Diabetes & Metabolism Journal

Yong Ki Kim (Kim YK)

19 Articles

High Glucose and/or Free Fatty Acid Damage Vascular Endothelial Cells via Stimulating of NAD(P)H Oxidase-induced Superoxide Production from Neutrophils.: Sang Soo Kim, Sun Young Kim, Soo Hyung Lee, Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son; Korean Diabetes J. 2009;33(2):94-104. Published online April 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.2.94

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Abstract PDF: BACKGROUND
Oxidative stress and inflammation are important factors in the pathogenesis of diabetes and contribute to the development of diabetic complications. To understand the mechanisms that cause vascular complications in diabetes, we examined the effects of high glucose and/or free fatty acids on the production of superoxide from neutrophils and their role in endothelial cell damage. METHODS: Human neutrophils were incubated in the media containing 5.5 mM D-glucose, 30 mM D-glucose, 3 nM oleic acid, or 30 microM oleic acid for 1 hour to evaluate superoxide production through NAD(P)H oxidase activation. Human aortic endothelial cells were co-cultured with neutrophils exposed to high glucose and oleic acid. We then measured neutrophil adhesion to endothelial cells, neutrophil activation and superoxide production, neutrophil-mediated endothelial cell cytotoxicity and subunits of neutrophil NAD(P)H oxidase. RESULTS: After 1 hour of incubation with various concentrations of glucose and oleic acid, neutrophil adherence to high glucose and oleic acid-treated endothelial cells was significantly increased compared with adhesion to low glucose and oleic acid-treated endothelial cells. Incubation of neutrophils with glucose and free fatty acids increased superoxide production in a dose-dependent manner. High glucose and oleic acid treatment significantly increased expression of the membrane components of NAD(P)H oxidase of neutrophil (gp91(phox)). Endothelial cells co-cultured with neutrophils exposed to high glucose and oleic acid showed increased cytolysis, which could be prevented by an antioxidant, N-acetylcysteine. CONCLUSION: These results suggest that high glucose and/orfree fatty acidsincrease injury of endothelial cells via stimulating NAD(P)H oxidase-induced superoxide production from neutrophils.

Cause-of-Death Trends for Diabetes Mellitus over 10 Years.: Su Kyung Park, Mi Kyoung Park, Ji Hye Suk, Mi Kyung Kim, Yong Ki Kim, In Ju Kim, Yang Ho Kang, Kwang Jae Lee, Hyun Seung Lee, Chang Won Lee, Bo Hyun Kim, Kyung Il Lee, Mi Kyoung Kim, Duk Kyu Kim; Korean Diabetes J. 2009;33(1):65-72. Published online February 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.1.65

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BACKGROUND
Recently, diabetic mortality is lower than ever before, likely due to dramatic improvements in diabetes care. This study set to analyze changes in the cause of death in type 2 diabetes mellitus (T2DM) in the past 10 years. METHODS: All subjects were T2DM patients over the age of 30 whose death certificates were issued at six hospitals in the Busan metropolitan area from 2000 to 2004. The patients were excluded if they had been clinically diagnosed with significant tuberculosis, liver, thyroid, renal, connective tissue diseases and cancers, prior to T2DM diagnosis. We classified the cause of death into several groups by KCD-4. The results were compared with published data on the period from 1990 to 1994. RESULTS: The study comprised 680 patients, of which 374 (55.0%) were male. The average age of death was 66.3 +/- 10.7 years. The most common cause of death was cardiovascular disease (30.6%), followed by infectious disease (25.3%), cancer (21.9%), congestive heart failure (7.1%), renal disease (4.7%), liver disease (2.7%), and T2DM itself (1.9%). In the study from the earlier period, the most common cause of death was also cardiovascular disease (37.6%), followed by infectious disease (24.2%), T2DM (6.0%), liver disease (5.4%), cancer (4.7%), and renal disease (3.3%). CONCLUSION: Over both study periods, the first and second cause of death in T2DM were cardiovascular disease and infectious disease, respectively. However, death by cerebral infarction among cardiovascular disease patients was significantly lower in the latter period, while death by malignancy was markedly increased.

