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Sung Dae Moon  (Moon SD) 15 Articles
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 J. 2009;33(6):475-484.   Published online December 1, 2009
DOI: https://doi.org/10.4093/kdj.2009.33.6.475
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AbstractAbstract PDF
BACKGROUND
Despite a recent breakthough in human islet transplantation for treating type 1 diabetes mellitus, the limited availability of donor pancreases remains a major obstacle. Endocrine cells within the gut epithelium (enteroendocrine cells) and pancreatic beta cells share similar pathways of differentiation during embryonic development. In particular, K-cells that secrete glucose-dependent insulinotropic polypeptide (GIP) have been shown to express many of the key proteins found in beta cells. Therefore, we hypothesize that K-cells can be transdifferentiated into beta cells because both cells have remarkable similarities in their embryonic development and cellular phenotypes. METHODS: K-cells were purified from heterogeneous STC-1 cells originating from an endocrine tumor of a mouse intestine. In addition, a K-cell subclone expressing stable Nkx6.1, called "Kn4-cells," was successfully obtained. In vitro differentiation of K-cells or Kn4-cells into beta cells was completed after exendin-4 treatment and serum deprivation. The expressions of insulin mRNA and protein were examined by RT-PCR and immunocytochemistry. The interacellular insulin content was also measured. RESULTS: K-cells were found to express glucokinase and GIP as assessed by RT-PCR and Western blot analysis. RT-PCR showed that K-cells also expressed Pdx-1, NeuroD1/Beta2, and MafA, but not Nkx6.1. After exendin-4 treatment and serum deprivation, insulin mRNA and insulin or C-peptide were clearly detected in Kn4-cells. The intracellular insulin content was also increased significantly in these cells. CONCLUSION: K-cells are an attractive potential source of insulin-producing cells for treatment of type 1 diabetes mellitus. However, more experiments are necessary to optimize a strategy for converting K-cells into beta cells.

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  • Reprogramming of enteroendocrine K cells to pancreatic β-cells through the combined expression of Nkx6.1 and Neurogenin3, and reaggregation in suspension culture
    Esder Lee, Gyeong Ryul Ryu, Sung-Dae Moon, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song
    Biochemical and Biophysical Research Communications.2014; 443(3): 1021.     CrossRef
Treatment of Type 1 Diabetes through Genetically Engineered K-cell Transplantation in a Mouse Model.
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 J. 2009;33(6):466-474.   Published online December 1, 2009
DOI: https://doi.org/10.4093/kdj.2009.33.6.466
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AbstractAbstract PDF
BACKGROUND
K-cells function as targets for insulin gene therapy. In a previous study, we constructed EBV-based plasmids expressing rat preproinsulin controlled by glucose-dependent insulinotropic polypeptide promoters. In the present study, we attempted to correct hyperglycemia in vivo using genetically engineered K-cells in a mouse model of type 1 diabetes. METHODS: K-cells expressing insulin were transplanted under the kidney capsules of STZ-induced diabetic mice. The blood glucose levels and body weights of the experimental animals were measured daily. After four weeks, the mice were injected intra-peritoneally with 2 g/kg glucose following a 6 hr fast. Blood glucose levels were measured immediately following glucose injections. All animals were sacrificed at the end of the glucose tolerance study, and pancreas and graft-bearing kidney tissue samples were stained with antibodies against insulin, glucagon, and C-peptide. RESULTS: The body weights of K-cell-transplanted diabetic mice increased after transplantation, whereas those of untreated diabetic control mice continued to decline. The blood glucose levels of K-cell-transplanted diabetic mice decreased gradually during the two weeks following transplantation. After intra-peritoneal injection of glucose into K-cell-transplanted diabetic mice, blood glucose levels increased at 30 minutes, and were restored to the normal range between 60 and 90 minutes, while untreated control diabetic mice continued to experience hyperglycemia. Kidney capsules containing transplanted K-cells were removed, and sections were stained with anti-insulin antibodies. We detected insulin-positive cells in the kidney capsules of K-cell-transplanted diabetic mice, but not in untreated control mice. CONCLUSION: We detected glucose-dependent insulin secretion in genetically engineered K-cells in a mouse model of type 1 diabetes. Our results suggest that genetically modified insulin producing K-cells may act as surrogate beta-cells to effectively treat type 1 diabetes.
Incidence of Diabetic Foot and Associated Risk Factors in Type 2 Diabetic Patients: A Five-year Observational Study.
