Diabetes & Metabolism Journal

Original Articles

Cardiovascular Risk/Epidemiology
The Ratio of Estimated Glomerular Filtration Rate Based on Cystatin C and Creatinine Reflecting Cardiovascular Risk in Diabetic Patients: Ah Reum Khang, Min Jin Lee, Dongwon Yi, Yang Ho Kang; Diabetes Metab J. 2023;47(3):415-425. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0177

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Background
The ratio of estimated glomerular filtration rate (eGFR) based on cystatin C and creatinine (eGFR_{cystatin C}/eGF_Rcreatinine ratio) is related to accumulating atherosclerosis-promoting proteins and increased mortality in several cohorts.
Methods
We assessed whether the eGFR_{cystatin C}/eGFR_creatinine ratio is a predictor of arterial stiffness and sub-clinical atherosclerosis in type 2 diabetes mellitus (T2DM) patients, who were followed up during 2008 to 2016. GFR was estimated using an equation based on cystatin C and creatinine.
Results
A total of 860 patients were stratified according to their eGFR_{cystatin C}/eGF_Rcreatinine ratio (i.e., <0.9, 0.9–1.1 [a reference group], and >1.1). Intima-media thickness was comparable among the groups; however, presence of carotid plaque was frequent in the <0.9 group (<0.9 group, 38.3%; 0.9–1.1 group, 21.6% vs. >1.1 group, 17.2%, P<0.001). Brachial-ankle pulse wave velocity (baPWV) was faster in the <0.9 group (<0.9 group, 1,656.3±333.0 cm/sec; 0.9–1.1 group, 1,550.5±294.8 cm/sec vs. >1.1 group, 1,494.0±252.2 cm/sec, P<0.001). On comparing the <0.9 group with the 0.9–1.1 group, the multivariate-adjusted odds ratios of prevalence of high baPWV and carotid plaque were 2.54 (P=0.007) and 1.95 (P=0.042), respectively. Cox regression analysis demonstrated near or over 3-fold higher risks of the prevalence of high baPWV and carotid plaque in the <0.9 group without chronic kidney disease (CKD).
Conclusion
We concluded that eGFR_{cystatin C}/eGFR_creatinine ratio <0.9 was related to an increased risk of high baPWV and carotid plaque in T2DM patients, especially, those without CKD. Careful monitoring of cardiovascular disease is needed for T2DM patients with low eGFR_{cystatin C}/eGFR_creatinine ratio.

Citations

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Research Progress of Creatinine, Cystatin C, and Their Ratio in Renal Diseases
广智杨
Advances in Clinical Medicine.2024; 14(04): 976. CrossRef
Muscle mass, creatinine, cystatin C and selective glomerular hypofiltration syndromes
Linnea Malmgren, Anders Grubb
Clinical Kidney Journal.2023; 16(8): 1206. CrossRef
Investigating kidney function changes in young adults with COVID-19: Serum creatinine level, glomerular filtration rate, and biochemical profile analysis
Nikita Matyushin, Dmitriy Ermakov, Inna Vasileva, Roza Vakolyuk, Anastasiya Spaska
Electronic Journal of General Medicine.2023; 20(6): em547. CrossRef
Intraindividual difference in estimated GFR by creatinine and cystatin C, cognitive trajectories and motoric cognitive risk syndrome
Jinqi Wang, Yueruijing Liu, Rui Jin, Xiaoyu Zhao, Zhiyuan Wu, Ze Han, Zongkai Xu, Xiuhua Guo, Lixin Tao
Nephrology Dialysis Transplantation.2023;[Epub] CrossRef

Metabolic Risk/Epidemiology
Synergistic Interaction between Hyperuricemia and Abdominal Obesity as a Risk Factor for Metabolic Syndrome Components in Korean Population: Min Jin Lee, Ah Reum Khang, Yang Ho Kang, Mi Sook Yun, Dongwon Yi; Diabetes Metab J. 2022;46(5):756-766. Published online January 20, 2022; DOI: https://doi.org/10.4093/dmj.2021.0166

