Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
Interactions between Tau Phosphorylation and Endoplasmic Reticulum Stress in Diabetic Nephropathy: Eun Soo Lee, Jeong Suk Kang, Seong-Woo Lee, Su Ho Jo, Ji-Hye Lee, Eun Young Lee, Choon Hee Chung; Received October 7, 2024 Accepted July 18, 2025 Published online November 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0618 [Epub ahead of print]

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Tau is a microtubule-associated protein whose abnormal phosphorylation disrupts the cytoskeleton and induces cell death. While its role is well known in neuro degenerative diseases, its function in kidney pathology, particularly diabetic nephropathy (DN), is not well understood.
Methods
DN was induced in NADPH oxidase 5 (NOX5) pod⁺ mice through a high-fat diet (HFD; 60% kcal fat) for 3, 6, and 12 weeks. Kidney tissues and cultured mesangial cells were analyzed for tau phosphorylation at specific residues (Ser202 and Thr205), fibrosis markers (e.g., α-smooth muscle actin), and endoplasmic reticulum (ER) stress. Tau phosphorylation was modulated using thousand and one amino acid kinase inhibitor and ER stress inhibitors. Immunohistochemistry was also performed on human renal biopsy samples from DN patients.
Results
pTau Ser202 and Thr205 expression levels were elevated by 6 weeks of the HFD and remained persistently upregulated at 12 weeks. Human biopsy analysis further revealed elevated pTau Ser202 and Thr205 expression in the patients with DN, which correlated with proteinuria. In NOX5 pod⁺ mice, early metabolic changes developed by HFD led to tau phosphorylation and kidney damage. Transforming growth factor β-induced fibrosis or thapsigargin-induced ER stress increased tau phosphorylation, while inhibiting tau phosphorylation or ER stress alleviated mesangial cell damage.
Conclusion
Our findings demonstrate that site-specific tau phosphorylation is associated with renal injury in DN and may serve as a potential marker of disease severity. The interplay between tau phosphorylation and ER stress appears to contribute to disease progression. Targeting tau phosphorylation and its upstream stress pathways may offer new therapeutic strategies for DN.

Complications
STING Promotes Renal Fibrosis of Diabetic Kidney Disease via ID1-Dependent Epithelial-Mesenchymal Transition: Hongya Wang, Xiaobing Mao, Yuqing Huang, Xiaozhen Tan, Yuling Yang, Mengting Huang, Zongzhe Jiang, Yang Long, Xia Fang, Yong Xu; Received October 18, 2024 Accepted May 30, 2025 Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2024.0645 [Epub ahead of print]

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Tubulointerstitial fibrosis (TIF) due to epithelial-mesenchymal transition (EMT) is an inseparable feature of diabetic renal fibrosis. Although stimulator of interferon genes (STING) has been shown to have potential in regulating EMT, whether and how it modulates EMT in diabetic kidney disease (DKD) mice remains unclear. Here, we investigated the role and the underlying mechanisms of STING-mediated EMT on TIF in DKD.
Methods
STING expression was detected in human renal biopsy tissues and serum samples with DKD. Mouse models with genetic deletion of STING or inhibition by a STING inhibitor (C176) were established to further investigate the functions of STING in vivo. The in vitro roles of STING were analyzed in human renal tubular epithelial (HK2) cells with STING overexpression or STING knockdown. RNA sequencing was used to explore the underlying mechanisms.
Results
STING was upregulated in the kidneys and serum from patients with DKD and negatively correlated with kidney function. STING deletion or pharmacologic inhibition with C176 ameliorated pathological lesions, renal function and fibrosis in mouse models of DKD. STING deficiency alleviated renal fibrosis in DKD mice via inhibiting EMT. Mechanistically, by RNA sequencing, inhibitor of differentiation 1 (ID1) was found to a downstream molecule of STING. Inhibition of ID1 on the basis of overexpression of STING could suppress EMT and renal fibrosis.
Conclusion
Our study provides evidence that STING deficiency relieves renal fibrosis by inhibiting ID1-mediated EMT and that inhibition of STING and ID1 has the potential therapeutic prospects for patients with DKD.

