Endocrinology and Metabolism

Original Articles

Endocrine Research
Deficiency of Sphingosine-1-Phosphate Reduces the Expression of Prohibitin and Causes β-Cell Impairment via Mitochondrial Dysregulation: Seok-Woo Hong, Jinmi Lee, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee; Endocrinol Metab. 2018;33(3):403-412. Published online September 18, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.3.403

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Background

Emerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB).

Methods

We examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels.

Results

Lack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends.

Conclusion

Altogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.

Citations

Citations to this article as recorded by

Mitochondrial Cristae Morphology Reflecting Metabolism, Superoxide Formation, Redox Homeostasis, and Pathology
Petr Ježek, Martin Jabůrek, Blanka Holendová, Hana Engstová, Andrea Dlasková
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Maryam Jamil, Lauren Ashley Cowart
Frontiers in Cell and Developmental Biology.2023;[Epub] CrossRef
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Meng Duan, Pan Gao, Sheng‐xi Chen, Petr Novák, Kai Yin, Xiao Zhu
Obesity Reviews.2022;[Epub] CrossRef
Involvement of miR‐27a‐3p in diabetic nephropathy via affecting renal fibrosis, mitochondrial dysfunction, and endoplasmic reticulum stress
Lina Wu, Qingzhu Wang, Feng Guo, Xiaojun Ma, Jiao Wang, Yanyan Zhao, Yushan Yan, Guijun Qin
Journal of Cellular Physiology.2021; 236(2): 1454. CrossRef
Sphingosine‐1‐phosphate in acute exercise and training
Katarzyna Hodun, Adrian Chabowski, Marcin Baranowski
Scandinavian Journal of Medicine & Science in Sports.2021; 31(5): 945. CrossRef
The Ethyl Acetate Extract From Celastrus orbiculatus Promotes Apoptosis of Gastric Cancer Cells Through Mitochondria Regulation by PHB
Lide Tao, Zixin Yin, Tengyang Ni, Zewen Chu, Shihua Hao, Zeyu Wang, Masataka Sunagawa, Haibo Wang, Yanqing Liu
Frontiers in Pharmacology.2021;[Epub] CrossRef
Sphingosine 1-phosphate Stimulates Insulin Secretion and Improves Cell Survival by Blocking Voltage-dependent K+ Channels in β Cells
Zhihong Liu, Huanhuan Yang, Linping Zhi, Huan Xue, Zhihong Lu, Yanli Zhao, Lijuan Cui, Tao Liu, Shouan Ren, Peifeng He, Yunfeng Liu, Yi Zhang
Frontiers in Pharmacology.2021;[Epub] CrossRef
Sphingosine-1 Phosphate Lyase Regulates Sensitivity of Pancreatic Beta-Cells to Lipotoxicity
Yadi Tang, Thomas Plötz, Markus H. Gräler, Ewa Gurgul-Convey
International Journal of Molecular Sciences.2021; 22(19): 10893. CrossRef
Sphingolipids and Mitochondrial Dynamic
Lais Brigliadori Fugio, Fernanda B. Coeli-Lacchini, Andréia Machado Leopoldino
Cells.2020; 9(3): 581. CrossRef
Diminished Sphingolipid Metabolism, a Hallmark of Future Type 2 Diabetes Pathogenesis, Is Linked to Pancreatic β Cell Dysfunction
Saifur R. Khan, Yousef Manialawy, Andreea Obersterescu, Brian J. Cox, Erica P. Gunderson, Michael B. Wheeler
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Neuronal Metabolism and Neuroprotection: Neuroprotective Effect of Fingolimod on Menadione-Induced Mitochondrial Damage
Antonio Gil, Elisa Martín-Montañez, Nadia Valverde, Estrella Lara, Federica Boraldi, Silvia Claros, Silvana-Yanina Romero-Zerbo, Oscar Fernández, Jose Pavia, Maria Garcia-Fernandez
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WITHDRAWN: Ceramide and Sphingosine 1-Phosphate in adipose dysfunction
Zijian Fang, Susan Pyne, Nigel J. Pyne
Progress in Lipid Research.2019; : 100991. CrossRef
Dynamic of mitochondrial network, cristae, and mitochondrial nucleoids in pancreatic β-cells
Petr Ježek, Andrea Dlasková
Mitochondrion.2019; 49: 245. CrossRef
Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells
I. Pulli, C. Löf, T. Blom, M.Y. Asghar, T. Lassila, N. Bäck, K.-L. Lin, J.H. Nyström, K. Kemppainen, D.M. Toivola, E. Dufour, A. Sanz, H.M. Cooper, J.B. Parys, K. Törnquist
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Ceramide and sphingosine 1-phosphate in adipose dysfunction
Zijian Fang, Susan Pyne, Nigel J. Pyne
Progress in Lipid Research.2019; 74: 145. CrossRef
S1P/S1P Receptor Signaling in Neuromuscolar Disorders
Elisabetta Meacci, Mercedes Garcia-Gil
International Journal of Molecular Sciences.2019; 20(24): 6364. CrossRef

Diabetes
Pioglitazone Attenuates Palmitate-Induced Inflammation and Endoplasmic Reticulum Stress in Pancreatic β-Cells: Seok-Woo Hong, Jinmi Lee, Jung Hwan Cho, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee; Endocrinol Metab. 2018;33(1):105-113. Published online March 21, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.1.105

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Background

The nuclear receptor peroxisome proliferator-activator gamma (PPARγ) is a useful therapeutic target for obesity and diabetes, but its role in protecting β-cell function and viability is unclear.

