was isolated and PCR and RFLP by MvaI were carried. RESULTS: 1. The difference in frequency of Trp64Arg mutation between two groups was highly significant. (12 subjects (63%) in obese group and 21 subjects (30%) in non obese group, p<0.02) 2. There was significantly high allele frequency in obese group. (obese group: 32 %; non obese group: 15 %, p<0.02). 3. According to BMI, there were significantly high WHR (0.88+0.04 vs 0.83+0.06,p=0.01), total body fat (29.8+7.4 vs 24.4+6.5%, p=0.01) and systolic blood pressure(132+19 vs 124+14mmHg, p=0.04) in obese group. 4. According to b3-AR genotype, there were significantly high WHR (0.830.056 vs. 0.860.05) and 120 min (260.5+171. 5 vs 355.9+234.6 pmol/L, p=0.04) insulin level during OGTT in heterozygote group. CONCLUSION: These results suggest that the frequency of the b3-AR gene mutation was significantly higher in obese Koreans and b3-AR gene polymorphism might play a role in the pathogenesis of obesity.
- Lowering Effect of Voglibose, Monotherapy on Uncontrolled Postprandial Glucose in Patients with Non-Insulin Dependent Diabetes Mellitus (NIDDM) Being Treated with Strict Diet Control: Multicenter Open-Study.
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Jeong Taek Woo, Young Seol Kim, Young Kil Choi, Jin Woo Kim, In Myung Yang, Sung Woon Kim, Deog Yoon Kim, Kwang Won Kim, Moon Kyu Lee, Myung Shik Lee, Jae Hoon Jung, Kyu Jeong Ahn, Hyun Chul Lee, Young Deuk Song, Bong Soo Cha, Jee Hyun Lee, Hyung Joon Won
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Korean Diabetes J. 1998;22(3):419-428. Published online January 1, 2001
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Abstract
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- BACKGROUND
It is sometimes very difficult to control the elevation of postprandial glucose with diet therapy only in patients with NIDDM partly because of their defective insulin response to glucose. Recently the alpha-glucosidase inhibitors which inhibit carbohydrate digestion and suppress or delay absorption of the final breakdown products, glucose and fructose when it is taken orally with meal have been widely used in the treatment of diabetes. The drugs, however, provoke the adverse effects e.g. flatulence, diarrhea etc. in some patients. Therefore we studied the efficacy of the more recently developed alpha glucosidase inhibitor, Voglibose (Basen, Cheiljedang) METHODS: Fifty five patients whose postprandial two hour serum glucose levels were more than 11.1 mmol/L despite the strict diet therapy during the 4 week observation period were assigned to receive Voglibose 0.2 mg before each meal t.i.d. for 8 weeks. Of 55 subjects, 41 were given Voglibose 0.3 mg t..i.d. for the last 4 weeks because of their poor glucose control, RESULTS: The postprandial one and two hour serum glucose levels significantly decreased after therapy; 1 hour: 17.5+4.4 mmol/L(prior to therapy), 15.4+3.8 mmol/L(4 week after), 14.8+5.1 mmol/L(8 week), p <0.00l, 2 hour: 16.7+4.5 mmol/L, 14.8+3.9 mmol/ L, 14.8+4.5 mmol/L, p<0.00 l, t-tests for paired samples. Total serum cholesterol and HDL cholesterol levels also significantly decreased(5.24+1.06 - 4.90+1.27 mmol/L, p=0.036, 1.34+0.66 1.16 +0.3l mmol/L, p=0.035 respectively) However, HbAlc, serum fructosamine, insulin and triglyceride levels were not significantly changed. The prevalence of the adverse effects due to Voglibose was 14%(10/71). All of them were less than grade II of WHO criteria and disappeared despite continuing therapy. CONCLUSION: Voglibose monotherapy is considered as having an glucose lowering effect in patients with NIDDM whose adequate postprandial blood glucose cannot be achieved with diet therapy only.
- Clinical effect of topical capsaicin in painful diabetic polyneuropathy.
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Dai Ok Cho, Jae Man Kim, Deog Yoon Kim, Jeong Taek Woo, Sung Woon Kim, In Myung Yang, Jin Woo Kim, Young Seol Kim, Kwang Won Kim, Young Kil Choi
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Korean Diabetes J. 1993;17(4):411-417. Published online January 1, 2001
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- No abstract available.
- Glut4 in the insulin resistance of NIDDM.
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Kwang Won Kim
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Korean Diabetes J. 1993;17(2):157-159. Published online January 1, 2001
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- No abstract available.
- The influence of feedback inhibition of insulin secretion by insulin itself in isolated rat islets.
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Sung Hoon Kim, Sung Yi Kang, Deog Yoon Kim, Kwang Sik Seo, Jeong Taek Woo, Sung Woon Kim, In Myung Yang, jin Woo Kim, Young Seol Kim, Kwang Won Kim, Young Kil Choi
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Korean Diabetes J. 1993;17(1):35-43. Published online January 1, 2001
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- No abstract available.
- Three dimensional long-term culture of rat islets using gelatin gel.
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Deog Yoon Kim, Kwang Sik Seo, Eun Mi Koh, Jeong Taek Woo, Seong Woon Kim, In Myung Yang, Jin Woo Kim, Young Seol Kim, Kwang Won Kim, Young Kil Choi
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Korean Diabetes J. 1992;16(4):299-307. Published online January 1, 2001
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- No abstract available.
- Serum lipoprotein(a) concentration in patients with diabetic retinopathy.
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Seung Joon Oh, Deog Yoon Kim, Jung Taek Woo, Sung Woon Kim, In Myung Yang, Ji Woo Kim, Young Seol Kim, Kwang Won Kim, Young Kil Choi
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Korean Diabetes J. 1992;16(4):281-287. Published online January 1, 2001
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- No abstract available.
- Combined effect of hyperglycemia and interleukin-1 beta on the insulin secretion of isolated rat islets.
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Kwang Won Kim, Deog Yoon Kim, Kwang Sik Seo, Eun Mi Koh, Jeong Taek Woo, Sung Woon Kim, In Myung Yang, Jin Woo Kim, Young Seol Kim, Young Kil Choi
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Korean Diabetes J. 1992;16(3):187-198. Published online January 1, 2001
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- Increased aldose reductase activity of cultured endothelial cell inhigh glucose media and reserve by epalrestat.
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Seug Young Na, Jung Taik Woo, Jin Woo Kim, Kwang Won Kim, Young Seol Kim, Young Kil Choi, Kang Sik Seo, Jeong Rung Paeng
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Korean Diabetes J. 1992;16(1):17-23. Published online January 1, 2001
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- Changes of plasma endothelin in non-insulin dependent diabetes mellitus.
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Jeung Taek Woo, Hae Ran Lee, Jin Woo Kim, Young Seol Kim, Kwang Won Kim, Young Kil Choi
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Korean Diabetes J. 1991;15(2):251-256. Published online January 1, 2001
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- No abstract available.
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