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The Socio-Economic Cost of Diabetes Mellitus in Korea Using National Health Insurance Claim Data, 2017
Heesun Kim, Eun-Jung Kim
Healthcare.2022; 10(9): 1601. CrossRef
Arterial stiffness is an independent predictor for risk of mortality in patients with type 2 diabetes mellitus: the REBOUND study
Jeong Mi Kim, Sang Soo Kim, In Joo Kim, Jong Ho Kim, Bo Hyun Kim, Mi Kyung Kim, Soon Hee Lee, Chang Won Lee, Min Chul Kim, Jun Hyeob Ahn, Jinmi Kim
Cardiovascular Diabetology.2020;[Epub] CrossRef
The Mentors, The Social Support and Patients with Diabetes Mellitus
Yu Jeong Park
The Journal of Korean Diabetes.2019; 20(2): 112. CrossRef
How to build nomogram for type 2 diabetes using a naïve Bayesian classifier technique
Jae-Cheol Park, Jea-Young Lee
Journal of Applied Statistics.2018; 45(16): 2999. CrossRef
Impact of change in job status on mortality for newly onset type II diabetes patients: 7 years follow-up using cohort data of National Health Insurance, Korea
Donggyo Shin, Ji Man Kim, Tinyami Erick Tandi, Eun-Cheol Park
Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2016; 10(1): S1. CrossRef
Factors Associated with Poor Glycemic Control among Patients with Type 2 Diabetes Mellitus: The Fifth Korea National Health and Nutrition Examination Survey (2010-2012)
Jinhyun Park, Seungji Lim, Eunshil Yim, Youngdae Kim, Woojin Chung
Health Policy and Management.2016; 26(2): 125. CrossRef
Mortality and causes of death in a national sample of type 2 diabetic patients in Korea from 2002 to 2013
Yu Mi Kang, Ye-Jee Kim, Joong-Yeol Park, Woo Je Lee, Chang Hee Jung
Cardiovascular Diabetology.2016;[Epub] CrossRef
Development of Cell Phone Application for Blood Glucose Self-Monitoring Based on ISO/IEEE 11073 and HL7 CCD
Hyun Sang Park, Hune Cho, Hwa Sun Kim
Healthcare Informatics Research.2015; 21(2): 83. CrossRef
Cost-Utility Analysis of Screening Strategies for Diabetic Retinopathy in Korea
Sang-Won Kim, Gil-Won Kang
Journal of Korean Medical Science.2015; 30(12): 1723. CrossRef
Quality characteristics of brown rice boiled with medicinal herbs extract for diabetes prevention
Kyung-Mi Yang, Jung-Ran Park, Su-Jung Hwang
Korean Journal of Food Preservation.2014; 21(1): 55. CrossRef
Does Diabetes Mellitus Influence Standardized Uptake Values of Fluorodeoxyglucose Positron Emission Tomography in Colorectal Cancer?
Da Yeon Oh, Ji Won Kim, Seong-Joon Koh, Mingoo Kim, Ji Hoon Park, Su Yeon Cho, Byeong Gwan Kim, Kook Lae Lee, Jong Pil Im
Intestinal Research.2014; 12(2): 146. CrossRef
The Relationship between Metformin and Cancer in Patients with Type 2 Diabetes
Hyun Hee Chung, Jun Sung Moon, Ji Sung Yoon, Hyoung Woo Lee, Kyu Chang Won
Diabetes & Metabolism Journal.2013; 37(2): 125. CrossRef
Relationship between Milk and Calcium Intake and Lipid Metabolism in Female Patients with Type 2 Diabetes
JaeHee Kim, Ji-Yun Hwang, Ki Nam Kim, Young-Ju Choi, Namsoo Chang, Kap-Bum Huh
Yonsei Medical Journal.2013; 54(3): 626. CrossRef
Comorbidity Study on Type 2 Diabetes Mellitus Using Data Mining
Hye Soon Kim, A Mi Shin, Mi Kyung Kim, Yoon Nyun Kim
The Korean Journal of Internal Medicine.2012; 27(2): 197. CrossRef
Glucose, Blood Pressure, and Lipid Control in Korean Adults with Diagnosed Diabetes
Sun-Joo Boo
Korean Journal of Adult Nursing.2012; 24(4): 406. CrossRef
A Comparative Study of Eating Habits and Food Intake in Women with Gestational Diabetes according to Early Postpartum Glucose Tolerance Status
You Jeong Hwang, Bo Kyung Park, Sunmin Park, Sung-Hoon Kim
Diabetes & Metabolism Journal.2011; 35(4): 354. CrossRef
Diabetes and Cancer: Is Diabetes Causally Related to Cancer?
Sunghwan Suh, Kwang-Won Kim
Diabetes & Metabolism Journal.2011; 35(3): 193. CrossRef
The Association between Type 2 Diabetes Mellitus and Colorectal Cancer
Byeong Do Yi, Young Pil Bae, Bong Gun Kim, Jong Wha Park, Dong Hyun Kim, Ja Young Park, Seong Ho Choi, Hee Seung Park, Jae Seung Lee, Chang Won Lee, Sang Soo Kim, Bo Hyun Kim, Moon Ki Choi, In Joo Kim
Endocrinology and Metabolism.2011; 26(2): 126. CrossRef
The Hypoglycemic Effect of Complex of Chinese Traditional Herbs (CTH) and Macelignan in Type 2 Diabetic Animal Model

Journal of Life Science.2010; 20(7): 1113. CrossRef
The Relationship Between Coronary Artery Calcification and Serum Apolipoprotein A-1 in Patients with Type 2 Diabetes
Hyun Ae Seo, Yeon Kyung Choi, Jae Han Jeon, Jung Eun Lee, Ji Yun Jeong, Seong Su Moon, In Kyu Lee, Bo Wan Kim, Jung Guk Kim
Korean Diabetes Journal.2009; 33(6): 485. CrossRef
Epidemiologic Characteristics of Diabetes Mellitus in Korea: Current Status of Diabetic Patients Using Korean Health Insurance Database
Ie Byung Park, Sei Hyun Baik
Korean Diabetes Journal.2009; 33(5): 357. CrossRef
Cause-of-Death Trends for Diabetes Mellitus over 10 Years (Korean Diabetes J 33(1):65-72, 2009)
Hae Jin Kim
Korean Diabetes Journal.2009; 33(2): 164. CrossRef

Association of Serum Cystatin C with Metabolic Syndrome and Its Related Components in Korean Adults.: Sun Young Kim, Sang Heon Song, Yun Kyung Jeon, Ji Ryang Kim, Jung Ho Bae, Sang Soo Kim, Soo Hyung Lee, Seok Man Son, In Ju Kim, Yong Ki Kim, Yang Ho Kang; Korean Diabetes J. 2008;32(5):409-417. Published online October 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.5.409

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Abstract PDF

BACKGROUND
Serum cystatin C has been reported as a better marker than serum creatinine for estimation of kidney function and may be associated with cardiovascular disease. The aim of this study was to elucidate the association of serum cystatin C with metabolic syndrome (MS), a constellation of cardiovascular risk factors, and its related components and the usefulness of serum cystatin C for the cardiovascular risk assessment. METHODS: 1,468 healthy subjects (814 men and 655 women), who visited health promotion center of Pusan National University Hospital for routine medical checkup were included. MS was defined by modified, revised National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria. RESULTS: Mean serum cystatin C value was 0.87 +/- 0.17 mg/L. In partial correlation analysis adjusted by age, sex and Glomerular Filtration Rate (GFR), cystatin C was associated with most of metabolic parameters and especially had significant positive correlation with waist circumference (r = 0.215), triglyceride (TG) (r = 0.141), diastolic blood pressure (BP) (r = 0.116), and correlated negatively with high density lipoprotein (HDL) cholesterol (r = -0.152) (all P < 0.001). There were increasing trends of prevalence of MS with the increase of quartiles of cystatin C and as the number of MS components increased, cystatin C values significantly increased. Serum cystatin C was also significantly increased in MS (0.90 +/- 0.19 mg/L vs. 0.86 +/- 0.16 mg/L). In stepwise multiple regression analysis including the components of MS, Waist circumference, diastolic BP, triglyceride, and HDL cholesterol were independent determinants of serum cystatin C, but with creatinine, only waist circumference was independent determinant. CONCLUSIONS: Serum cystatin C was closely associated with MS and its related cardiovascular risk factors and might be useful as a tool of cardiovascular risk assessment.