Methods

To identify the potential functions of PPARγ in β-cells, we treated mouse insulinoma 6 (MIN6) cells with the PPARγ agonist pioglitazone in conditions of lipotoxicity, endoplasmic reticulum (ER) stress, and inflammation.

Results

Palmitate-treated cells incubated with pioglitazone exhibited significant improvements in glucose-stimulated insulin secretion and the repression of apoptosis, as shown by decreased caspase-3 cleavage and poly (adenosine diphosphate [ADP]-ribose) polymerase activity. Pioglitazone also reversed the palmitate-induced expression of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], and IL-1β) and ER stress markers (phosphor-eukaryotic translation initiation factor 2α, glucose-regulated protein 78 [GRP78], cleaved-activating transcription factor 6 [ATF6], and C/EBP homologous protein [CHOP]), and pioglitazone significantly attenuated inflammation and ER stress in lipopolysaccharide- or tunicamycin-treated MIN6 cells. The protective effect of pioglitazone was also tested in pancreatic islets from high-fat-fed KK-Ay mice administered 0.02% (wt/wt) pioglitazone or vehicle for 6 weeks. Pioglitazone remarkably reduced the expression of ATF6α, GRP78, and monocyte chemoattractant protein-1, prevented α-cell infiltration into the pancreatic islets, and upregulated glucose transporter 2 (Glut2) expression in β-cells. Moreover, the preservation of β-cells by pioglitazone was accompanied by a significant reduction of blood glucose levels.

Conclusion

Altogether, these results support the proposal that PPARγ agonists not only suppress insulin resistance, but also prevent β-cell impairment via protection against ER stress and inflammation. The activation of PPARγ might be a new therapeutic approach for improving β-cell survival and insulin secretion in patients with diabetes mellitus

Citations

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Diabetes
The Association between Persistent Hypertriglyceridemia and the Risk of Diabetes Development: The Kangbuk Samsung Health Study: Yu Hyun Kwon, Seul-Ki Kim, Jung Hwan Cho, Hyemi Kwon, Se Eun Park, Hyung-Geun Oh, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2018;33(1):55-61. Published online January 30, 2018; DOI: https://doi.org/10.3803/EnM.2018.33.1.55

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Background

Hypertriglyceridemia is known to have an association with increased risks of insulin resistance and diabetes. The aim of this study was to investigate the risk of diabetes mellitus, according to changes in the concentrations of triglycerides, over time.

Methods

A total of 15,932 non-diabetic participants (mean age 43.2 years, 68% men) who attended five consecutive annual health check-ups at Kangbuk Samsung Hospital, between January 2010 and December 2014, were recruited. Participants were classified according to their triglyceride concentrations; normal (<150 mg/dL) and abnormal (≥150 mg/dL). According to the triglyceride levels in 2010 and 2012, subjects were divided into four groups: normal-normal, normal-abnormal, abnormal-normal, and abnormal-abnormal. The risk for incident diabetes was assessed in 2014.

Results

Among the total subjects, 67.5% belonged to the normal-normal group, 8.6% to the normal-abnormal group, 9.4% to the abnormal-normal group, and 14.5% to the abnormal-abnormal group. A total of 234 subjects (1.5%) were newly diagnosed with diabetes, between 2010 and 2014. Over 4 years, 1%, 1.5%, 2.1%, and 3.0% of the subjects developed diabetes in the normal-normal, normal-abnormal, abnormal-normal, and abnormal-abnormal groups, respectively. When the risk for incident diabetes was analyzed in the groups, after adjusting the confounding variables, a 1.58-fold increase in the risk of diabetes (95% confidence interval [CI], 1.10 to 2.26) was observed in the participants with persistent hypertriglyceridemia (abnormal-abnormal group). This was attenuated by further adjustments for body mass index (BMI) (hazard ratio, 1.25; 95% CI, 0.86 to 1.80).

Conclusion

In this large study population, persistent hypertriglyceridemia, over a period of 2 years, was significantly associated with the risk of incident diabetes, which was attenuated after adjustment for BMI.

Citations

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Cumulative exposure to hypertriglyceridemia and risk of type 2 diabetes in young adults
Min-Kyung Lee, Kyungdo Han, Bongsung Kim, Jong-Dai Kim, Moon Jung Kim, Byungpyo Kim, Jung Heo, Jiyeon Ahn, Seo-Young Sohn, Jae-Hyuk Lee
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Response: The Association between Persistent Hypertriglyceridemia and the Risk of Diabetes Development: The Kangbuk Samsung Health Study (Endocrinol Metab 2018;33:55–61, Yu Hyun Kwon et al.)
Eun-Jung Rhee, Yu Hyun Kwon
Endocrinology and Metabolism.2018; 33(3): 425. CrossRef
The Association between Persistent Hypertriglyceridemia and the Risk of Diabetes Development: The Kangbuk Samsung Health Study (Endocrinol Metab 2018;33:55–61, Yu Hyun Kwon et al.)
Mi Hae Seo
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Clinical Study
Changes in Body Composition According to Age and Sex among Young Non-Diabetic Korean Adults: The Kangbuk Samsung Health Study: Seul-Ki Kim, Yu-Hyun Kwon, Jung Hwan Cho, Da Young Lee, Se Eun Park, Hyung-Geun Oh, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2017;32(4):442-450. Published online November 21, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.4.442

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Background

Age-related decreases in lean mass represent a serious health problem. We aimed to analyze the risks of rapid decreases in lean mass by age and sex in relatively young Korean adults during a 4-year follow-up study.