Shin Ae Park, Seung Hyun Ko, Seung Hwan Lee, Jae Hyoung Cho, Sung Dae Moon, Sang A Jang, Hyun Shik Son, Ki Ho Song, Bong Yun Cha, Ho Young Son, Yu Bae Ahn
Korean Diabetes J. 2009;33(4):315-323.   Published online August 1, 2009
DOI: https://doi.org/10.4093/kdj.2009.33.4.315
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AbstractAbstract PDF
BACKGROUND
The frequency of lower extremity amputation due to diabetic foot has been increasing in type 2 diabetic patients. The aim of this study was to observe the incidence, clinical aspects and associated risk factors for diabetic foot. METHODS: We evaluated the incidence of diabetic foot through a five-year observation of type 2 diabetic patients who presented to St. vincent's Hospital between January and December 2003. To identify the risk factors for diabetic foot, we evaluated mean glycosylated hemoglobin A1c (HbA1c) every six months and assessed renal function based on the existence of proteinuria and estimated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) equation. Patients were also evaluated for retinopathy, peripheral neuropathy and autonomic neuropathy using Ewing's method. RESULTS: From an initial pool of 613 patients, the observational study of 508 patients (82.9%) was completed. The mean age, duration of diabetes and HbA1c were 50.3 +/- 10.6 yrs, 7.2 +/- 6.5 yrs and 8.8 +/- 2.1%, respectively. Diabetic foot occurred in 32 patients (6.3%). The incidence of diabetic foot increased when diabetic retinopathy (OR = 6.707, 2.314~19.439), peripheral neuropathy (OR = 2.949, 1.075~8.090), and autonomic neuropathy (OR = 3.967, 1.476~10.660) were present and when the MDRD GFR (OR = 5.089, 1.712~15.130) decreased. Mean HbA1c (OR = 12.013, 1.470~98.179) was found to be an independent risk factor for diabetic foot. CONCLUSION: The present study confirmed the importance of intensive glycemic control and the role of autonomic dysfunction in the development of diabetic foot. In addition, diabetic retinopathy and impaired renal function proved to be factors associated with the occurrence of diabetic foot. Therefore, intensive glycemic control, as well as periodic examination of renal function, are essential for the prevention of diabetic foot.

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  • The Risk of the Aggravation of Diabetic Foot According to Air Quality Factors in the Republic of Korea: A Nationwide Population-Based Study
    Saintpee Kim, Sungho Won, Young Yi
    International Journal of Environmental Research and Public Health.2024; 21(6): 775.     CrossRef
  • Microbiological, Clinical and Radiological Aspects of Diabetic Foot Ulcers Infected with Methicillin-Resistant and -Sensitive Staphylococcus aureus
    Maria Stańkowska, Katarzyna Garbacz, Anna Korzon-Burakowska, Marek Bronk, Monika Skotarczak, Anna Szymańska-Dubowik
    Pathogens.2022; 11(6): 701.     CrossRef
  • Potential of Nanoencapsulated Quercetin Topical Formulations in the Management of Diabetic Foot Ulcer
    Shashank Chaturvedi, Shruti Agrawal, Anuj Garg, Vaibhav Rastogi
    Revista Brasileira de Farmacognosia.2022; 33(3): 484.     CrossRef
  • Development of a Diabetic Foot Ulceration Prediction Model and Nomogram
    Eun Joo Lee, Ihn Sook Jeong, Seung Hun Woo, Hyuk Jae Jung, Eun Jin Han, Chang Wan Kang, Sookyung Hyun
    Journal of Korean Academy of Nursing.2021; 51(3): 280.     CrossRef
  • Regional Variation in the Incidence of Diabetes-Related Lower Limb Amputations and Its Relationship with the Regional Factors
    Sung Hun Won, Jahyung Kim, Dong-Il Chun, Young Yi, Suyeon Park, Kwang-Young Jung, Gun-Hyun Park, Jaeho Cho
    Journal of Korean Foot and Ankle Society.2019; 23(3): 121.     CrossRef
  • The Changes of Trends in the Diagnosis and Treatment of Diabetic Foot Ulcer over a 10-Year Period: Single Center Study
    Choong Hee Kim, Jun Sung Moon, Seung Min Chung, Eun Jung Kong, Chul Hyun Park, Woo Sung Yoon, Tae Gon Kim, Woong Kim, Ji Sung Yoon, Kyu Chang Won, Hyoung Woo Lee
    Diabetes & Metabolism Journal.2018; 42(4): 308.     CrossRef
  • The Relationship between Body Mass Index and Diabetic Foot Ulcer, Sensory, Blood Circulation of Foot on Type II Diabetes Mellitus Patients
    Yi Kyu Park, Jun Young Lee, Sung Jung, Kang Hyeon Ryu
    Journal of the Korean Orthopaedic Association.2018; 53(2): 136.     CrossRef
  • Factors Contributing to Diabetic Foot Ulcer among Patients with Type 2 Diabetes Mellitus
    Seo Jin Park, Taeyoung Yang, Jun Young Lee, Jinhee Kim
    Korean Journal of Adult Nursing.2018; 30(1): 106.     CrossRef
  • A Report on Diabetic Foot and Amputation from the Korean Health Insurance Review & Assessment Service Data
    Jong-Kil Kim, Young-Ran Jung, Kyung-Tae Kim, Chung-Shik Shin, Kwang-Bok Lee
    Journal of Korean Foot and Ankle Society.2017; 21(2): 66.     CrossRef
  • Prevalence and Current Status of Treatment of Diabetic Foot in South Korea
    Jae-Ik Bae, Je Hwan Won, Jun Su Kim, Man Deuk Kim, Chang Jin Yoon, Yun Ku Cho
    Journal of the Korean Society of Radiology.2016; 74(3): 169.     CrossRef
  • Diabetic Foot Disease—Incidence and Risk Factors: A Clinical Study
    Rajesh Kapila, Rakesh Sharma, Ashwani K Sharma, Jagsir Mann
    Journal of Foot and Ankle Surgery (Asia Pacific).2016; 3(1): 41.     CrossRef
  • Diabetic Peripheral Neuropathy in Type 2 Diabetes Mellitus in Korea
    Seung-Hyun Ko, Bong-Yun Cha
    Diabetes & Metabolism Journal.2012; 36(1): 6.     CrossRef
  • Diabetics' Preference in the Design Factors and Performance Requirements of Diabetic Socks
    Ji-Eun Lee, Young-Ah Kwon
    Journal of the Korean Society of Clothing and Textiles.2011; 35(5): 527.     CrossRef
  • Epidemiology of Diabetic Foot Disease
    Kyu Jeung Ahn
    Journal of Korean Diabetes.2011; 12(2): 72.     CrossRef
Average Daily Risk Range-Index of Glycemic Variability-Related Factor in Type 2 Diabetic Inpatients.