Cardiovascular Risk/Epidemiology
E2F5 Accelerates Vascular Smooth Muscle Cells Phenotype Switching in Diabetic Atherosclerosis through Activating Wnt/β-Catenin Pathway: Mingxue Di, Jie Wang, Lin Sun, Guang Yang, Qun Xu; Received September 25, 2024 Accepted April 21, 2025 Published online September 1, 2025; DOI: https://doi.org/10.4093/dmj.2024.0588 [Epub ahead of print]

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We determined the precise function of E2F transcription factor 5 (E2F5) on the development of diabetic atherosclerosis (DAS) and the underlying mechanisms.
Methods
Apolipoprotein E-knockout mice were intraperitoneally injected streptozotocin for 5 days and fed a high-fat diet for 12 weeks for establishing an in vivo DAS model. To establish a DAS vascular smooth muscle cells (VSMCs) model, VSMCs were stimulated with fresh medium containing glucose and oxidized low-density lipoprotein. After the final treatment, serum lipids were detected, and aorta tissues were collected for hematoxylin and eosin staining, Western blot, Oil red O staining, and quantitative reverse transcription polymerase chain reaction. The effect of E2F5 on the proliferation, migration, cell cycle, phenotype switching, and cell cycle-related markers of VSMCs were evaluated.
Results
In vivo, the expression of E2F5 was elevated in aorta tissues of DAS mice. The downregulation of E2F5 alleviated the symptoms of DAS in mice. Moreover, E2F5 downregulation inhibited the phenotypic transformation of VSMCs in DAS mice. In vitro, the knockdown of E2F5 inhibited the phenotypic transformation of VSMCs. CyclinE overexpression reversed the inhibitory effect of E2F5 silencing on phenotypic transformation of VSMCs. Additionally, we also found that the treatment of BML-284 significantly attenuated the inhibitory effect of E2F5 silencing on phenotypic transformation of VSMCs.
Conclusion
E2F5 is an injurious factor in the pathogenesis of DAS, and the downregulation of E2F5 could repress VSMCs phenotype switching through inactivating Wnt/β-catenin pathway, and ultimately inhibit the progression of DAS.

Complications
Comparison of Efficacy and Safety of Cilostazol/Extract of Ginkgo biloba vs. Aspirin in Carotid Atherosclerosis in Patients with Diabetes Mellitus: You-Cheol Hwang, Mi Kyung Kim, Jung Hwan Park, Han Mi Yun, Sang Yong Kim, Soo Lim; Received February 24, 2025 Accepted May 16, 2025 Published online August 13, 2025; DOI: https://doi.org/10.4093/dmj.2025.0146 [Epub ahead of print]

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We conducted a prospective, randomized study to evaluate the combination of cilostazol (CTZ) and extract of Ginkgo biloba (EGb) and compare it with aspirin for the prevention of atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM).
Methods
One hundred five patients with T2DM and increased carotid intima-media thickness (IMT) were randomly assigned to receive either CTZ 200 mg plus EGb 160 mg once daily or aspirin (ASA) 100 mg/day for 12 months. The primary endpoint was the change in maximum carotid IMT.
Results
The mean age and body mass index were 61.6±8.4 years and 25.2±3.1 kg/m² in the CTZ/EGb group and 61.6±7.6 years and 24.5±3.3 kg/m² in the ASA group, respectively. CTZ/EGb treatment reduced the maximum IMT in the bulb area (from 1.435±0.690 to 1.346±0.688 mm on the right; from 1.359±0.528 to 1.299±0.528 mm on the left), whereas ASA treatment did not, resulting in significant between-group differences (P<0.05). No significant differences were observed in the common carotid and internal carotid arteries. The CTZ/EGb group showed a reduction in triglycerides and an increase in high-density lipoprotein cholesterol levels. Additionally, aspartate and alanine aminotransferase levels decreased only in the CTZ/EGb group. There were no significant differences in Mini-Mental State Examination (MMSE) score changes or adverse events (ClinicalTrials.gov number: NCT05906199).
Conclusion
Twelve months of CTZ/EGb combination therapy significantly attenuated the progression of carotid atherosclerosis compared with aspirin in patients with T2DM.