Methods

A total of 65,856 non-diabetic participants (59.5% men, mean age 39.1 years) in a health screening program were subjected to bioimpedance body composition analyses and metabolic parameter analyses at baseline and after 4 years. The participants were sub-divided according to age, and additionally to six groups by age and the degree of body weight change over the 4-year period. The actual changes in body weight, lean mass, and fat mass and the percent changes over the 4-year period were assessed.

Results

The percent change in lean mass decreased and the percent change of fat mass increased with increasing age in every age and sex group. However, the annual percent decrease in lean mass and percent increase in fat mass were significantly higher among women than among men (−0.26% vs. −0.15% and 0.34% vs. 0.42%, respectively; P<0.01). Participants who were older than 50 years and had a weight loss <−5% during the 4 years had significantly greater decreases in lean mass and smaller decreases in fat mass, compared to those who were younger than 50 years. An odds ratio analysis to determine the lowest quartile of the percent change in lean mass according to age group revealed that participants older than 60 years had a significantly increased risk of a rapid decrease in the lean mass percentage (2.081; 95% confidence interval, 1.678 to 2.581).

Conclusion

Even in this relatively young study population, the lean mass decreased significantly with age, and the risk of a rapid decrease in lean mass was higher among women than among men. Furthermore, the elderly exhibited a significantly more rapid decrease in lean mass, compared with younger participants.

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Clinical Study
Waist Circumference as a Marker of Obesity Is More Predictive of Coronary Artery Calcification than Body Mass Index in Apparently Healthy Korean Adults: The Kangbuk Samsung Health Study: Jongsin Park, Eun Seo Lee, Da Young Lee, Jihyun Kim, Se Eun Park, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2016;31(4):559-566. Published online December 20, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.4.559

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Background

We aimed to assess the risk for coronary artery calcification (CAC) according to groups subdivided by body mass index (BMI) and waist circumference (WC) in apparently healthy Korean adults.

Methods

Thirty-three thousand four hundred and thirty-two participants (mean age, 42 years) in a health screening program were divided into three groups according to BMI: <23 kg/m² (normal), 23 to 25 kg/m² (overweight), and >25 kg/m² (obese). In addition, the participants were divided into two groups according to WC. Coronary artery calcium score (CACS) was measured with multi-detector computed tomography in all participants. Presence of CAC was defined as CACS >0.

Results

When logistic regression analysis was performed with the presence of CAC as the dependent variable, the risk for CAC increased as BMI increased after adjusting for confounding variables (1.102 [95% confidence interval (CI), 1.000 to 1.216]; 1.284 [95% CI, 1.169 to 1.410]; in the overweight and obese groups vs. the normal weight group). When the participants were divided into six groups according to BMI and WC, the subjects with BMI and WC in the obese range showed the highest risk for CAC (1.321 [95% CI, 1.194 to 1.461]) and those with BMI in the overweight range and WC in the obese range showed the second highest risk for CAC (1.235 [95% CI, 1.194 to 1.461]).

Conclusion

Participants with obesity defined by both BMI and WC showed the highest risk for CAC. Those with BMIs in the overweight range but with WC in the obese range showed the second highest risk for CAC, suggesting that WC as a marker of obesity is more predictive of CAC than BMI.

Citations

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Clinical Study
Eligibility for Statin Treatment in Korean Subjects with Reduced Renal Function: An Observational Study: Byung Sub Moon, Jongho Kim, Ji Hyun Kim, Young Youl Hyun, Se Eun Park, Hyung-Geun Oh, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Kyu-Beck Lee, Hyang Kim, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2016;31(3):402-409. Published online August 26, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.3.402

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Background

The purpose of this study was to investigate the relationship between statin eligibility and the degree of renal dysfunction using the Adult Treatment Panel (ATP) III and the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines in Korean adults.

Methods

Renal function was assessed in 18,746 participants of the Kangbuk Samsung Health Study from January 2011 to December 2012. Subjects were divided into three groups according to estimated glomerular filtration rate (eGFR): stage 1, eGFR ≥90 mL/min/1.73 m²; stage 2, eGFR 60 to 89 mL/min/1.73 m²; and stages 3 to 5, eGFR <60 mL/min/1.73 m². Statin eligibility in these groups was determined using the ATP III and ACC/AHA guidelines, and the risk for 10-year atherosclerotic cardiovascular disease (ASCVD) was calculated using the Framingham Risk Score (FRS) and Pooled Cohort Equation (PCE).

Results

There were 3,546 (18.9%) and 4,048 (21.5%) statin-eligible subjects according to ATP III and ACC/AHA guidelines, respectively. The proportion of statin-eligible subjects increased as renal function deteriorated. Statin eligibility by the ACC/AHA guidelines showed better agreement with the Kidney Disease Improving Global Outcomes (KDIGO) recommendations compared to the ATP III guidelines in subjects with stage 3 to 5 chronic kidney disease (CKD) (κ value, 0.689 vs. 0.531). When the 10-year ASCVD risk was assessed using the FRS and PCE, the mean risk calculated by both equations significantly increased as renal function declined.