Shin Ae Park, Seung Hyun Ko, Seung Hwan Lee, Jae Hyung Cho, Sung Dae Moon, Sang A Jang, Ki Ho Song, Hyun Shik Son, Kun Ho Yoon, Bong Yun Cha, Ho Young Son, Yu Bae Ahn
Korean Diabetes J. 2009;33(1):31-39.   Published online February 1, 2009
DOI: https://doi.org/10.4093/kdj.2009.33.1.31
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AbstractAbstract PDF
BACKGROUND
It is known that chronic sustained hyperglycemia and its consequent oxidative stress causes diabetic complication in type 2 diabetes. It has been further proven that glycemic variability causes oxidative stress. The aim of this study is to measure the average daily risk range (ADDR)-index of glycemic variability, and to evaluate relevant variables. METHODS: We measured the blood glucose level of type 2 diabetic patients who were treated with multiple daily injections from January to July, 2008. The blood glucose levels were checked four times a day for 14 days and were conversed according to the ADRR formula. The degree of glycemic variability was categorized into non-fluctuation and fluctuation groups. We collected patient data on age, sex, duration of diabetes, body mass index, HOMA(IR), HOMA(betacell) and HbA1c. RESULTS: A total of 97 patients were enrolled in this study. The mean age, duration of diabetes, HbA1c and mean ADRR were 57.6 +/- 13.4, 11.5 +/- 8.5 years, 10.7 +/- 2.5%, and 26.6 +/- 9.8, respectively. We classified 18.5% of the patients to the non-fluctuation group, and 81.5% to the fluctuation group. ADRR was significantly correlated with duration of diabetes, fasting and postprandial glucose, fructosamine, HbA1c and BMI and HOMAbetacell. In addition, this study confirmed that BMI, HOMAbetacell and HbA1c were ADRR-related independent variables. CONCLUSION: ADRR can be used as an index for blood glucose fluctuation in type 2 diabetic patients. Measuring ADRR in patients with low BMI and a long duration of diabetes is helpful to improve the effectiveness of their care.

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  • Relationships between Thigh and Waist Circumference, Hemoglobin Glycation Index, and Carotid Plaque in Patients with Type 2 Diabetes
    Myung Ki Yoon, Jun Goo Kang, Seong Jin Lee, Sung-Hee Ihm, Kap Bum Huh, Chul Sik Kim
    Endocrinology and Metabolism.2020; 35(2): 319.     CrossRef
  • Reversal of Hypoglycemia Unawareness with a Single-donor, Marginal Dose Allogeneic Islet Transplantation in Korea: A Case Report
    Hae Kyung Yang, Dong-Sik Ham, Heon-Seok Park, Marie Rhee, Young Hye You, Min Jung Kim, Ji-Won Kim, Seung-Hwan Lee, Tae Ho Hong, Byung Gil Choi, Jae Hyoung Cho, Kun-Ho Yoon
    Journal of Korean Medical Science.2015; 30(7): 991.     CrossRef
Differentiation of Pancreatic beta Cells from Human Pancreatic Duct Cells Derived from a Partial Pancreas Tissue.