Complications
The Causal Relationship and Association between Biomarkers, Dietary Intake, and Diabetic Retinopathy: Insights from Mendelian Randomization and Cross-Sectional Study: Xuehao Cui, Dejia Wen, Jishan Xiao, Xiaorong Li; Diabetes Metab J. 2025;49(5):1087-1105. Published online March 31, 2025; DOI: https://doi.org/10.4093/dmj.2024.0731

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Background
Diabetic retinopathy (DR) is a major cause of vision loss, linked to hyperglycemia, oxidative stress, and inflammation. Despite advancements in DR treatments, approximately 40% of patients do not respond effectively, underscoring the need for novel, noninvasive biomarkers to predict DR risk and progression. This study investigates causal relationships between specific biomarkers, dietary factors, and DR development using Mendelian randomization (MR) and cross-sectional data.
Methods
We conducted a two-phase analysis combining MR and cross-sectional methods. First, MR analysis examined causal associations between 35 biomarkers, 226 dietary factors, and DR progression using data from the UK Biobank and Genome-Wide Association Study (GWAS) datasets. Second, a cross-sectional study with National Health and Nutrition Examination Survey (NHANES) and a clinical cohort from Tianjin Medical University Eye Hospital validated findings and explored biomarkers’ predictive capabilities through a nomogram-based prediction model.
Results
MR analysis identified eight biomarkers (e.g., glycosylated hemoglobin [HbA1c], high-density lipoprotein cholesterol [HDL-C]) with significant causal links to DR. Inflammatory markers and metabolic factors, such as high glucose and HDL-C levels, were strongly associated with DR risk and progression. Specific dietary factors, like cheese intake, exhibited protective roles, while alcohol intake increased DR risk. Validation within NHANES and Tianjin cohorts supported these causal associations.
Conclusion
This study elucidates causal relationships between biomarkers, dietary habits, and DR progression, emphasizing the potential for personalized dietary interventions to prevent or manage DR. Findings support the use of HDL-C, HbA1c, and dietary factors as biomarkers or therapeutics in DR, though further studies are needed for broader applicability.

Citations

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Exploring potential therapeutic targets for myopia: Causal analysis and biological annotation with gut microbiota
Zixun Wang, Yimeng Sun, Xiaoling Zhang, Luqiang Wang, Desheng Song, Jingtao Yu, Xiaoxue Hu, Weiping Lin, Ruihua Wei
Computational Biology and Chemistry.2026; 120: 108634. CrossRef
Association between weight-adjusted-waist index and retinopathy among American adults: a cross-sectional study and mediation analysis
Junmeng Li, Qianshuo Yin, Jianchen Hao, Ruilin Zhu, Jing Zhang, Yadi Zhang, Xiaopeng Gu, Zihui Wu, Liu Yang
Frontiers in Nutrition.2025;[Epub] CrossRef
Exploring the impact of diet, sleep, and metabolomic pathways on Glaucoma subtypes: insights from Mendelian randomization and cross-sectional analyses
Zhang Shengnan, Wang Tao, Zhang Yanan, Sun Chao
Nutrition & Metabolism.2025;[Epub] CrossRef
Association between endothelial activation and stress index and diabetic retinopathy in patients with diabetic kidney disease: a cross-sectional study based on NHANES database
Jinping Liu, Di’en Yan, Xiaohui Wang, Yinhua Yao, Ling Wang
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Hypertriglyceridemic waist phenotype in relation to diabetes mellitus and cardiovascular diseases in the Indonesian and Korean populations: evidence from two national surveys
Fathimah S. Sigit, Sinyoung Cho, Farid Kurniawan, Hye-Ryeong Jeon, Ratu Ayu Dewi Sartika, Dicky L. Tahapary, Hyuktae Kwon
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Non-linear association between Life’s Essential 8 and diabetic retinopathy: mediating role of depression in US adults with diabetes
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Complications
Does 10-Year Atherosclerotic Cardiovascular Disease Risk Predict Incident Diabetic Nephropathy and Retinopathy in Patients with Type 2 Diabetes Mellitus? Results from Two Prospective Cohort Studies in Southern China: Jiaheng Chen, Yu Ting Li, Zimin Niu, Zhanpeng He, Yao Jie Xie, Jose Hernandez, Wenyong Huang, Harry H.X. Wang, on Behalf of the Guangzhou Diabetic Eye Study Group; Diabetes Metab J. 2025;49(2):298-310. Published online February 4, 2025; DOI: https://doi.org/10.4093/dmj.2024.0239