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Background
The present study investigated the role of synergistic interaction between hyperuricemia and abdominal obesity as a risk factor for the components of metabolic syndrome.
Methods
We performed a cross-sectional study using the data of 16,094 individuals from the seventh Korean National Health and Nutrition Examination Survey (2016 to 2018). The adjusted odds ratios of metabolic syndrome and its components were analyzed by multivariate logistic regression analysis. The presence of synergistic interaction between hyperuricemia and abdominal obesity was evaluated by calculating the additive scales—the relative excess risk due to interaction, attributable proportion due to interaction, and synergy index (SI).
Results
There was a synergistic interaction between hyperuricemia and abdominal obesity in hypertriglyceridemia (men: SI, 1.39; 95% confidence interval [CI], 1.01 to 1.98; women: SI, 1.61; 95% CI, 1.02 to 2.69), and low high-density lipoprotein cholesterol (HDL-C) (men: SI, 2.03; 95% CI, 1.41 to 2.91; women: SI, 1.70; 95% CI, 1.05 to 2.95). There was no significant synergistic interaction between hyperuricemia and abdominal obesity for the risk of high blood pressure (men: SI, 1.22; 95% CI, 0.85 to 1.77; women: SI, 1.53; 95% CI, 0.79 to 2.97), and hyperglycemia (men: SI, 1.03; 95% CI, 0.72 to 1.47; women: SI, 1.39; 95% CI, 0.75 to 2.57).
Conclusion
Hyperuricemia and abdominal obesity synergistically increased the risk of hypertriglyceridemia and low HDL-C in both sexes.

Citations

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Prevalence and factors associated with overweight, obesity and central obesity among adults in Shenmu City, Shaanxi Province, China
Mingxia Liu, Chunjiao Jia, Yaoda Hu, Juan Liu, Lizhen Liu, Shengli Sun, Haiying Wang, Yonglin Liu
Preventive Medicine Reports.2024; 40: 102673. CrossRef
Synergistic interaction between hyperlipidemia and obesity as a risk factor for stress urinary incontinence in Americans
Fangyi Zhu, Mao Chen, Ya Xiao, Xiaoyu Huang, Liying Chen, Li Hong
Scientific Reports.2024;[Epub] CrossRef
The role of cognitive function in the relationship between surrogate markers of visceral fat and depressive symptoms in general middle-aged and elderly population: A nationwide population-based study
Na Zhang, Jianqian Chao, Xueyu Wu, Hongling Chen, Min Bao
Journal of Affective Disorders.2023; 338: 581. CrossRef
Biodegradation of Uric Acid by Bacillus paramycoides-YC02
Xiaoyu Cao, Jingyuan Cai, Yu Zhang, Chao Liu, Meijie Song, Qianqian Xu, Yang Liu, Hai Yan
Microorganisms.2023; 11(8): 1989. CrossRef
A predictive model for hyperuricemia among type 2 diabetes mellitus patients in Urumqi, China
Palizhati Abudureyimu, Yuesheng Pang, Lirun Huang, Qianqian Luo, Xiaozheng Zhang, Yifan Xu, Liang Jiang, Patamu Mohemaiti
BMC Public Health.2023;[Epub] CrossRef
Dietary Ferulic Acid Ameliorates Metabolism Syndrome-Associated Hyperuricemia in Rats via Regulating Uric Acid Synthesis, Glycolipid Metabolism, and Hepatic Injury
Nanhai Zhang, Jingxuan Zhou, Lei Zhao, Ou Wang, Liebing Zhang, Feng Zhou
Frontiers in Nutrition.2022;[Epub] CrossRef

Response

Response: The Association of Serum Cystatin C with Glycosylated Hemoglobin in Korean Adults (Diabetes Metab J 2016;40:62-9): Yang Ho Kang; Diabetes Metab J. 2016;40(2):173-174. Published online April 25, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.2.173

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Original Articles

The Association of Serum Cystatin C with Glycosylated Hemoglobin in Korean Adults: Eun Hee Sim, Hye Won Lee, Hyun Ju Choi, Dong Wook Jeong, Seok Man Son, Yang Ho Kang; Diabetes Metab J. 2016;40(1):62-69. Published online November 27, 2015; DOI: https://doi.org/10.4093/dmj.2016.40.1.62

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Background

Cystatin C has been known to be associated not only with early renal impairment but also with the incidence of diabetic conditions (prediabetes plus diabetes). However, it is not clear whether cystatin C levels are associated with the prevalence of diabetic conditions in Asian populations. We evaluated this association using glycosylated hemoglobin (HbA1c) levels as the definition of diabetes in Korean adults.

Methods

We analyzed data from 1,559 Korean adults (937 men and 622 women) with available serum cystatin C and HbA1c values.