Ki Ho Song, Myung Mee Kim, Min Kyung Lee, Gyeong Ryul Ryu, Seung Hyun Ko, Sung Dae Moon, Yu Bae Ahn, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang, Hyung Min Chin
Korean Diabetes J. 2007;31(3):236-242.   Published online May 1, 2007
DOI: https://doi.org/10.4093/jkda.2007.31.3.236
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AbstractAbstract PDF
BACKGROUND
Despite a recent breakthrough in human islet transplantation for treating diabetes mellitus, the limited availability of insulin-producing tissue is still a major obstacle. This has led to a search for alternative sources of transplantable insulin-producing cells including pancreatic duct cells. We aimed to establish in vitro culture of pancreatic duct cells from a partial pancreas tissue in human, which could be harnessed to differentiate into pancreatic beta cells. METHODS: We isolated pancreatic duct cells from small pieces of pancreas tissue (1~3 g) derived from non-diabetic humans (n = 8) undergoing pancreatic surgery due to cancer. Pancreas tissue was finely minced after injection of collagenase P into the parenchyma. The mince was incubated in a shaking water bath at 37degrees C for 25 min and passed through a 150 micrometer mesh. The released cells were recovered, washed, and plated in a dish containing CMRL culture medium with serum. RESULTS: Isolated pancreatic cells grew in monolayer and became confluent in 1~2 wks showing typical epithelial cobblestone morphology. Immunochemistry demonstrated that ~90% of the cultured cells were cytokeratin7-positive duct cells. To induce beta cell differentiation, the cells were incubated in DMEM/F12 culture medium without serum. In addition, treatment with Matrigel overlay, exendin-4, cholera toxin or forskolin was done. Though beta cell differentiation was found by immunostaining and RT-PCR, the differentiation efficiency was very low. Over-expression of neurogenin-3 by recombinant adenovirus did not increase beta cell differentiation of the cultured duct cells significantly. CONCLUSION: We established in vitro culture of pancreatic duct cells from a partial pancreas tissue in human, which differentiate into pancreatic cells. However, a strategy to optimize beta cell differentiation in this model is needed.

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  • Transdifferentiation of Enteroendocrine K-cells into Insulin-expressing Cells
    Esder Lee, Jun Mo Yu, Min Kyung Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Sung-Dae Moon, Ki-Ho Song
    Korean Diabetes Journal.2009; 33(6): 475.     CrossRef
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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AbstractAbstract PDF
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
Inducible Nitric Oxide Synthase (iNOS) Expression in the Hypoxic Injury to Pancreatic Beta (MIN6) Cells.
Seung Hyun Ko, Seung Bum Kim, Kyung Ryul Ryu, Ji Won Kim, Yu Bai Ahn, Sung Dae Moon, Sung Rae Kim, Jung Min Lee, Hyuk Snag Kwon, Kun Ho Yoon, Ki Ho Song
Korean Diabetes J. 2006;30(5):336-346.   Published online September 1, 2006
DOI: https://doi.org/10.4093/jkda.2006.30.5.336
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AbstractAbstract PDF
BACKGROUND
Islet transplantation is an alternative potential strategy to cure type 1 diabetes mellitus. However, two or more donors are usually needed for one recipient because a substantial part of the graft becomes nonfunctional due to several factors including hypoxia. Though hypoxic exposure of pancreatic beta cells has been reported to induce apoptotic cell death, the molecular processes involved in hypoxia-induced cell death are poorly understood. In type I diabetes, Nitric Oxide (NO) is known as an important cytokine, involved in the pathogenesis of beta cell dysfunction. Pancreatic beta cells are sensitive to the induction of inducible nitric oxide synthase (iNOS) when stimulated by TNF-a or IL-1beta. But contribution of iNOS in response to hypoxia is not yet fully understood. METHODS: Mouse insulinoma cells (MIN6) were incubated in an anaerobic chamber (75% N2/15% CO2/5% H2) for up to 12 hours. Cell viability was measured after AO/PI staining. Caspase-3 activation was also determined using Western blot analysis. Nitric Oxide (NO) release into culture medium was measured using a Griess reagent. The expression of iNOS and PDX-1 mRNA and iNOS protein was examined using real time PCR and Western blot analysis. RESULTS: Marked cell death was observed within 6 hours after hypoxic exposure of MIN6 cells (control, < 5%; 2 hr, 11.0+/-7.6%; 6 hr, 46.2+/-12.8%, P < 0.05). Immunoreactivity to activated caspase-3 was observed at 2, 4 and 6 hrs. NO production was increased in a time dependent manner. Expression of iNOS mRNA and protein was significantly increased at 4 and 6 hour after hypoxia. iNOS expression was confirmed by immunostaining. Of note, Pdx-1 mRNA expression was markedly attenuated by hypoxic treatment. Pretreatment with a selective iNOS inhibitor, 1400 W, significantly prevented beta cell death induced by hypoxic injury. CONCLUSION: Our data suggest that iNOS-NO play an important role in hypoxic injury to MIN6 cells. Therefore, iNOS-NO might be a potential therapeutic target for improving engraftment of the transplanted islets and suppression of iNOS would be helpful for prevention of beta cells damage to hypoxic injury.
The long-term effect of ramipril on Gialpha2-protein and Protein Tyrosine Phosphatase 1B in an animal model of type 2 diabetes(OLETF rat).