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Background
Diabetic macrovascular and microvascular complications often coexist and may share similar risk factors and pathological pathways. We aimed to investigate whether 10-year atherosclerotic cardiovascular disease (ASCVD) risk, which is commonly assessed in diabetes management, can predict incident diabetic nephropathy (DN) and retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).
Methods
This prospective cohort study enrolled 2,891 patients with clinically diagnosed T2DM who were free of ASCVD, nephropathy, or retinopathy at baseline in the Guangzhou (2017–2022) and Shaoguan (2019–2021) Diabetic Eye Study in southern China. The 10-year ASCVD risk was calculated by the Prediction for ASCVD Risk in China (China-PAR) equations. Multivariable- adjusted Cox proportional hazard models were developed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). The area under the receiver operating characteristic curve (AUC) was used to evaluate predictive capability.
Results
During follow-up, a total of 171 cases of DN and 532 cases of DR were documented. Each 1% increment in 10-year ASCVD risk was associated with increased risk of DN (pooled HR, 1.122; 95% CI, 1.094 to 1.150) but not DR (pooled HR, 0.996; 95% CI, 0.979 to 1.013). The model demonstrated acceptable performance in predicting new-onset DN (pooled AUC, 0.670; 95% CI, 0.628 to 0.715). These results were consistent across cohorts and subgroups, with the association appearing to be more pronounced in women.
Conclusion
Ten-year ASCVD risk predicts incident DN but not DR in our study population with T2DM. Regular monitoring of ASCVD risk in routine diabetes practice may add to the ability to enhance population-based prevention for both macrovascular and microvascular diseases, particularly among women.

Citations

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Investigation of the Potential Association Between Atherosclerotic Cardiovascular Disease Risk Score and Diabetic Retinopathy in Patients with Type 2 Diabetes: A Cross-Sectional Study
Chrysa Agapitou, Theodoros N. Sergentanis, Effie G. Papageorgiou, Panagiotis Theodossiadis, Ignatios Ikonomidis, Vaia Lambadiari, Irini Chatziralli
Biomedicines.2025; 13(3): 633. CrossRef

Cardiovascular Risk/Epidemiology
Normalized Creatinine-to-Cystatin C Ratio and Risk of Cardiometabolic Multimorbidity in Middle-Aged and Older Adults: Insights from the China Health and Retirement Longitudinal Study: Honglin Sun, Zhenyu Wu, Guang Wang, Jia Liu; Diabetes Metab J. 2025;49(3):448-461. Published online January 20, 2025; DOI: https://doi.org/10.4093/dmj.2024.0100