Results

The serum cystatin C levels in subjects with prediabetes and diabetes were significantly increased (0.91±0.14 mg/L in prediabetes and 0.91±0.17 mg/L in diabetes vs. 0.88±0.13 mg/L in patients with normal glucose levels, P=0.001). At increasing cystatin C levels, the prevalence of subjects with prediabetes (30.2% vs. 14.6%, P<0.001) and those with diabetes (10.6% vs. 8.0%, P<0.001) significantly increased in the group with the highest cystatin C levels. The group with the highest cystatin C levels had a significantly increased odds ratio (OR) for the presence of diabetic conditions compared to the group with the lowest values in total subjects (OR, 2.35; 95% confidence interval [CI], 1.54 to 3.58; P<0.001) and in women (OR, 4.13; 95% CI, 1.97 to 8.65; P<0.001), though there was no significant increase after adjusting for multiple variables.

Conclusions

Higher levels of serum cystatin C are associated with an increased prevalence of diabetic conditions in Korean adults. Our findings may extend the positive association of cystatin C with diabetes incidence to an Asian population.

Citations

Citations to this article as recorded by

Prognostic significance of serum cystatin C in acute brainstem infarctions patients
H. Li, B. Zhang, Z. Huang, H. Wu, B. Qin, L. Zhou, Z. Lu, F. Qin
Revue Neurologique.2024;[Epub] CrossRef
Cardiovascular risk assessment in prediabetic patients in a hypertensive population: The role of cystatin C
Rafael Garcia-Carretero, Luis Vigil-Medina, Inmaculada Mora-Jimenez, Cristina Soguero-Ruiz, Rebeca Goya-Esteban, Javier Ramos-Lopez, Oscar Barquero-Perez
Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2018; 12(5): 625. CrossRef
Characteristics of Dapagliflozin Responders: A Longitudinal, Prospective, Nationwide Dapagliflozin Surveillance Study in Korea
Eugene Han, Ari Kim, Sung Jae Lee, Je-Yon Kim, Jae Hyeon Kim, Woo Je Lee, Byung-Wan Lee
Diabetes Therapy.2018; 9(4): 1689. 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
Prevalence of Reduced Kidney Function by Estimated Glomerular Filtration Rate Using an Equation Based on Creatinine and Cystatin C in Metabolic Syndrome and Its Components in Korean Adults
Yang Ho Kang, Dong Wook Jeong, Seok Man Son
Endocrinology and Metabolism.2016; 31(3): 446. CrossRef
Letter: The Association of Serum Cystatin C with Glycosylated Hemoglobin in Korean Adults (Diabetes Metab J 2016;40:62-9)
Kyung-Soo Kim
Diabetes & Metabolism Journal.2016; 40(2): 171. CrossRef
Response: The Association of Serum Cystatin C with Glycosylated Hemoglobin in Korean Adults (Diabetes Metab J 2016;40:62-9)
Yang Ho Kang
Diabetes & Metabolism Journal.2016; 40(2): 173. CrossRef

The Association between Apolipoprotein A-II and Metabolic Syndrome in Korean Adults: A Comparison Study of Apolipoprotein A-I and Apolipoprotein B: Dong Won Yi, Dong Wook Jeong, Sang Yeoup Lee, Seok Man Son, Yang Ho Kang; Diabetes Metab J. 2012;36(1):56-63. Published online February 17, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.1.56

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Background

Apolipoprotein A-II (apoA-II) is the second-most abundant apolipoprotein in human high-density lipoprotein and its role in cardio metabolic risk is not entirely clear. It has been suggested to have poor anti-atherogenic or even pro-atherogenic properties, but there are few studies on the possible role of apoA-II in Asian populations. The aim of this study is to evaluate the role of apoA-II in metabolic syndrome (MetS) compared with apolipoprotein A-I (apoA-I) and apolipoprotein B (apoB) in Korean adults.

Methods

We analyzed data from 244 adults who visited the Center for Health Promotion in Pusan National University Yangsan Hospital for routine health examinations.

Results

The mean apoB level was significantly higher, and the mean apoA-I level was significantly lower, in MetS; however, there was no significant difference in apoA-II levels (30.5±4.6 mg/dL vs. 31.2±4.6 mg/dL, P=0.261). ApoA-II levels were more positively correlated with apoA-I levels than apoB levels. ApoA-II levels were less negatively correlated with homocysteine and high sensitivity C-reactive protein levels than apoA-I levels. The differences in MetS prevalence from the lowest to highest quartile of apoA-II were not significant (9.0%, 5.7%, 4.9%, and 6.6%, P=0.279). The relative risk of the highest quartile of apoA-II compared with the lowest quartile also was not significantly different (odds ratio, 0.96; 95% confidence interval, 0.95 to 1.04; P=0.956).