Jung Min Lee, Ok Ki Hong, Hyuk Sang Kwon, Sung Dae Moon, Sang Ah Chang, Hyun Shik Son, Kun Ho Yoon, Bong Yun Cha, Sung Koo Kang
Korean Diabetes J. 2006;30(1):25-38.   Published online January 1, 2006
DOI: https://doi.org/10.4093/jkda.2006.30.1.25
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AbstractAbstract PDF
BACKGROUND
The regulation of tyrosine phosphorylation/dephosphorylation is an important mechanism in various intracellular metabolism. Also impaired insulin signal transduction is important in pathogenesis of type 2 diabetes. It has been reported that PTP1B is a negative regulator of insulin action, and Gialpha2-protein is related to the regulation of PTP1B. Herein we investigated the long-term effects of ramipril on PTP1B/insulin signal protein interaction and the relation between Gialpha2 and PTP1B in animal model of type 2 diabetes (OLETF rat). METHODS: OLETF rats and age-matched LETO rats were divided into two groups. One group of rats received ramipril (10 mg/kg body weight) for 12 weeks, and another group did not. Finally, each group was divided into 2 subgroups, with or without insulin injection intravenously, before sacrifice. After sacrifice, tissues extracts of liver, hind limb muscle, and epididymal fat were obtained for quantification of PTP1B, Gialpha2, and several insulin signal proteins by western blotting. RESULTS: In liver and muscle, the levels of basal PTP1B and activated PTP1B of OLETF rats treated with ramipril and insulin were significantly decreased. The levels of Gialpha2, activated IRS-2, and activated p-85alpha were significantly increased in OLETF rats treated with ramipril and insulin. In adipose tissue, the levels of Gialpha2 and activated p-85alpha of OLETF rats treated with ramipril and insulin were slightly increased as in liver and muscle. But, the levels of basal PTP1B and activated PTP1B were significantly increased. And, the levels of activated IRS-1 and activated IRS-2 were decreased. CONCLUSION: These results suggest that the improvement of insulin sensitivity by treatment with ramipril was related to the decreased level of activated PTP1B. Also, we could suggest that the changes of activated PTP1B level was related with the changes of Gialpha2-protein. However, the results of adipose tissue were different from those of liver and muscle. So it seemed likely that there would be various major modulators for regulation of insulin signal pathway according to tissue.
The Effect of Nitric Oxide on Insulin Binding and Insulin Receptor Recycling in Bovine Aortic Endothelial Cells.
Hyuk Sang Kwon, Oak Kee Hong, Hee Soo Kim, Jung Min Lee, Sung Rae Kim, Sung Dae Moon, Sang Ah Jang, Hyun Shik Son, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang
Korean Diabetes J. 2003;27(3):213-227.   Published online June 1, 2003
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AbstractAbstract PDF
BACKGROUND
The coexistence of insulin resistance and endothelial dysfunction is commonly observed in a variety of metabolic and cardiovascular disorders, including athero-sclerosis and type 2 diabetes mellitus. Because nitric oxide (NO), or nitric oxide synthase (NOS), has been suggested as a significant contributing factor in the development of endothelial dysfunction and insulin resistance, reactive NO or NOS were investigated to see if they contribute to the insulin internalization pathway. METHODS: The production of NO (Nitrite), the expression of eNOS (endothelial NOS), insulin binding and the insulin receptor internalization and recycling, following 48 hours of incubation with bradykinin (BK), acetylcholine (Ach), NG-monomethyl- L-arginine (L-NMMA) and N-nitro-L-arginine methylester (L-NAME) in Bovine aortic endothelial cells (BAECs), were examined. RESULTS: The results were as follows: 1. In relation to the time course, the production of eNOS was increased, but was decreased after 8 hours of incubation. The production of eNOS in the L-NMMA and L-NAME treated groups was significantly decreased compared with that of the controls (p<0.05). 2. The specific insulin bindings to the receptors of the endothelial cells were maximized within 20 mins, and then decreased. At 20 mins, the binding rate of the L-NMMA treated group was significantly decreased compared to that of the controls. At a concentration of 0.4ng/ml of unlabelled insulin, the specific insulin binding of the L-NMMA treated group was significantly decreased compared to that of the controls (p<0.05). 3. The internalization of 125I-insulin into the endothelial cells, as assessed by the acid washing dissociation method, occurred rapidly. The internalized radioactivity of 125I-insulin, at 20 mins, was significantly increased in the BK and Ach groups compared with the controls (p<0.05). 4. The recycling of the internalized insulin receptors showed no significant differences between the study groups, but the recycling was slightly delayed compared with controls in the Ach group. CONCLUSION: In conclusion, the NO generating substances, BK and Ach, and the inhibitory substance, L-NMMA, may influence the binding and internalization of insulin-insulin receptors. Our results suggest that NO might contribute to the transcytosis of insulin in BAECs
Effect of Gi-proteins on Insulin Binding, Internalization and Recycling of Insulin Receptor in Bovine Aorta Endothelial Cell.