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Background
Normalized creatinine-to-cystatin C ratio (NCCR) was reported to approximate relative skeletal muscle mass and diabetes risk. However, the association between NCCR and cardiometabolic multimorbidity (CMM) remains elusive. This study aimed to explore their relationship in a large-scale prospective cohort.
Methods
This study included 5,849 middle-age and older participants from the China Health and Retirement Longitudinal Study (CHARLS) enrolled between 2011 and 2012. The baseline NCCR was determined as creatinine (mg/dL)/cystatin C (mg/L)×10/body mass (kg). CMM was defined as the simultaneous occurrence of two or more of the following conditions: heart disease, stroke, and type 2 diabetes mellitus. Logistic regression analysis and Cox regression analysis were employed to estimate the relationship between NCCR and CMM. The joint effect of body mass index and NCCR on the risk of CMM were further analyzed.
Results
During a median 4-year follow-up, 227 (3.9%) participants developed CMM. The risk of CMM was significantly decreased with per standard deviation increase of NCCR (odds ratio, 0.72; 95% confidence interval, 0.62 to 0.85) after adjustment for confounders (P<0.001). Further sex-specific analysis found significant negative associations between NCCR and CMM in female either without or with one CMM component at baseline, which was attenuated in males but remained statistically significant among those with one basal CMM component. Notably, non-obese individuals with high NCCR levels had the lowest CMM risk compared to obese counterparts with low NCCR levels in both genders.
Conclusion
High NCCR was independently associated with reduced risk of CMM in middle-aged and older adults in China, particularly females.

Citations

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Monitoring Sarcopenia With Incretin Receptor Activator Treatment
Zachary T. Bloomgarden
Journal of Diabetes.2025;[Epub] CrossRef
Correlation Between Serum Creatinine-to-Cystatin C Ratio and Prognosis of Patients with Hip Fracture
Wenbin Lu, Miaomiao Rao, Fan Jia, Wubin Chen, Bin Li, Jinjun Bian, Jiafeng Wang
International Journal of General Medicine.2025; Volume 18: 4147. CrossRef
Association between creatinine to cystatin C ratio and the incidence of depressive symptoms among middle-aged and older adults: insight from the CHARLS study
Xiaohui Li, Guirong Song, Jiaqi Ding, Dongmei Hu, Ying Zhang, Guorong Li, Xiao Tang
BMC Psychology.2025;[Epub] CrossRef
Cardiometabolic multimorbidity in relation to the metabolic score for insulin resistance and creatinine-to-cystatin C ratio in a middle-aged and aged population
Roushan Zhang, Jian Ma, Li Wang
Frontiers in Endocrinology.2025;[Epub] CrossRef
Elevated Serum Triglycerides Independently Predict Incident Falls in Middle‐Aged and Older Adults
Kai Deng
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Metabolic Risk/Epidemiology
Longitudinal Association of Changes in Metabolic Syndrome with Cognitive Function: 12-Year Follow-up of the Guangzhou Biobank Cohort Study: Yu Meng Tian, Wei Sen Zhang, Chao Qiang Jiang, Feng Zhu, Ya Li Jin, Shiu Lun Au Yeung, Jiao Wang, Kar Keung Cheng, Tai Hing Lam, Lin Xu; Diabetes Metab J. 2025;49(1):60-79. Published online October 29, 2024; DOI: https://doi.org/10.4093/dmj.2024.0117

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Abstract PDF Supplementary Material PubReader ePub: Background
The association of changes in metabolic syndrome (MetS) with cognitive function remains unclear. We explored this association using prospective and Mendelian randomization (MR) studies.
Methods
MetS components including high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), waist circumference (WC), fasting plasma glucose (FPG), and triglycerides were measured at baseline and two follow-ups, constructing a MetS index. Immediate, delayed memory recall, and cognitive function along with its dimensions were assessed by immediate 10- word recall test (IWRT) and delayed 10-word recall test (DWRT), and mini-mental state examination (MMSE), respectively, at baseline and follow-ups. Linear mixed-effect model was used. Additionally, the genome-wide association study (GWAS) of MetS was conducted and one-sample MR was performed to assess the causality between MetS and cognitive function.
Results
Elevated MetS index was associated with decreasing annual change rates (decrease) in DWRT and MMSE scores, and with decreases in attention, calculation and recall dimensions. HDL-C was positively associated with an increase in DWRT scores, while SBP and FPG were negatively associated. HDL-C showed a positive association, whereas WC was negatively associated with increases in MMSE scores, including attention, calculation and recall dimensions. Interaction analysis indicated that the association of MetS index on cognitive decline was predominantly observed in low family income group. The GWAS of MetS identified some genetic variants. MR results showed a non-significant causality between MetS and decrease in DWRT, IWRT, nor MMSE scores.
Conclusion
Our study indicated a significant association of MetS and its components with declines in memory and cognitive function, especially in delayed memory recall.