Conclusions

The proportion of statin-eligible subjects significantly increased according to worsening renal function in this Korean cohort. ACC/AHA guideline showed better agreement for statin eligibility with that recommended by KDIGO guideline compared to ATP III in subjects with CKD.

Citations

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Clinical Study
C-Peptide-Based Index Is More Related to Incident Type 2 Diabetes in Non-Diabetic Subjects than Insulin-Based Index: Jong-Dai Kim, Sung Ju Kang, Min Kyung Lee, Se Eun Park, Eun Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee; Endocrinol Metab. 2016;31(2):320-327. Published online June 21, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.2.320

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Background

Diabetes can be efficiently prevented by life style modification and medical therapy. So, identification for high risk subjects for incident type 2 diabetes is important. The aim of this study is to identify the best β-cell function index to identify high risk subjects in non-diabetic Koreans.

Methods

This is a retrospective longitudinal study. Total 140 non-diabetic subjects who underwent standard 2-hour 75 g oral glucose tolerance test from January 2007 to February 2007 at Kangbuk Samsung Hospital and followed up for more than 1 year were analyzed (mean follow-up, 54.9±16.4 months). The subjects were consist of subjects with normal glucose tolerance (n=44) and subjects with prediabetes (n=97) who were 20 years of age or older. Samples for insulin and C-peptide levels were obtained at 0 and 30 minutes at baseline.

Results

Thirty subjects out of 140 subjects (21.4%) developed type 2 diabetes. When insulin-based index and C-peptide-based index are compared between progressor and non-progressor to diabetes, all C-peptide-based indices were statistically different between two groups, but only insulinogenic index and disposition index among insulin-based index were statistically different. C-peptide-based index had higher value of area under receiver operating characteristic curve (AROC) value than that of insulin-based index. "C-peptidogenic" index had highest AROC value among indices (AROC, 0.850; 95% confidence interval, 0.761 to 0.915). C-peptidogenic index had significantly higher AROC than insulinogenic index (0.850 vs. 0.731 respectively; P=0.014).

Conclusion

C-peptide-based index was more closely related to incident type 2 diabetes in non-diabetic subjects than insulin-based index.

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Won-Young Lee
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Clinical Study
The Relationship between 10-Year Cardiovascular Risk Calculated Using the Pooled Cohort Equation and the Severity of Non-Alcoholic Fatty Liver Disease: Jeong In Lee, Min Chul Kim, Byung Sub Moon, Young Seok Song, Eun Na Han, Hyo Sun Lee, Yoonjeong Son, Jihyun Kim, Eun Jin Han, Hye-Jeong Park, Se Eun Park, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2016;31(1):86-92. Published online March 16, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.1.86

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Background

We investigated the association between the severity of non-alcoholic fatty liver disease (NAFLD) and the estimated 10-year risk of cardiovascular disease (CVD) calculated by Pooled Cohort Equation (PCE) and Framingham risk score (FRS).

Methods

A total of 15,913 participants (mean age, 46.3 years) in a health screening program were selected for analysis. The presence and severity of fatty liver was assessed by abdominal ultrasonogram. Subjects who drank alcohol more than three times a week were excluded from the study.

Results

Among the participants, 57.6% had no NAFLD, 35.4% had grade I, 6.5% had grade II, and 0.5% had grade III NAFLD. Mean estimated 10-year CVD risk was 2.59%, 3.93%, 4.68%, and 5.23% calculated using the PCE (P for trend <0.01) and 4.55%, 6.39%, 7.33%, and 7.13% calculated using FRS, according to NAFLD severity from none to severe (P for trend <0.01). The odds ratio for ≥7.5% estimated CVD risk calculated using the PCE showed a higher correlation with increasing severity of NAFLD even after adjustment for conventional CVD risk factors (1.52, 2.56, 3.35 vs. the no NAFLD group as a reference, P<0.01) compared with calculated risk using FRS (1.65, 1.62, 1.72 vs. no NAFLD group as a reference, P<0.01).

Conclusion

In our study of apparently healthy Korean adults, increasing severity of NAFLD showed a higher correlation with estimated 10-year CVD risk when calculated using the PCE than when calculated using FRS.