Hyuk Ho Kwon, Hyun Shik Son, Jung Min Lee, Seung Hyun Ko, Ok Ki Hong, Sung Dae Moon, Sang Ah Chang, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang
Korean Diabetes J. 2003;27(1):26-38.   Published online February 1, 2003
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AbstractAbstract PDF
BACKGROUND
Guanine nucleotide binding proteins (G-proteins) play important roles in the hormonal actions of many signal transduction systems. Possible roles for the Gi-protein in insulin action have been suggested. It is reported that Gi-protein is associated with insulin actions to a greater extent than Gs-protein. There are at least three different subtypes of Gi-proteins (Gi(alpha1), Gi(alpha2), and Gi(alpha3)), however, it is not certain which subtypes are associated with insulin receptors and their action. METHODS: To investigate the effects of Gi-proteins on insulin action, the Gi-proteins were overexpressed in cultured bovine aortic endothelial cells (BAEC), using the DNA-polylysine-adenovirus complex transfection method. After incubating for 24 hours, the BAEC were treated with 200 ng/mL insulin to evaluate the insulin binding, receptor internalization and recycling. RESULTS: The following results were found : 1) The binding of specific insulin bindings to the insulin receptors of endothelial cells were time-dependent, reaching their maximal levels in all cells after 30 minutes. The maximal specific bindings of the control, Gi(alpha1), Gi(alpha2), and Gi(alpha3) were 0.58+/-0.1, 0.54+/-0.08, 0.54+/-0.1, 0.53+/-0.09%, respectively. 2) The internalization of 125I-insulin, into endothelial cells, was assessed by the acid washing dissociation method, and occurred rapidly. There was a significant difference in the internalized radioactivity of the 125I-insulin in the overexpressed Gi(alpha2) protein group compared to the two groups. 3) The recycling of the insulin receptors in the three types of Gi-protein showed no significant difference between the three group. CONCLUSION: In conclusion, the Gi(alpha2) protein may be associated with internalization of the insulin-insulin receptor complex, and appears to be important in both the action of insulin and the intracellular processing of insulin receptors.
Effect of Oxidized LDL on the Amount of Insulin Receptor and Gi-proteins in the Caveolae of Bovine Aortic Endothelial Cells (BAEC).
Sung Yoon Jeon, Hyun Shik Son, Jung Min Lee, Sung Dae Moon, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang
Korean Diabetes J. 2001;25(1):71-82.   Published online February 1, 2001
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AbstractAbstract PDF
BACKGROUND
AND AIMS: Oxidized LDL (ox-LDL) may induce endothelial cell dysfunction and suggested to have an association with atherosclerosis or insulin resistance. Several studies have shown that ox-LDL inhibits signaling pathways mediated by inhibitory GTP-binding proteins (Gi-proteins). G-protein coupled receptors (GPCRs) can be internalized via caveolae. Caveolae are small flask-shaped invaginations of the plasma membrane, characterized by high levels of cholesterol and glycosphingolipids and also by the presence of caveolin, a 20-24 kDa integral membrane protein. G-proteins are enriched within caveolae membranes, where caveolin-1 directly interacts with the -subunits of G-proteins. It is reported that functional changes of G-proteins such as mutational or pharmacological activation of G-proteins affect direct interaction between G-proteins and caveolin-1. Thus, we investigated the effect of ox-LDL on the change of the amount of insulin receptor and Gi proteins in the caveolae. MATERIALS AND METHODS: ox-LDL was prepared by exposing samples of native LDL (n-LDL) to CuSO4 for 24 hours. Caveolae were extracted after treating BAECs at several concentrations of ox-LDL (10, 50, 100 g/mL) for various durations (0-48 hr), and we investigated the changes of the amount of caveolin-1, Gi -proteins and insulin receptor using immunoblot. RESULTS: While the amount of caveolin-1 was decreased, the amount of insulin receptor, Gi 2 and Gi 3 proteins in caveolae were also decreased after treatment of ox-LDL on the BAECs (insulin receptor: 66%; Gi 2 protein: 33%; Gi 3 protein: 66%, p<0.05). The amount of caveolin-1 was increased for the first 6 hours and then decreased, however, the amount of Gi -proteins and insulin receptor were vice versa during 48 hours incubation. CONCLUSION: These results indicate that ox-LDL can affect the change of the amount of insulin receptor and Gi-proteins in caveolae and it may induce endothelial cell dysfunction.
Effect of Overexpression of Gi Proteins on Insulin Actions in 3T3-L1 Adipocytes.