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Cystatin C in Patients of Metabolic Syndrome and its Correlation with the Individual Components of Metabolic Syndrome
Sunita Aghade, Jayshree S Bavikar, Pragati S Kadam, Reshakiran J Shendye
Indian Journal of Medical Biochemistry.2019; 23(2): 293. CrossRef
Cystatin C as a Predictor for Diabetes according to Glycosylated Hemoglobin Levels in Korean Patients
Eon Ju Jeon, Ji Hyun Lee
Diabetes & Metabolism Journal.2016; 40(1): 32. CrossRef
Association of Obesity with Serum Cystatin C in Korean Adults
Yang Ho Kang
The Korean Journal of Obesity.2015; 24(4): 199. CrossRef

Migration of Vascular Smooth Muscle Cells by High Glucose is Reactive Oxygen Dependent.: Yong Seong An, Ji Hae Kwon, Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son; Korean Diabetes J. 2008;32(3):185-195. Published online June 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.3.185

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Abstract PDF: BACKGROUND
Oxidative stress contributes to vascular diseases in patients with diabetes. As the mechanism of development and progression of diabetic vascular complications is poorly understood, this study was aimed to assess the potential role of hyperglycemia-induced oxidative stress and to determine whether the oxidative stress is a major factor in hyperglycemia-induced migration of vascular smooth muscle cells (VSMCs). METHODS: We treated primary cultured rat aortic smooth muscle cells for 72 hours with medium containing 5.5 mM D-glucose (normal glucose), 30 mM D-glucose (high glucose) or 5.5 mM D-glucose plus 24.5 mM mannitol (osmotic control). We measured the migration of VSMCs and superoxide production. Immunoblotting of PKC isozymes using phoshospecific antibodies was performed, and PKC activity was also measured. RESULTS: Migration of VSMCs incubated under high glucose condition were markedly increased compared to normal glucose condition. Treatment with diphenyleneiodonium (DPI, 10 micromol/L) and superoxide dismutase (SOD, 500 U/mL) significantly suppressed high glucose-induced migration of VSMCs. Superoxide production was significantly increased in high glucose condition and was markedly decreased after treatment with DPI and SOD. High glucose also markedly increased activity of PKC-delta isozyme. When VSMCs were treated with rottlerin or transfected with PKC-delta siRNA, nitro blue tetrazolium (NBT) staining and NAD(P)H oxidase activity were significantly attenuated in the high glucose-treated VSMCs. Furthermore, inhibition of PKC-delta markedly decreased VSMC migration by high glucose. CONCLUSION: These results suggest that high glucose-induced VSMC migration is dependent upon activation of PKC-delta, which may responsible for elevated intracellular ROS production in VSMCs, and this is mediated by NAD(P)H oxidase.

The Association between Arterial Stiffness and Albuminuria in Type 2 Diabetes.: Seong Geun Lee, Yong Ki Kim, Seo Rin Kim, Yong Sung Ahn, Ji Hae Kwon, Yang Ho Kang, Suk Man Son, In Joo Kim, Ju Sung Kim; Korean Diabetes J. 2007;31(5):421-428. Published online September 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.5.421

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Abstract PDF

BACKGROUND
Brachial ankle pulse wave velocity (BaPWV) and cardio ankle vascular index (CAVI), as indicators of arterial stiffness, are increased in type 2 diabetes. Albuminuria, as a cardiovascular risk factor in type 2 diabetes, can cause endothelial dysfunction and atherosclerosis, and these can increase arterial stiffness. So we investigated the hypothesis that increased albuminuria reflects increased BaPWV and CAVI in type 2 diabetes. METHODS: We retrospectively analyzed 106 patients (58 men and 48 women) with type 2 diabetes from March 2005 to September 2006. Urine albumin creatinine ratio (ACR) to evaluate urinary albumin excretion, BaPWV and CAVI were measured in all patients. RESULTS: All patients were divided 3 groups, normal group (ACR < 30 mg/g Cr., n = 31), microalbuminuria group(30 < or = ACR < or = 30 mg/g Cr., n = 42), proteinuria group(ACR > 300 mg/g Cr., n = 33). BaPWV and CAVI in microalbuminuria group and proteinuria group are faster than normal group. In bivariate correlation analysis, BaPWV was not associated with ACR, but CAVI was positively correlated to ACR (r = 0.285, P = 0.003). BaPWV was positively correlated to age, diabetes duration, body mass index, systolic blood pressure, diastolic pressure, pulse pressure and negatively correlated to glomerular filtration rate (GFR). CAVI was positively correlated to age, diabetes duration and negatively correlated to GFR. In multiple linear stepwise regression analysis, BaPWV was not associated with ACR, but ACR was independent predictor for CAVI (P = 0.002). CONCLUSION: In type 2 diabetes, albuminuria was independent predictor for indicators of arterial stiffness, especially CAVI.