Citations

Citations to this article as recorded by

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Dana Kablawi, Faisal Aljohani, Chiara Saroli Palumbo, Sophie Restellini, Alain Bitton, Gary Wild, Waqqas Afif, Peter L Lakatos, Talat Bessissow, Giada Sebastiani
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Low Relative Handgrip Strength Is Associated with a High Risk of Non-Alcoholic Fatty Liver Disease in Italian Adults: A Retrospective Cohort Study
Samantha Maurotti, Roberta Pujia, Elisa Mazza, Maria Francesca Pileggi, Franco Arturi, Maria Grazia Tarsitano, Tiziana Montalcini, Arturo Pujia, Yvelise Ferro
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Yedidya Saiman, Andres Duarte-Rojo, Mary E. Rinella
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Adriana Cervo, Giada Sebastiani, Jovana Milic, Thomas Krahn, Sergio Mazzola, Salvatore Petta, Antonio Cascio, Giovanni Guaraldi, Giovanni Mazzola
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Value of the triglyceride glucose index combined with body mass index in identifying non-alcoholic fatty liver disease in patients with type 2 diabetes
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Triglyceride Glucose Index and Related Parameters (Triglyceride Glucose-Body Mass Index and Triglyceride Glucose-Waist Circumference) Identify Nonalcoholic Fatty Liver and Liver Fibrosis in Individuals with Overweight/Obesity
Mohammad E. Khamseh, Mojtaba Malek, Rowshanak Abbasi, Hoda Taheri, Maryam Lahouti, Fariba Alaei-Shahmiri
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Grazia Pennisi, Vito Di Marco, Carola Buscemi, Giovanni Mazzola, Cristiana Randazzo, Federica Spatola, Antonio Craxì, Silvio Buscemi, Salvatore Petta
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Ga Eun Nam, Soon Young Hwang, Hye Soo Chung, Ju Hee Choi, Hyun Jung Lee, Nam Hoon Kim, Hye Jin Yoo, Ji-A Seo, Sin Gon Kim, Nan Hee Kim, Sei Hyun Baik, Kyung Mook Choi
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Clinical Study
Association of Waist-Height Ratio with Diabetes Risk: A 4-Year Longitudinal Retrospective Study: Yoon Jeong Son, Jihyun Kim, Hye-Jeong Park, Se Eun Park, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2016;31(1):127-133. Published online March 16, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.1.127

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Background

Waist-to-height ratio (WHtR) is an easy and inexpensive adiposity index that reflects central obesity. In this study, we examined the association of various baseline adiposity indices, including WHtR, with the development of diabetes over 4 years of follow-up in apparently healthy Korean individuals.

Methods

A total of 2,900 nondiabetic participants (mean age, 44.3 years; 2,078 men) in a health screening program, who repeated the medical check-up in 2005 and 2009, were recruited. Subjects were divided into two groups according to development of diabetes after 4 years. The cut-off values of baseline body mass index (BMI), waist circumference (WC), and WHtR for the development of diabetes over 4 years were calculated. The sensitivity, specificity, and mean area under the receiver operator characteristic curve (AUROC) of each index were assessed. The odds ratio (OR) for diabetes development was analyzed for each of the three baseline adiposity indices.

Results

During the follow-up period, 101 new cases (3.5%) of diabetes were diagnosed. The cut-off WHtR value for diabetes development was 0.51. Moreover, WHtR had the highest AUROC value for diabetes development among the three adiposity indices (0.716, 95% confidence interval [CI], 0.669 to 0.763; 0.702, 95% CI, 0.655 to 0.750 for WC; 0.700, 95% CI, 0.651 to 0.750 for BMI). After adjusting for confounding variables, the ORs of WHtR and WC for diabetes development were 1.95 (95% CI, 1.14 to 3.34) and 1.96 (95% CI, 1.10 to 3.49), respectively. No significant differences were observed between the two groups regarding BMI.

Conclusion

Increased baseline WHtR and WC correlated with the development of diabetes after 4 years. WHtR might be a useful screening measurement to identify individuals at high risk for diabetes.

Citations

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Rachana Manandhar Shrestha, Thuy Thi Phuong Pham, Shohei Yamamoto, Chau Que Nguyen, Ami Fukunaga, Phan Cong Danh, Masahiko Hachiya, Huy Xuan Le, Hung Thai Do, Tetsuya Mizoue, Yosuke Inoue
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Jiang-Feng Ke, Jun-Wei Wang, Jun-Xi Lu, Zhi-Hui Zhang, Yun Liu, Lian-Xi Li
Diabetes Research and Clinical Practice.2022; 183: 109151. CrossRef
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Eun-Jung Rhee, Jung-Hwan Cho, Hyemi Kwon, Se-Eun Park, Jin-Hyung Jung, Kyung-Do Han, Yong-Gyu Park, Yang-Hyun Kim, Won-Young Lee
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Clinical Study
Metabolic Health Is More Important than Obesity in the Development of Nonalcoholic Fatty Liver Disease: A 4-Year Retrospective Study: Min-Kyung Lee, Eun-Jung Rhee, Min Chul Kim, Byung Sub Moon, Jeong In Lee, Young Seok Song, Eun Na Han, Hyo Sun Lee, Yoonjeong Son, Se Eun Park, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee; Endocrinol Metab. 2015;30(4):522-530. Published online December 31, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.4.522

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Background

The aim of this study is to compare the risk for future development of nonalcoholic fatty liver disease (NAFLD) according to different status of metabolic health and obesity.

Methods

A total of 3,045 subjects without NAFLD and diabetes at baseline were followed for 4 years. Subjects were categorized into four groups according to the following baseline metabolic health and obesity statuses: metabolically healthy, non-obese (MHNO); metabolically healthy, obese (MHO); metabolically unhealthy, non-obese (MUHNO); and metabolically unhealthy, obese (MUHO). Being metabolically healthy was defined as having fewer than two of the following five components: high blood pressure, high fasting blood glucose, high triglyceride, low high density lipoprotein cholesterol, and being in the highest decile of the homeostasis model assessment-insulin resistance index. Obesity was defined as a body mass index >25 kg/m². The presence of NAFLD was assessed by ultrasonography.