Hyun Shik Son, Bong Yun Cha, Sung Dae Moon, Jung Min Lee, Ok Ki Hong, Sang Ah Chang, Yu Bae Ahn, Kun Ho Yoon, Kwang Woo Lee, Ho Young Son, Sung Koo Kang
Korean Diabetes J. 2000;24(4):404-412.   Published online January 1, 2001
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BACKGROUND
It has been reported that G proteins are involved in biological actions of insulin. Especially, Gi protein is more associated with insulin actions than Gs proteins. Gi protein has at least three different subtypes of Gi 1, Gi 2 and Gi 3 protein. However, it is not certain which subtypes of Gi proteins are associated with biological actions of insulin. METHODS: To investigate which subtypes of Gi proteins are associated with insulin action, we overexpressed three different kinds of Gi protein, Gi 1, Gi 2 and Gi 3 protein, in 3T3-L1 adipocytes using DNA-polylysine-adenovirus complex transfection method. After incubating for 2 hours, 3T3-L1 adipocytes were treated with 100 nM insulin for the evaluation of biological actions of insulin. Moreover, to elucidate insulin stimulated insulin receptor autophosphorylation and IRS-1 phosphorylation, 3T3-L1 adipocytes were stimulated with 100 nM insulin for 10 minutes, homogenized and immunoprecipitated with anti-phosphotyrosine antibody. RESULTS: Transfection with Gi 2 gene resulted in increment in insulin-stimulated [3H]2-deoxyglucose (DOG) uptake without affecting basal 2-DOG uptake, but not with Gi 1 and Gi 3 gene transfection. There was unchanged glycogen synthesis rate in all three Gialphasubtypes. Insulin-induced increments of insulin receptor autophos phorylation and IRS-1 phosphorylation were found in Gi 2 protein overexpressed group, only. CONCLUSION: These results suggest that Gi 2 protein may be associated with regulation of biological actions of insulin.
Effect of Oxidezed LDL in Insulin Binding, Internalization and Recycling of Insulin Receptor in Cultured Bovine Aortic Endothelial Cells.
Sung Dae Moon, Bong Yun Cha, Hye Soo Kim, Sang Ah Jang, Yu Bae An, Ki Ho Song, Je Ho Han, Soon Jib You, Kun Ho Yoon, Moo Il Kang, Kwang Woo Lee, Ho Young Son, Sung Koo Kang
Korean Diabetes J. 1999;23(3):243-255.   Published online January 1, 2001
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BACKGROUND
Endothelial dysfunction is perhaps one of the earliest manifestations of atherosclerosis. This abnormality is in part due to altered membrane signal transduction in endothelial cells. Oxidized LDL that is atherogenic may induce endothelial dysfunction, and its presence has been documented in atherosclerotic vessels. Many studies have shown that oxidized LDL inhibits signaling pathways mediated by inhibitory GTP-binding proteins (Gi- protein). It is also known that G-protein is involved in insulin recycling on cultured human umbilical vein endothelial cells. Therefore, to determine the effect of oxidized LDL on endothelial cells: insulin binding, internalization, and the recycling of insulin receptors were assessed in cultured bovine aortic endothelial cells treated with native LDL, oxidized LDL, and in some cells pretreated with pertussis toxin before the incubation with oxidized LDL. METHOD: Native LDL (density 1.019 1.063 g/mL) was obtained from using the rapid single discontinuous density gradient ultracentrifugation of plasma samples from a single donor. Oxidized LDL was prepared by exposing samples of native LDL to CuSO4 (5 uM) at 37't for 24 hours. Endothelial cells at 80% confluence were treated with the indicated concentrations of native LDL, oxidized LDL, and some cells were pretreated with pertussis toxin for 6 hrs before the incubation with oxidized LDL. These cells were incubated for 24 72 hours. RESULTS: 1. Binding of (125)I-insulin(0.17nM) to endothelial cells treated with increasing concentrations of oxidized LDL shows dose-dependent decrease. There were significant differences in insulin binding between native LDL and oxidized LDL-treated cells (p<0.05). Binding of 'I-insulin (0.17 nM) to endothelial cells treated with increasing culture time of oxidized LDL shows more decreased than that of native LDL significantly (p<0.05). And oxidized LDL had additive effect, but not significant, with pertussis toxin on the specific (125)I-insulin binding to bovine aortic endothelial cells. 2. Internalization of insulin receptors reached rapidly to its maximal level around 30min at 37'C. At 60 min, oxidized-LDL treated cells was less increased in internalization of insulin receptors than that of native LDL treated cells [59.1+1.9% of total cell associated insulin (mean+SE) vs. 67.5+1.1%, p<0.05]. There were additive effects, but not significant differences, between oxidized LDL and pretreated with pertussis toxin before the incubation with oxidized LDL. 3. After 30 min of incubation with unlabeled insulin (33 nM), insulin binding in oxidized LDL treated cells was significantly higher compared to native LDL treated cells (69.0+2.5% of control values vs. 63.7+1.2%, p<0.05), suggesting that oxidized-LDL decreased internalization of insulin receptors. And during the process of recycling, there were significant differences in insulin receptor recycling between the oxidized LDL and native LDL treated cells, but oxidized LDL had an additive effect, but not significant, with pertussis toxin on insulin receptor recycling to the bovine aortic endothelial cells. CONCLUSION: 1. The findings in this study suggest that oxidized LDL may play a causative role to produce the insulin resistance by inhibiting insulin binding, internalization and recycling of insulin receptor in cultured bovine aortic endothelial cells 2. This study suggests that the effect of oxidized LDL to the bovine aortic endothelial cells in insulin binding and receptor-mediated transcytosis is caused by inhibiting pertussis toxin sensitive Gi-protein.