Conclusion

Compared with apoA-I (negative association with MetS) and apoB (positive association with MetS) levels, apoA-II levels did not show any association with MetS in this study involving Korean adults. However, apoA-II may have both anti-atherogenic and pro-atherogenic properties.

Citations

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Association of apolipoproteins and lipoprotein(a) with metabolic syndrome: a systematic review and meta-analysis
Juan R. Ulloque-Badaracco, Ali Al-kassab-Córdova, Enrique A. Hernandez-Bustamante, Esteban A. Alarcon-Braga, Miguel Huayta-Cortez, Ximena L. Carballo-Tello, Rosa A. Seminario-Amez, Percy Herrera-Añazco, Vicente A. Benites-Zapata
Lipids in Health and Disease.2023;[Epub] CrossRef
Interaction between Apo A-II –265T > C polymorphism and dietary total antioxidant capacity on some oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus
Banafsheh Jafari Azad, Mehdi Yaseri, Elnaz Daneshzad, Fariba Koohdani
British Journal of Nutrition.2022; 128(1): 13. CrossRef
Dietary acid load modifies the effects of ApoA2–265 T > C polymorphism on lipid profile and serum leptin and ghrelin levels among type 2 diabetic patients
Faezeh Abaj, Zahra Esmaeily, Zeinab Naeini, Masoumeh Rafiee, Fariba Koohdani
BMC Endocrine Disorders.2022;[Epub] CrossRef
Can biomarkers be used to improve diagnosis and prediction of metabolic syndrome in childhood cancer survivors? A systematic review
Vincent G. Pluimakers, Selveta S. van Santen, Marta Fiocco, Marie‐Christine E. Bakker, Aart J. van der Lelij, Marry M. van den Heuvel‐Eibrink, Sebastian J. C. M. M. Neggers
Obesity Reviews.2021;[Epub] CrossRef
Decreased Antiatherogenic Protein Levels are Associated with Aneurysm Structure Alterations in MR Vessel Wall Imaging
Daizo Ishii, Toshinori Matsushige, Shigeyuki Sakamoto, Koji Shimonaga, Yuji Akiyama, Takahito Okazaki, Jumpei Oshita, Kaoru Kurisu
Journal of Stroke and Cerebrovascular Diseases.2019; 28(8): 2221. CrossRef
Low levels of ApoA1 improve risk prediction of type 2 diabetes mellitus
Xing Wu, Zhexin Yu, Wen Su, Daniel A. Isquith, Moni B. Neradilek, Ning Lu, Fusheng Gu, Hongwei Li, Xue-Qiao Zhao
Journal of Clinical Lipidology.2017; 11(2): 362. CrossRef
Apolipoprotein A2 −265 T>C polymorphism interacts with dietary fatty acids intake to modulate inflammation in type 2 diabetes mellitus patients
Laleh Keramat, Haleh Sadrzadeh-Yeganeh, Gity Sotoudeh, Elham Zamani, Mohammadreza Eshraghian, Anahita Mansoori, Fariba Koohdani
Nutrition.2017; 37: 86. CrossRef
APO A2 -265T/C Polymorphism Is Associated with Increased Inflammatory Responses in Patients with Type 2 Diabetes Mellitus
Fariba Koohdani, Haleh Sadrzadeh-Yeganeh, Mahmoud Djalali, Mohammadreza Eshraghian, Elham Zamani, Gity Sotoudeh, Mohammad-Ali Mansournia, Laleh Keramat
Diabetes & Metabolism Journal.2016; 40(3): 222. CrossRef
Association between ApoA-II -265T/C polymorphism and oxidative stress in patients with type 2 diabetes mellitus
Fariba Koohdani, Haleh Sadrzadeh-Yeganeh, Mahmoud Djalali, Mohammadreza Eshraghian, Laleh Keramat, Mohammad-Ali Mansournia, Elham Zamani
Journal of Diabetes and its Complications.2015; 29(7): 908. CrossRef
Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review
C. Roger White, David W. Garber, G.M. Anantharamaiah
Journal of Lipid Research.2014; 55(10): 2007. CrossRef

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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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.

Citations

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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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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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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

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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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.

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