Results

The proportions of subjects included in the MHNO, MHO, MUHNO, and MUHO groups were 71.4%, 9.8%, 13.0%, and 5.8%, respectively. The proportions of subjects who developed NAFLD were 10.5%, 31.4%, 23.2%, and 42% in the MHNO, MHO, MUHNO, and MUHO groups, respectively. The risk for developing NAFLD was highest in subjects who were metabolically unhealthy both at baseline and after 4 years compared with subjects who were consistently metabolically healthy during the follow-up period (odds ratio, 2.862). Using the MHNO group as reference, the odds ratios for the MHO, MUHNO, and MUHO groups were 1.731, 1.877, and 2.501, respectively.

Conclusion

The risk for NAFLD was lower in MHO subjects than in MUNO subjects.

Citations

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Circulation.2018; 138(23): 2627. CrossRef
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Eugene Han, Yong-ho Lee
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Lean, but not healthy
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Obesity and Metabolism
Comparison of Serum Adipocytokine Levels according to Metabolic Health and Obesity Status: Tae Hoon Lee, Won Seon Jeon, Ki Joong Han, Shin Yeoung Lee, Nam Hee Kim, Hyun Beom Chae, Choel Min Jang, Kyung Mo Yoo, Hae Jung Park, Min Kyung Lee, Se Eun Park, Hyung Geun Oh, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2015;30(2):185-194. Published online June 30, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.2.185

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Background

Metabolic health is an emerging concept that is highly correlated with various metabolic complications, and adipocytokines have been causally linked to a wide range of metabolic diseases. Thus, this study compared serum adipocytokine levels according to metabolic health and obesity status.

Methods

Four hundred and fifty-six nondiabetic subjects (mean age, 40.5 years) were categorized into four groups according to metabolic health and obesity status: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUHNO), and metabolically unhealthy obese (MUHO). Being metabolically healthy was defined as the presence of fewer than two of the following five metabolic abnormalities: high blood pressure, high fasting blood glucose, high triglyceride, low high density lipoprotein cholesterol, and being in the highest decile of the homeostatic model assessment of insulin resistance index. Obesity status was assessed using body mass index (BMI), with obesity defined as a BMI higher than 25 kg/m². Levels of serum interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α (TNF-α), and adipocyte fatty acid binding protein (A-FABP) were also evaluated.

Results

Of the 456 subjects, 247 (54.2%) were in the MHNO group, 66 (14.5%) were in the MHO group, 66 (14.5%) were in the MUHNO group, and 77 (16.9%) were in the MUHO group. There were no significant differences in IL-6 or MCP-1 levels among the groups, but levels of TNF-α and A-FABP were significantly higher in the MUHNO group compared to the MHNO group.

Conclusion

High TNF-α and A-FABP levels are significantly associated with metabolically unhealthiness in nonobese Korean individuals.

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Poor Vitamin D Status in Active Pulmonary Tuberculosis Patients and Its Correlation with Leptin and TNF-α
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Ligiane Marques Loureiro, Suzane Lessa, Rodrigo Mendes, Sílvia Pereira, Carlos José Saboya, Andrea Ramalho
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Finja Jockenhöfer, Knut Kröger, Joachim Klode, Regina Renner, Cornelia Erfurt‐Berge, Joachim Dissemond
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JDDG: Journal der Deutschen Dermatologischen Gesellschaft.2016; 14(3): 277. CrossRef
Response: Comparison of Serum Adipocytokine Levels according to Metabolic Health and Obesity Status (Endocrinol Metab2015;30:185-94, Tae Hoon Lee et al.)
Eun-Jung Rhee
Endocrinology and Metabolism.2015; 30(3): 416. CrossRef
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Endocrinology and Metabolism.2015; 30(3): 414. CrossRef
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Obesity and Metabolism
Exendin-4 Inhibits the Expression of SEPP1 and Fetuin-A via Improvement of Palmitic Acid-Induced Endoplasmic Reticulum Stress by AMPK: Jinmi Lee, Seok-Woo Hong, Se Eun Park, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee; Endocrinol Metab. 2015;30(2):177-184. Published online June 30, 2015; DOI: https://doi.org/10.3803/EnM.2015.30.2.177

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Background

Selenoprotein P (SEPP1) and fetuin-A, both circulating liver-derived glycoproteins, are novel biomarkers for insulin resistance and nonalcoholic fatty liver disease. However, the effect of exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, on the expression of hepatokines, SEPP1, and fetuin-A, is unknown.

Methods

The human hepatoma cell line HepG2 was treated with palmitic acid (PA; 0.4 mM) and tunicamycin (tuni; 2ug/ml) with or without exendin-4 (100 nM) for 24 hours. The change in expression of PA-induced SEPP1, fetuin-A, and endoplasmic reticulum (ER) stress markers by exendin-4 treatment were evaluated using quantitative real-time reverse transcription polymerase chain reaction and Western blotting. Transfection of cells with AMP-activated protein kinase (AMPK) small interfering RNA (siRNA) was performed to establish the effect of exendin-4-mediated AMPK in the regulation of SEPP1 and fetuin-A expression.