Fasting Serum Insulin Levels in Relation to Age and Body Mass Index and Serum Glucose Level in Healthy Subjects in Korea.
Sang Ah Chang, Ho Young Son, Bong Yun Cha, Sung Dae Moon, Ki Ho Song, Soon Jib Yoo, Kun Ho Yoon, Moo Il Kang, Kwang Woo Lee, Sung Ku Kang
Korean Diabetes J. 1997;21(4):433-443.   Published online January 1, 2001
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BACKGROUND
Ethnic variability in the relationship between glucose tolerance and insulin secretion has been reported. Clinical characteristics of Korean diabetic patients are different from that of diabetic patients in Western countries. It is generally assumed that typical IDDM or obese diabetic patients are relatively rare among Korean subjects. This study attempted to define the characteristics of fasting serum insulin levels of healthy Korean adult subjects. Futhermore, we tried to evaluate the relationship between fasting serum insulin level and age, body mass index, serum glucose. METHODS: We examined 1917 Korean subjects who had fasting blood glucose within normal range (3.6~6.4mmol/L). The fasting insulin levels, total choiesterol, triglyceride concentrations and anthropometric characteristics(body weight, height and body mass index(BMI)) of these subjects were measured. RESULTS: 1) Mean fasting insulin levels were 33.9+0.5pmol/ L, the fasting insulin levels in men and women were 34.9+0.6 and 31.8+0.6pmol/L, respectively. 2) The fasting insulin levels of obese(BMI>25) subjects were significantly higher than those of non-obese subjects(43.2+ 1.2 pmol/L vs. 30.6+0.6 pmol/L, p<0.001). 3) There were significant differences in the basal insulin levels among the age groups, and fasting blood glucose levels were increased with aging. 4) In a multiple stepwise regression analysis, insulin levels were positively correlated with serum triglycerides, fasting blood glucose, body mass index and negatively correlated with age. Conclusion : The fasting insulin levels of healthy subjects in Korea were relatively lower than the previously measured value of Caucasians. The insulin levels were decreased with aging and increased with the elevation of BMI, fasting blood glucose and triglyceride.
The Effect of Metformin Monotherapy in Patients with NIDDM.
Yu Bae Ahn, Sung Dae Moon, Sang Ah Jang, Jong Min Lee, Hyun Shik Son, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang
Korean Diabetes J. 1997;21(2):185-193.   Published online January 1, 2001
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BACKGROUND
We performed this study to investigate the effect of metformin on glycemia, insulin secretion and body weight in patients with non-insulin-dependent diabetes melltus(NIDDM) who could not aehieve satisfactory glycemic control by sulfonylurea or diet therapy. METHODS: A total of 167 patients with NIDDM were included in this study. At baseline the patients underwent anthropometry and a 75g oral glucose tolerance test. Jn addition, levels of hemoglobin Alc (HbAlc), setum lipids, fasting and postprandial 2hr glucose were measured. Metformin was given in an initial dose of 500mg twice daily and increased by 500mg every month as long as the fasting blood sugar(FBS) concentration exceeded 7.8mmol/L and the side effects were tolerable. After 3 rnonths of metformin therapy we defined a responder as a patient who experienced a FBS of under 7.8 mmol/L or a HbAlc of under 7%. Patients who failed to respond to metformin monotherapy were excluded in the study. Anthrapometric changes and results of a 75 g oral glucose tolerance test were reevaluated in the responder group after 6 months of metformin treatment. RESULTS: I) The overall response rate to metformin mono-therapy was 55.6%(79/142) in the study population. 2) There were significant changes in body weight (64.4+/-8.2 vs 62.9+/-8.4 kg, p(0.01) and body mass index(25.3+/-2.3 vs 24.6+/-2.3kg/m, p<0.01) during metformin treatment. 3) There were significant decreases in the fasting, postprandial 2hr serum glucose(10.1+/-2.8 vs 7.9+1.6, 15,2+/-5.0 vs 12.2+/-3.9 mmol/L, p 0.01) and HbAlc levels(8.4+/-1.7 vs 6.5+/-0.9%, p<0.05) after 6 months of metformin treatment. 4) There were significant decreases in the levels of AUC[g](59.2+/-15.5 vs 49.4+/-9.4mmol L-1. Min-1, p =C0.01) without changes of AUC[I] and AUC[I]/ AUC[g] ratio (558.0+486.0 vs 536.4+374.4 pmol.L-1. Min-1, p=0.71, 11.7+/-13.0 vs 11.8+/-10.0, p=0.89). 5) The incidence of side effects was 25% in the study population, but most of them were mild and fade away with continuous use of metformin, CONCLUSION: Metforrnin monotherapy improved glycemic control in NlDDM patients who failed to respond to diet or sulfonylurea therapy and may be a useful hypoglycemic agent for the treatment of NIBDM.

Diabetes Metab J : Diabetes & Metabolism Journal
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