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Associations Between Cardio-Ankle Vascular Index and Microvascular Complications in Type 2 Diabetes Mellitus Patients
Kwang Joon Kim, Byung-Wan Lee, Hyun-min Kim, Joo Youn Shin, Eun Seok Kang, Bong Soo Cha, Eun Jig Lee, Sung-Kil Lim, Hyun Chul Lee
Journal of Atherosclerosis and Thrombosis.2011; 18(4): 328. CrossRef

Oxidative Stress Causes Vascular Insulin Resistance in OLETF Rat Through Increased IRS-1 Degradation.: Jung Lae Park, Young Sil Lee, Bo Hyun Kim, Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son; Korean Diabetes J. 2007;31(1):22-32. Published online January 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.1.22

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Abstract PDF

BACKGROUND
Insulin resistance and oxidative stress have been reported to play essential pathophysiological roles in diabetic cardiovascular complication. The relationship between insulin resistance and oxidative stress in vasculature remains unclear. The study was conducted to assess whether oxidative stress induce vascular insulin resistance in OLETF rat, a model of type 2 diabetes METHODS: We used OLETF rats (20/30/40 weeks, n = 5/5/5), as models of type 2 DM, and LETO rats (20/30/40 weeks, n = 5/5/5) as controls. Aortas of each rats were extracted. Superoxide anion production was detected by NBT assay and lucigenin assay. 8-hydroxyguanosine (OHdG) and nitrotyrosine were detected as markers of oxidative stress in 20 and 40 weeks groups. The glucose uptake of aortas was measured by detecting 2-deoxyglucose uptake in both groups. The expression of IR, IRS-1, PI3-K and Akt/PKB were detected by immuno precipitation and immunoblotting in 20, 30 and 40 weeks groups RESULTS: Superoxide anion production and markers of oxidative stress (8-OHdG, nitrotyrosine) were significantly increased in aortas of OLETF rats compared with controls. Aortas of OLETF rats exhibited decreased IRS-1 content and increased phosphorylation of IRS-1 at Ser307 compared with LETO rats. There were no significant differences in expressions of IR, PI3-K and Akt/PKB between two groups CONCLUSION: These results suggest that oxidative stress induces insulin resistance in vasculature of OLETF rat specifically through increasing serine phosphorylation of IRS-1 and its degradation by a proteasome-dependent pathway, providing an alternative mechanism that may explain the association with insulin resistance and diabetic vascular complications.

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Anti-diabetic effects of benfotiamine on an animal model of type 2 diabetes mellitus
Kang Min Chung, Wonyoung Kang, Dong Geon Kim, Hyun Ju Hong, Youngjae Lee, Chang-Hoon Han
Korean Journal of Veterinary Research.2014; 54(1): 21. CrossRef

Comparison of the Efficacy and Safety of Glimepiride/Metformin Fixed Combination Versus Free Combination in Patients with Type 2 Diabetes: Multicenter, Randomized, Controlled Trial.: Seung Hwan Lee, In Kyu Lee, Sei Hyun Baik, Dong Seop Choi, Kyong Soo Park, Ki Ho Song, Kwan Woo Lee, Bong Soo Cha, Chul Woo Ahn, Hyoung Woo Lee, Choon Hee Chung, Moon Suk Nam, Hong Sun Baek, Yong Ki Kim, Hyo Young Rhim, Ho Young Son; Korean Diabetes J. 2006;30(6):466-475. Published online November 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.6.466

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Abstract PDF

BACKGROUND
Failure to manage diabetes mellitus receiving monotherapy increases as the duration of the disease is protracted, and in many cases it becomes inevitable to introduce combined therapies. However, compliance of the patients tends to decrease. We conducted a clinical study to compare the efficacy and safety of preconstituted and fixed combination therapy of glimepiride plus metformin to those of free combination therapy. METHODS: Two hundred and thirteen patients with type 2 diabetes who had been diagnosed at least six months ago were randomly assigned either to a fixed group or a free group. The initial dosage was chosen according to the previous treatment history and then adjusted every two weeks following a predefined titration algorithm to meet the target mean fasting glucose levels (140 mg/dL). The medications were given for 16 weeks. The primary endpoint was the change in HbA1c level from baseline to week 16. Various parameters were checked as secondary outcome measures and safety criteria. RESULTS: HbA1c level of the fixed group and the free group decreased by 1.09% and 1.08%, respectively. The 95% CI of the changes' difference between the two groups (-0.21%, +0.19%) was within the predefined equivalence interval (-0.5%, +0.5%). Secondary outcome measures (the changes of fasting and postprandial plasma glucose level, response rate and compliance) and safety criteria (frequency of hypoglycemia and adverse reactions) were similar between the two groups. CONCLUSION: Fixed combination of glimepiride/metformin is as effective and safe therapy as free combination in type 2 diabetes patients.

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Efficacy and safety of glimepiride/metformin sustained release once daily vs. glimepiride/metformin twice daily in patients with type 2 diabetes
Y.-C. Hwang, M. Kang, C. W. Ahn, J. S. Park, S. H. Baik, D. J. Chung, H. C. Jang, K.-A. Kim, I.-K. Lee, K. W. Min, M. Nam, T. S. Park, S. M. Son, Y.-A. Sung, J.-T. Woo, K. S. Park, M.-K. Lee
International Journal of Clinical Practice.2013; 67(3): 236. CrossRef
Pharmacokinetic comparison of a new glimepiride 1-mg + metformin 500-mg combination tablet formulation and a glimepiride 2-mg + metformin 500-mg combination tablet formulation: A single-dose, randomized, open-label, two-period, two-way crossover study in
Bo-Hyung Kim, Kwang-Hee Shin, JaeWoo Kim, Kyoung Soo Lim, Kyu-pyo Kim, Jung-Ryul Kim, Joo-Youn Cho, Sang-Goo Shin, In-Jin Jang, Kyung-Sang Yu
Clinical Therapeutics.2009; 31(11): 2755. CrossRef

High Glucose Modulates Vascular Smooth Muscle Cell Proliferation Through Activation of PKC-sigma-dependent NAD(P)H oxidase.: Bo Hyun Kim, Chang Won Lee, Jung Lae Park, Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son; Korean Diabetes J. 2006;30(6):416-427. Published online November 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.6.416