Results

Exendin-4 reduced the expression of SEPP1, fetuin-A, and ER stress markers including PKR-like ER kinase, inositol-requiring kinase 1α, activating transcription factor 6, and C/EBP homologous protein in HepG2 cells. Exendin-4 also reduced the expression of SEPP1 and fetuin-A in cells treated with tunicamycin, an ER stress inducer. In cells treated with the AMPK activator 5-aminoidazole-4-carboxamide ribonucleotide (AICAR), the expression of hepatic SEPP1 and fetuin-A were negatively related by AMPK, which is the target of exendin-4. In addition, exendin-4 treatment did not decrease SEPP1 and fetuin-A expression in cells transfected with AMPK siRNA.

Conclusion

These data suggest that exendin-4 can attenuate the expression of hepatic SEPP1 and fetuin-A via improvement of PA-induced ER stress by AMPK.

Citations

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Maternal Organic Selenium Supplementation Relieves Intestinal Endoplasmic Reticulum Stress in Piglets by Enhancing the Expression of Glutathione Peroxidase 4 and Selenoprotein S
Dajiang Ding, Daolin Mou, Heng Zhu, Xuemei Jiang, Lianqiang Che, Zhengfeng Fang, Shengyu Xu, Yan Lin, Yong Zhuo, Jian Li, Chao Huang, Yuanfeng Zou, Lixia Li, De Wu, Bin Feng
Frontiers in Nutrition.2022;[Epub] CrossRef
Alliin, capsaicin, and gingerol attenuate endoplasmic reticulum stress-induced hepatic steatosis in HepG2 cells and C57BL/6N mice
Ye-Rang Yun, Ji-Eun Lee
Journal of Functional Foods.2022; 95: 105186. CrossRef
PNPLA3 I148M is involved in the variability in anti-NAFLD response to exenatide
Yunzhi Chen, Xuemei Yan, Xiao Xu, Shuhua Yuan, Fen Xu, Hua Liang
Endocrine.2020; 70(3): 517. CrossRef
Green tea extracts reduce leukocyte cell–Derived chemotaxin 2 and selenoprotein P levels in the livers of C57BL/6J mice fed a high-fat diet
Shintaro Onishi, Hidefumi Kitazawa, Shinichi Meguro, Ichiro Tokimitsu
Bioscience, Biotechnology, and Biochemistry.2018; 82(9): 1568. CrossRef
Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha‐2‐HS‐glycoprotein
Jee‐In Heo, Dae Wui Yoon, Ji Hee Yu, Nam Hoon Kim, Hye Jin Yoo, Ji A. Seo, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Dong Seop Choi, Nan Hee Kim
Journal of Pineal Research.2018;[Epub] CrossRef
Palmitic acid induces ceramide accumulation, mitochondrial protein hyperacetylation, and mitochondrial dysfunction in porcine oocytes†
Nobuhiko Itami, Koumei Shirasuna, Takehito Kuwayama, Hisataka Iwata
Biology of Reproduction.2018; 98(5): 644. CrossRef
Astragaloside IV attenuates free fatty acid-induced ER stress and lipid accumulation in hepatocytes via AMPK activation
Bing Zhou, Dan-li Zhou, Xiao-hong Wei, Rong-yu Zhong, Jie Xu, Liao Sun
Acta Pharmacologica Sinica.2017; 38(7): 998. CrossRef
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Won-Young Lee
Endocrinology and Metabolism.2017; 32(1): 1. CrossRef
Selenoprotein P neutralizes lipopolysaccharide and participates in hepatic cell endoplasmic reticulum stress response
Yongzhong Zhao, Shuvojit Banerjee, Ping Huang, Xinning Wang, Candece L. Gladson, Warren D. Heston, Charles B. Foster
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Hans-Ulrich Häring
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Obesity and Metabolism
Activation of AMP-Activated Protein Kinase Attenuates Tumor Necrosis Factor-α-Induced Lipolysis via Protection of Perilipin in 3T3-L1 Adipocytes: Seok-Woo Hong, Jinmi Lee, Se Eun Park, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Sung-Woo Park, Won-Young Lee; Endocrinol Metab. 2014;29(4):553-560. Published online December 29, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.4.553

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Background

Tumor necrosis factor (TNF)-α and AMP-activated protein kinase (AMPK) are known to stimulate and repress lipolysis in adipocytes, respectively; however, the mechanisms regulating these processes have not been completely elucidated.

Methods

The key factors and mechanism of action of TNF-α and AMPK in lipolysis were investigated by evaluating perilipin expression and activity of protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 α (eIF2α) by Western blot and an immunofluorescence assay in 24-hour TNF-α-treated 3T3-L1 adipocytes with artificial manipulation of AMPK activation.

Results

Enhancement of AMPK activity by the addition of activator minoimidazole carboxamide ribonucleotide (AICAR) suppressed TNF-α-induced lipolysis, whereas the addition of compound C, an inhibitor of AMPK phosphorylation, enhanced lipolysis. Perilipin, a lipid droplet-associated protein, was decreased by TNF-α and recovered following treatment with AICAR, showing a correlation with the antilipolytic effect of AICAR. Significant activation of PERK/eIF2α, a component of the unfolded protein response signaling pathway, was observed in TNF-α or vesicle-treated 3T3-L1 adipocytes. The antilipolytic effect and recovery of perilipin expression by AICAR in TNF-α-treated 3T3-L1 adipocytes were significantly diminished by treatment with 2-aminopurine, a specific inhibitor of eIF2α.