Metabolic Risk/Epidemiology
Healthy Lifestyle and the Risk of Metabolic Dysfunction-Associated Fatty Liver Disease: A Large Prospective Cohort Study: Qing Chang, Yixiao Zhang, Tingjing Zhang, Zuyun Liu, Limin Cao, Qing Zhang, Li Liu, Shaomei Sun, Xing Wang, Ming Zhou, Qiyu Jia, Kun Song, Yang Ding, Yuhong Zhao, Kaijun Niu, Yang Xia; Diabetes Metab J. 2024;48(5):971-982. Published online March 19, 2024; DOI: https://doi.org/10.4093/dmj.2023.0133

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Background
The incidence density of metabolic dysfunction-associated fatty liver disease (MAFLD) and the effect of a healthy lifestyle on the risk of MAFLD remain unknown. We evaluated the prevalence and incidence density of MAFLD and investigated the association between healthy lifestyle and the risk of MAFLD.
Methods
A cross-sectional analysis was conducted on 37,422 participants to explore the prevalence of MAFLD. A cohort analysis of 18,964 individuals was conducted to identify the incidence of MAFLD, as well as the association between healthy lifestyle and MAFLD. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) with adjustments for confounding factors.
Results
The prevalence of MAFLD, non-alcoholic fatty liver disease, and their comorbidities were 30.38%, 28.09%, and 26.13%, respectively. After approximately 70 thousand person-years of follow-up, the incidence densities of the three conditions were 61.03, 55.49, and 51.64 per 1,000 person-years, respectively. Adherence to an overall healthy lifestyle was associated with a 19% decreased risk of MAFLD (HR, 0.81; 95% CI, 0.72 to 0.92), and the effects were modified by baseline age, sex, and body mass index (BMI). Subgroup analyses revealed that younger participants, men, and those with a lower BMI experienced more significant beneficial effects from healthy lifestyle.
Conclusion
Our results highlight the beneficial effect of adherence to a healthy lifestyle on the prevention of MAFLD. Health management for improving dietary intake, physical activity, and smoking and drinking habits are critical to improving MAFLD.

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Impact of healthy lifestyles on the risk of metabolic dysfunction‐associated steatotic liver disease among adults with comorbid hypertension and diabetes: Novel insight from a largely middle‐aged and elderly cohort in South China
Jun‐Yan Xi, Yi‐Jing Wang, Xiao‐Heng Li, Nuo‐Min Sun, Rui‐Qi Ming, Hua‐Ling Yan, Huan‐Le Cai, Jian‐Jun Bai, Yi‐Ning Xiang, Jing Gu, Xiao Lin, Gang Liu, Yuan‐Tao Hao
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Cholesteryl ester transfer protein gene variants and metabolic dysfunction-associated steatotic liver disease: genetic associations with steatosis in obese and lean individuals
Asmaa AbdelFattah, Mahmoud Kattab, Hosny Abdel Ghany, Lamiaa Aly, Ahmed Mady, Aly Hamdi, Riham Soliman, Gamal Shiha, Nada El-Domiaty
Egyptian Liver Journal.2025;[Epub] CrossRef
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Can Huang, Meng Chen, Yanfang Sun, Lin Zhang, Wei Liu
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Yicheng Jiang, Yuancheng Shao, Jiaming Xue, Zhigang Chen, Qi Liu, Shuai Chen, Xihan Gu, Shufan Zhang, Liming Tang
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Multiorgan crosstalk in MASLD/MASH: from hepatic pathogenesis to systemic complications
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Tianzhu Chen, Xiang Qin, Jianping Jiang, Beihui He
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Sex differences in pathogenesis and treatment of dyslipidemia in patients with type 2 diabetes and steatotic liver disease
Tatjana Ábel, Béla Benczúr, Éva Csajbókné Csobod
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Associations of traditional healthy lifestyle and sleep quality with metabolic dysfunction-associated fatty liver disease: two population-based studies
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Drug/Regimen
Safety and Effectiveness of Dulaglutide in the Treatment of Type 2 Diabetes Mellitus: A Korean Real-World Post-Marketing Study: Jeonghee Han, Woo Je Lee, Kyu Yeon Hur, Jae Hyoung Cho, Byung Wan Lee, Cheol-Young Park; Diabetes Metab J. 2024;48(3):418-428. Published online February 2, 2024; DOI: https://doi.org/10.4093/dmj.2023.0030