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Abstract PDF

BACKGROUND
Oxidative stress is thought to be one of the causative factors contributing to macrovascular complications in diabetes. However, the mechanisms of development and progression of diabetic vascular complications are poorly understood. We hypothesized that PKC-sigma isozyme contributes to ROS generation and determined their roles in the critical intermediary signaling events in high glucose-induced proliferation of vascular smooth muscle (VSM) cells. METHODS: We treated primary cultured rat aortic smooth muscle cells for 72 hours with medium containing 5.5 mmol/L D-glucose (normal glucose), 30 mmol/L D-glucose (high glucose) or 5.5 mmol/L D-glucose plus 24.5 mmol/L mannitol (osmotic control). We then measured cell number, BrdU incorporation, cell cycle and superoxide production in VSM cells. Immunoblotting of PKC isozymes using phoshospecific antibodies was performed, and PKC activity was also measured. RESULTS: High glucose increased VSM cell number and BrdU incorporation and displayed significantly greater percentages of S and G2/M phases than compared to 5.5 mmol/L glucose and osmotic control. The nitroblue tetrazolium (NBT) staining in high glucose-treated VSM cell was more prominent compared with normal glucose-treated VSM cell, which was significantly inhibited by DPI (10 micrometer), but not by inhibitors for other oxidases. High glucose also markedly increased activity of PKC-sigma isozyme. When VSM cells were treated with rottlerin, a specific inhibitor of PKC-sigma or transfected with PKC-sigma siRNA, NBT staining and NAD(P)H oxidase activity were significantly attenuated in the high glucose-treated VSM cells. Furthermore, inhibition of PKC-sigma markedly decreased VSM cell number by high glucose. CONCLUSION: These results suggest that high glucose-induced VSM cell proliferation is dependent upon activation of PKC-sigma, which may responsible for elevated intracellular ROS production in VSM cells, and this is mediated by NAD(P)H oxidase.

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High Glucose and/or Free Fatty Acid Damage Vascular Endothelial Cells via Stimulating of NAD(P)H Oxidase-induced Superoxide Production from Neutrophils
Sang Soo Kim, Sun Young Kim, Soo Hyung Lee, Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son
Korean Diabetes Journal.2009; 33(2): 94. CrossRef

Cell Cycle Progression of Vascular Smooth Muscle cell Through Modulation of p38 MAPK and GSK-3beta Activities Under High Glucose Condition.: Yang Ho Kang, In Ju Kim, Yong Ki Kim, Seok Man Son; Korean Diabetes J. 2005;29(5):418-431. Published online September 1, 2005

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Abstract PDF: BACKGOUND: Macroangiopathy, with atherosclerosis, is the leading cause of mortality and morbidity in diabetic patients. Vascular smooth muscle cells play a crucial role in atherosclerosis, as they proliferate, migrate and express genes that encode inducible growth factors. However, the mechanisms induced by hyperglycemia that accelerate the proliferative change of vascular smooth muscle cells in diabetes remain unclear. This study was aimed at clarifying the respective roles of hyperglycemia in the acceleration of vascular complications in diabetes, examine the effects of hyperglycemia on vascular smooth muscle cell proliferation and the possible underlying mechanisms, including cell cycle progression. METHODS: Primary cultured rat aortic RASMs were exposed to normal glucose(5 mmol/L D-glucose), high glucose(30 mmol/L D-glucose) or an osmotic control (5mmol/L D-glucose plus 24.5 mmol/L mannitol) for 72 hours. The effect of high glucose on cell proliferation was determined by assessing the cell count and BrdU incorporation. Proteins involved in the cell proliferation pathway (PDK1, Akt/PKB, p42/44 MAPK, p38 MAPK, GSK-3beta) and those in cell cycle progression (cdk4, cyclin D, cdk2, cyclin E and ppRb phosphorylation) were determined by Western blot analysis. cdk4 kinase and PKC activity assays were also performed. RESULTS: A high level of glucose increased both the cell count(P<0.01) and BrdU incorporation(P<0.01). The PDK1, Akt/PKB and p42/44 MAPK activities were not significantly increased. A high level of glucose significantly increased the activities of p38 MAPK (P<0.01) and GSK-3beta(P<0.05) and the expressions of cdk4, cyclin D and ppRb phosphorylation. The cdk4 (P<0.01) and PKC (P<0.05) activities were also significantly increased. The inhibition of protein kinase C with GF109203X markedly reduced the phosphorylations of p38 MAPK and GSK-3betaand the expressions of cdk4 and cyclin D. In addition, pretreatment with GF109203X decreased the cell number in response to a high glucose level. CONCLUSION: These findings suggest that a high level of glucose increases vascular smooth muscle cell proliferation, with the possible mechanism further increases the G1 to S phase cell cycle progression via the activation of PKC, p38 MAPK and GSK-3beta.

The Effect of High Glucose on the Proliferation and Migration of Vascular Smooth Muscle Cells.: Mi Kyoung Kim, Yang Ho Kang, Seok Man Son, In Ju Kim, Yong Ki Kim; Korean Diabetes J. 2004;28(5):407-415. Published online October 1, 2004

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Abstract PDF: BACKGROUND
Oxidative stress contributes to vascular diseases for patients with diabetes by promoting vascular smooth muscle cell (VSMC) proliferation, monocyte/macrophage infiltration, and vascular tone alteration. As the mechanism of development and progression of diabetic vascular complications is poorly understood, this study was aimed to assess the potential role of hyperglycemia-induced oxidative stress and to determine whether thise oxidative stress is a major factor in hyperglycemia-induced migration and proliferation of VSMCs. METHODS: Rat aortic VSMCs were incubated for 48 hours in either a normal glucose (NG, 5.5 mM) or a high glucose (HG, 30 mM) condition. We then measured the proliferation and migration of VSMCs and the superoxide production. RESULTS: The migration and proliferation of VSMCs incubated under a HG condition were markedly increased compared to the NG condition. Treatment with diphenyleneiodonium (DPI, 10 M) and superoxide dismutase (SOD, 500 U/mL) significantly suppressed the HG-induced migration and proliferation of VSMCs. Superoxide production was significantly increased in the HG condition, and it was markedly decreased after a treatment with DPI and SOD. CONCLUSION: These data suggest that HG-induced VSMC migration and proliferation are related to the production of superoxide anion that is derived from NAD(P)H oxidase.