Conclusion

These data indicated that AICAR-induced AMPK activation attenuates TNF-α-induced lipolysis via preservation of perilipin in 3T3-L1 adipocytes. In addition, PERK/eIF2α activity is a novel mechanism of the anti-lipolytic effect of AICAR.

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Chan Yoon Park, Donguk Kim, Min Kyeong Seo, Jimin Kim, Han Choe, Jong-Hyeok Kim, Joon Pio Hong, Yeon Ji Lee, Yoonseok Heo, Hwa Jung Kim, Hye Soon Park, Yeon Jin Jang
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Obesity and Metabolism
Increased Risk of Diabetes Development in Subjects with the Hypertriglyceridemic Waist Phenotype: A 4-Year Longitudinal Study: Ki Joong Han, Shin Yeoung Lee, Nam Hee Kim, Hyun Beom Chae, Tae Hoon Lee, Choel Min Jang, Kyung Mo Yoo, Hae Jung Park, Min Kyung Lee, Won Seon Jeon, Se Eun Park, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2014;29(4):514-521. Published online December 29, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.4.514

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Background

The hypertriglyceridemic waist (HTGW) phenotype is a simple and inexpensive screening parameter to identify people at increased risk of cardiovascular disease. We evaluated whether the HTGW phenotype predicts diabetes in urban Korean adults.

Methods

A total of 2,900 nondiabetic subjects (mean age 44.3 years), comprising 2,078 males (71.7%) and 822 females (28.3%) who underwent annual medical check-ups at our center between January 2005 and December 2009, were recruited. The subjects were divided into four groups according to baseline serum triglyceride (TG) level and waist circumference (WC): normal WC-normal TG (NWNT) level, normal WC-high TG level, enlarged WC-normal TG level, and enlarged WC-high TG (EWHT) level. High serum TG level was defined as ≥150 mg/dL and enlarged WC was defined as ≥90 cm for men and ≥85 cm for women. New cases of diabetes were determined according to questionnaires filled in by participants and the diagnostic criteria of the American Diabetes Association. Cox proportional hazards model analysis was used to assess the association of HTGW phenotype with the incidence of diabetes.

Results

A total of 101 (3.5%) new diabetes cases were diagnosed during the study period. The EWHT group had a higher incidence of diabetes (8.3%) compared with the NWNT group (2.2%). The adjusted hazard ratio for diabetes for subjects with the EWHT phenotype at baseline was 4.113 (95% confidence interval [CI], 2.397 to 7.059) after adjustment for age, and 2.429 (95% CI, 1.370 to 4.307) after adjustment for age, sex, total cholesterol, systolic blood pressure, and alcohol drinking history. It was attenuated by inclusion of baseline fasting glucose level in the model.

Conclusion

Subjects with the HTGW phenotype showed the highest risk of incident diabetes. This tool could be useful for identifying individuals at high risk of diabetes.

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Age Is the Strongest Effector for the Relationship between Estimated Glomerular Filtration Rate and Coronary Artery Calcification in Apparently Healthy Korean Adults: Hyun Beom Chae, Shin Yeoung Lee, Nam Hee Kim, Ki Joong Han, Tae Hoon Lee, Choel Min Jang, Kyung Mo Yoo, Hae Jung Park, Min Kyung Lee, Won Seon Jeon, Se Eun Park, Heui-Soo Moon, Cheol-Young Park, Won-Young Lee, Ki-Won Oh, Sung-Woo Park, Eun-Jung Rhee; Endocrinol Metab. 2014;29(3):312-319. Published online September 25, 2014; DOI: https://doi.org/10.3803/EnM.2014.29.3.312

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Background

Chronic kidney disease (CKD) is considered one of the most common risk factors for cardiovascular disease. Coronary artery calcification (CAC) is a potential mechanism that explains the association between renal function and cardiovascular mortality. We aimed to evaluate the association between renal function and CAC in apparently healthy Korean subjects.

Methods

A total of 23,617 participants in a health-screening program at Kangbuk Samsung Hospital were included in the study. Estimated glomerular filtration rate (eGFR) was assessed using the Cockcroft-Gault equation. Coronary artery calcium score (CACS) was measured via multidetector computed tomography. Subjects were divided into three groups according to the CKD Staging system with eGFR grade: stage 1, eGFR ≥90 mL/min/1.73 m²; stage 2, eGFR 60 to 89 mL/min/1.73 m²; and stage 3, eGFR 30 to 59 mL/min/1.73 m².

Results

The mean age of the participants was 41.4 years and the mean eGFR was 103.6±21.7 mL/min/1.73 m². Hypertension and diabetes were noted in 43.7% and 5.5% of the participants, respectively. eGFR showed a weakly negative but significant association with CACS in bivariate correlation analysis (r=-0.076, P<0.01). Mean CACS significantly increased from CKD stage 1 to 3. The proportion of subjects who had CAC significantly increased from CKD stage 1 to 3. Although the odds ratio for CAC significantly increased from stage 1 to 3 after adjustment for confounding factors, this significance was reversed when age was included in the model.

Conclusion

In early CKD, renal function negatively correlated with the degree of CAC in Korean subjects. Age was the strongest effector for this association.

Citations

Citations to this article as recorded by

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