Mechanism of Impaired Endothelium-dependent Vasodilation in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats .: Kook Jin Chun, Seok Man Son, In Ju Kim, Chi Dae Kim, Seok Dong Yoo, Yong Ki Kim; Korean Diabetes J. 2002;26(1):47-57. Published online February 1, 2002

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Abstract PDF: BACKGROUND
Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several long-term animals hyperglycemia models and human diabetic patients. Since oxidative stress has been implicated as a contributor to impaired vascular function, the mechanism of an impaired endothelium-dependent vasodilation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats was investigated. METHODS: This present study was undertaken to characterize both the vascular production and the enzymatic source of the superoxide anion in the type 2 diabetic rats. RESULTS: In the thoracic aortas of OLETF rats, endothelium-dependent relaxation was markedly attenuated compared to that of the control rats (LETO, Long-Evans Tokushima Otsuka) in association with a significant increase in superoxide production (2421.39+/-07.01 nmol/min/mg). There was no difference in eNOS expression between the OLETF rats and LETO rats. The increased production of superoxide anion was significantly attenuated by diphenyleneiodonium (DPI, 10 mol/L), NAD (P)H oxidase inhibitor. In line with these results, studies using various enzyme inhibitors such as DPI, allopurinol, rotenone and L-NMMA suggest that the main source of superoxide anions in the aorta is NAD (P)H oxidase. CONCLUSION: These results suggest that enhanced NAD(P)H oxidase activity and reduced nitric oxide (NO) availability through an interaction between NO and superoxide anion contribute to the impaired endothelium-dependent vasodilation in OLETF rats.

Study on the Mechanism of Neutrophil Adhesion to Retinal Capillary Endothelial Cells under High Glucose Condition.: Seok Man Son, Young Sil Lee, Chang Won Lee, Seok Dong Yoo, In Ju Kim, Yong Ki Kim; Korean Diabetes J. 2001;25(1):35-49. Published online February 1, 2001

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Abstract PDF: BACKGROUND
Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and occlusion. Capillary occlusion is the result of microvascular thrombi in which erythrocytes, platelets and leukocytes each may play a major role. Thus, we investigated the pathogenesis of leukocyte stasis by exposing bovine retinal capillary endothelial cells (BRCECs) for high glucose concentration. METHODS: We examined the adhesion of neutrophils to BRCECs incubated in media containing 5.5-30 mmol/L D-glucose for 24 hours. We also measured the expression of E-selectin on endothelial cells and the activation of NF(nuclear transcription factor)-kappaB in nuclear fractions of endothelial cells by using electrophoretic mobility shift assay. RESULTS: We observed that 30 mmol/L D-glucose significantly increased the adhesion of neutrophils to BRCECs (12.5% vs. 3.0%, p<0.01) and migration of neutrophil across cultured BRCEC monolayers (41.0% vs. 21.0%, p<0.05) in respect to 5.5 mmol/L D-glucose. The expression of E-selectin was increased incubated with 30 mmol/L D-glucose compared with 5.5 mmol/L D-glucose (1.45 OD vs. 0.54 OD, p<0.01). Electrophoretic mobility shift assay of nuclear extracts of BRCECs exposed for 24 h to 30 mmol/L D-glucose revealed an intense NF-kappaB activation compared with cells cultured in 5.5 mmol/L D-glucose (8.72x104 countsxmm2 vs.1.88x104 countsxmm2, p<0.01). CONCLUSION: These results suggest that high glucose concentration promote neutrophil adhesion to the BRCECs through upregulation of cell surface expression of E-selectin, possibly depending on NF-kappaB activation and may have implications for the induction of microvasculopathy of diabetic retinopathy.

Study on Role of Neutrophil in Endothelial Cell Injury under High Glucose Condition.: Seok Man Son, In Ju Kim, Yong Ki Kim; Korean Diabetes J. 2000;24(6):652-665. Published online January 1, 2001

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Abstract PDF: BACKGROUND
High glucose level plays a major role in the injury of endothelium during the early event in diabetic vascular complication. It was speculated that high glucose level may cause endothelial cell injury by neutrophil activation. METHODS: The human umbilical vein endothelial cells (HUVEC) were obtained from American Type Culture Collection. The cells were incubated as long as 24 hours to evaluate the expression of E-selectin on the cell surface using whole cell ELISA method. The adherence of neutrophils to human umbilical endothelial cell monolayers and transendothelial migration of 51Cr-labeled neutrophils were evaluated under the condition of different concentrations of D-glucose (5.5, 15, and 30 mmol/L). L-glucose (30 mmol/L) was used as an osmotic control after 24h incubation. We also measured neutrophil-mediated endothelial cell cytotoxicity using a 51Cr-release assay and release of activating markers (lactoferrin and myeloeroxidase) from neutrophils under the same conditions. RESULTS: The expression of E-selectin was increased on endothelium when incubated with medium containing high glucose (30 mmol/L) compared to control (5.5 mmol/L) preparation (1.36 OD vs. 0.79 OD, p<0.05). Increased adherence of neutrophils to HUVEC was observed with high glucose when compared to control (10.4% vs. 2.9%, p<0.01). Similarly, neutrophil migration across the cultured endothelial monolayers were also significantly increased by high glucose (49.8% vs. 27.3%, p<0.05). 51Cr-release from endothelial cells by neutrophils stimulated with high glucose was greater than that with control (27.5% vs. 10.6%, p<0.05). Release of activating markers from neutrophils incubated with high glucose was greater than that from neutrophils incubated with control. CONCLUSION: These results indicate that high glucose increases the adherence and transendothelial migration of neutrophils and cause endothelial cell injury through neutrophil activation. Thus, it is concluded that high glucose level maybe contribute to manifestation of the diabetic vascular disease, including the early step in the initiation of an acute inflammation of vascular endothelial cells.

Effect of Oxidized LDL on Neutrophil Adhesion and Transendothelial Migration.: Seok Man Son, In Ju Kim, Yong Ki Kim; Korean Diabetes J. 1999;23(1):12-24. Published online January 1, 2001

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Abstract PDF: BACKGROUND
It is well recognized that oxidized low density lipoproteins (ox-LDL) play a critical role in the pathogenesis of atherosclerosis. The activation of circulating leukocytes and their adhesion to the vascular endothelium in response to acute stimuli characterize the first step in initiation of an acute inflammatory response. Through the action of degranulation products, adherent leukocytes induce vascular hyperpermeability and contribute to vascular injury. So, we have investigated the neutrophil adhesion to vascular endothelium, a constant feature of early atherogenesis and transendothelial migration of neutrophil induced by ox-LDL. METHOD: In a series of experiments, human umbilical vascular endothelial cells (HUVECs) were incubated for 24 h after addition of native human LDL (100 ug/mL) and of ox-LDL (100 ug/mL) to the medium. The adherence of 51Cr-labeled neutrophils to endothelial monolayers was measured by neutrophil adhesion assay. For diapedesis experiments, HUVECs were grown to confluence on 8.0um pore cell culture inserts. 51Cr-labeled neutrophils were added to the apical surface of HUVEC monolayers and allowed to migrate into the lower chamber for 3 h under the same preparations of native and oxidized LDLs. Reaults: The secretion of IL-8 depended on the concentration of IL-1a and LPS used to stimulate endothelial monolayers in vitro. In addition, ox-LDL triggered secretion of IL-8 from cultured HUVECs compared to that of n-LDL (867.6 pg/mL vs. 273.1 pg/mL, p<0.01). Increased adherence of neutrophils to HUVECs vs observed with ox-LDL preparation compared to native LDL preparation (36.8+1.5% vs. 25.9+1.7%, p<0.05). Similarly, neutrophil migration across cultured endothelial monolayers was also significantly increased by ox-LDL (48.7+3.8% vs. 34.4+2.9%, p<0.05). CONCLUSION: These results show that ox-LD1. can induce increased neutrophil adhesion and migration through IL-8, a potent effector of neutophil functions, secreted by stimulated endothelial cells. So, we suggest that ox-LDL may affect many components of the atherogenic process, including the early step in the initiation of m acute inflammation of vascular endothelial cells.

Effect of High Glucose Concentration on Expression of Adhesion Molecules in Endothelial Cells.: In Ju Kim, Seok Man Son, Min Ki Lee, Hee Jeong, Yong Ki Kim; Korean Diabetes J. 1998;22(3):280-289. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Accelerated atherosclerotic vascular disease is the leading cause of mortality in patients with diabetes mellitus. Endothelial dysfunction, monocytes, and platelets are well known pathogenic factors in atherogenesis. Changes in the neutrophils and endothelial cells, an important early events in all inflammatory process, may contribute to the atherogenesis at early stage, but the significance of this process is not established yet. So we investigated the effects of glucose on the expression of adhesion molecules in endothelial cells, which retlects the change in endothelial-neutrophil adhesive interactions.METHODS: The human umbilical vein endothelial cells(HUVECs) are purchased from American Type Culture Collection. The cells were incubated upto 24 hours to evaluate the expression of E-selectin, PECAM-1, and P-selectin on the cell surface using whole cell ELISA method and soluble P-selectin under different glucose concentration(5.5, 15, and 30 mmol/L). Neutrophil adherence was also measured hy incubation of isolated human neutrophils with monolayers of HUVECs under same different glucose concentration. RESULTS: After 24h incubation with a various concentration of glucose, neutrophil adherence to high concentration of glucose(15 and 30mmol/L)- treated endothelium was significantly increased(5.0 +0.4 and 10.4+0.5%, respectively) compared with adhesion to low concentration of glucose(5.5mmol/ L)-treated endothelium(2.9.+0.4%). Incubation of HUVECs for 24 h in 30mmol/L glucose increased absorbance of E-selectin to 1.36+0.16(P<0.01) and reduced that of P-selectin to 0.56+0.04 compared with the results of respective control culture in 5.5mmol/L glucose(p<0.01), but not changed PECAM-1 expression. In addition, 24 h exposure of HUVECs to 30mmol/L glucose decreased soluble P-selectin concentration to 0.33+0.06ng/mL(P<0.01). CONCLUSION: The results of this study demonstrate that high concentration of glucose stimulates neutrophil adhesion to endothelial cells in association with increased expression of E-selectin. These results suggest that high glucose can directly affect interaction between neutrophil and endothelial cell through a adhesion molecule, especially E-selectin dependent mechanism. Further study should be necessary to investigate the significance of this phenomenon.

Elevated Levels of Soluble E-selectin and P-selectin in Patients with NIDDM.: Seok Dong Yoo, In Joo Kim, Yong Ki Kim; Korean Diabetes J. 1998;22(1):23-34. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Although there is wide spread agreement that patients with NIDDM are at increased risk of the premature development of atherosclerosis, it is not totally clear why this is so. This may be related to the interaction of blood leukocytes with vascular endothelium resulting from a loss of normal metabolic control. The adherence of leukocytes to the endothelium is at least partly mcdiated by cell adhesion molecules. In this study, we evaluated the level of soluble E-selectin and P-selectin in blood of normal controls and patients with NIDDM, and studied its relation to glycemic control and identifiable factors influencing the level of soluble E-selectin and P-selectin. METHODS: Serum soluble E-selectin and plasma soluble P-selectin levels were measured by ELISA method in 24 NIDDM patients without macrovascullar disease and 14 normal controls matched with age, sex and body mass index. Clinical characteristics and laboratory findings such as fasting plasma glucose, HbA1c and lipid profile were evaluated, and their relation with the levels of E-selectin and P-selectin was analized. RESULTS: 1) The levels of E-selectin and P-selectin in NIDDM patients were significantly higher than those of normal controls(55.69+21.97 vs. 42.11+13.57ng/ mL, P<0.05 for E-selectin, 41.60+20.90 vs. 27.16 +7.12ng/mL, P 0.01 for P-selectin). 2) The levels of E-selectin and P-selectin were positively correlated with the fasting plasma glucose level(r=0.400 P<0,05 for E-selectin, r=0.456 P<0.01 for P-selectin). They were also positively correlated with the levels of serum triglyceride(r=0.531 P<0.01 for E-selectin, r=0.415 P =0.05 for P-selectin) but not with the levels of serum total cholesterol, LDL and HDL cholestrol in NIDDM patients. 3) No significant correlation was noted between the levels of E-selectin or P-selectin and the duration of NIDDM. And the levels were not different according to the type of treatment. 4) E-selectin level, not P-selectin level, was significantly higher in the patients with nephropathy when compared to the patients without nephropathy. But such difference was not noted when the patients were classified according to the presence of retinopathy or neuropathy. 5) E-selectin level was positively correlated with P-selectin level in both NIDDM patients and normal controls(r=0.52, P<0.01). CONCLUSION: These findings suggest that endothelial dysfunction, revealed by increased cellular adhesion molecules, could play a role in the pathogenesis of diabetic atherosclerotic vascular disorders in NIDDM patients with increased fasting plasma glucose control and hypertriglyceridemia. In addition, elevated soluble E-selectin and P-selectin level in blood might be used as a marker of diabetic nephropathy.

Effect of Glucose on Adherence of Neutrophils to Endothelial Cells.: Seok Man Son, Seok Dong Yoo, In Ju Kim, Yong Ki Kim, Hee Bag Park, Chi Dae Kim, Ki Whan Hong; Korean Diabetes J. 1997;21(3):262-270. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Accelerated atherosclerotic vascular disease is the leading cause of mortality in patients with diabetes mellitus. To clarify the mechanisms that cause macrovascular dysfunction in diabetes, we examined the effect of high glucose on the adhesion of neutrophils to the endothelial cells and release of TNF-a from cultured rabbit aortic endotheIial cells. METHODS: Rabbit aortic endothelial cells in primary culture were prepared by the collagenase digestion method. Cells were incubated for various time upto 24 hours to evaluate TNF-a response to different glucose concentrations(0, 5.5, 11, 22mmol/L). Isolated rabbit neutrophils were incubated with monolayers of rabbit aortic endothelial cells under different glucose condition. RESULTS: After 24 hrs incubation with various concentrations of glucose, neutrophil adherence to high concentration of glucose(11 and 22mM)-treated endothelium was significantly increased(46+/-7 and 64 +/-6%, respectively) compared with adhesion to low concentration of glucose(0 or 5.5mM)-treated endothelium(3l +/-5 and 30+/-3%, respectively), In addition, when TNF-a imrnunoreactivity in the culture medium was measured by enzyme-linked immunoassay after 24 hours of incubation with various concentration of glucose, the secretion of TNF-a from endothelial cells was significantly increased in a concentration-dependent manner upon exposure to high concentration of glucose, CONCLUSION: The results of this study ciemonstrate tht high concentration of glucose stimulates neutrophil adhesion to endothelial cells in association with increased production of TNF-a from endothelial cells. These results suggest that glucose directly causes increased interaction between neutrophil and endothelial cell through a TNF-a-dependent mechaniasm,

Effect of high glucose on function of cultured rabbit vascular endothelial cells.: Seok Man Son, In Ju Kim, Yong Ki Kim, Chi Dae Kim, Ki Whan Hong; Korean Diabetes J. 1997;21(2):156-167. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Vascular disease accounts for the majority of the clinical complications of diabetes mellitus. Changes in local control of vascular tone such as imbalanced production of relaxing and contracting factors by endothelium may be related to the initiation and maintenance of abnormal vascular reactivity characteristically seen in diabetic vascular complications. Cytokines and growth factors released from injured endothelial cells, T-cells, and macro-phages enhance atherogenesis. In this study, we examined NO and TNF-a released from cultured rabbit aortic endothelial cells(RAECs) under different glucose concentration to investigate the relationship between high glucose and endothelial cell dysfunction. METHODS: The thoracic and abdominal aortae of rabbit(23kg) were isolated and periadventitial connective tissue was carefully removed. Rabbit aortic endothelial cells in primary culture were prepared by the m.ethod of Schwartz with modification. RAECs were grown to confluence in 25 cm2 flask in DMEM supplemented with 20% FBS, 150pg/mL endothelial cell growth supplernent, 90pg/mL heparin, 100 U/mL penicillin and 100pg/mL streptomycin at 37'C in humidified 5% carbon dioxide in air. For experiments, confluent cells were replaced in 1 1 mm, 48 well plate containing same medium composition. Cells were then incubated in the presence or absence of FBS for various times up to 48 hours(time course) to eveluate the NO and TNF-a response to different glucose concentrations(0, 5.5, 11, 22, and 44 mmol/ L). Cells were also incubated with various concentration of ACH and ADP(10, 10', 10 and 10' mol/L) and 10' mol/L of ACH or ADP with different glucose concentrations for 24 hours to evaluate stimulated effect of ACH and ADP on NO release. RESULTS: 1) Total NO release from RAECs was significantly in a time-dependent. After 48 hours incubation, the total secretion of NO was significantly higher in culture medium with FRS than without FBS. 2) Glucose concentration resembling severe hyper-glycemic conditions(22 and 44 mmol/L) significantly inhibited NO release from RAECs, 3) Acetylcholine and ADP induced a clear dose-dependent NO release in RAECs. 4) Stimulation of acetylcholine and ADP on NO release according to different glucose concentration was not significantly higher than NO release in culture medium with glucose alone. 5) The increment in TNF-a levels was associated with a significant increase at higher glucose concentration, 6) There was a negative correlation between NO and TNF-a release in culture medium with FBS but not in culture medium without FBS. CONCLUSION: Our data show that decreased NO release and increased TNF-a release from RAECs were noted under high glucose concentration. Such interaction could play a significant role in the development of diabetic vascular complication in hyperglycernic conditions.

A study of gastric emptying time and effect of cisapride in diabetic patients.: Yong Ki Kim, Kyoung Seog Lee, Jae Bok Lee, Chul Soo Choi, In Joo Kim; Korean Diabetes J. 1993;17(4):403-410. Published online January 1, 2001

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Abstract PDF: No abstract available.

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