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Background
To investigate the real-world safety and effectiveness of dulaglutide in Korean adults with type 2 diabetes mellitus (T2DM).
Methods
This was a real-world, prospective, non-interventional post-marketing safety study conducted from May 26, 2015 to May 25, 2021 at 85 Korean healthcare centers using electronic case data. Data on patients using dulaglutide 0.75 mg/0.5 mL or the dulaglutide 1.5 mg/0.5 mL single-use pens were collected and pooled. The primary objective was to report the frequency and proportion of adverse and serious adverse events that occurred. The secondary objective was to monitor the effectiveness of dulaglutide at 12 and 24 weeks by evaluating changes in glycosylated hemoglobin (HbA1c ), fasting plasma glucose, and body weight.
Results
Data were collected from 3,067 subjects, and 3,022 subjects who received ≥1 dose (of any strength) of dulaglutide were included in the safety analysis set (53% female, mean age 56 years; diabetes duration 11.2 years, mean HbA1c 8.8%). The number of adverse events reported was 819; of these, 68 (8.3%) were serious adverse events. One death was reported. Adverse events were mostly mild in severity; 60.81% of adverse events were considered related to dulaglutide. This study was completed by 72.73% (2,198/3,022) of subjects. At 12/24 weeks there were significant (P<0.0001) reductions from baseline in least-squares mean HbA1c (0.96%/0.95%), fasting blood glucose (26.24/24.43 mg/dL), and body weight (0.75/1.21 kg).
Conclusion
Dulaglutide was generally well tolerated and effective in real-world Korean individuals with T2DM. The results from this study contribute to the body of evidence for dulaglutide use in this population.

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Review

Metabolic Risk/Epidemiology
Hepatic Fibrosis and Cancer: The Silent Threats of Metabolic Syndrome: Scott L. Friedman; Diabetes Metab J. 2024;48(2):161-169. Published online January 26, 2024; DOI: https://doi.org/10.4093/dmj.2023.0240

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Metabolic dysfunction-associated steatotic (fatty) liver disease (MASLD), previously termed non-alcoholic fatty liver disease, is a worldwide epidemic that can lead to hepatic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The disease is typically a component of the metabolic syndrome that accompanies obesity, and is often overlooked because the liver manifestations are clinically silent until late-stage disease is present (i.e., cirrhosis). Moreover, Asian populations, including Koreans, have a higher fraction of patients who are lean, yet their illness has the same prognosis or worse than those who are obese. Nonetheless, ongoing injury can lead to hepatic inflammation and ballooning of hepatocytes as classic features. Over time, fibrosis develops following activation of hepatic stellate cells, the liver’s main fibrogenic cell type. The disease is usually more advanced in patients with type 2 diabetes mellitus, indicating that all diabetic patients should be screened for liver disease. Although there has been substantial progress in clarifying pathways of injury and fibrosis, there no approved therapies yet, but current research seeks to uncover the pathways driving hepatic inflammation and fibrosis, in hopes of identifying new therapeutic targets. Emerging molecular methods, especially single cell sequencing technologies, are revolutionizing our ability to clarify mechanisms underlying MASLD-associated fibrosis and HCC.

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Original Articles

Drug/Regimen
Comparative Efficacy of Rosuvastatin Monotherapy and Rosuvastatin/Ezetimibe Combination Therapy on Insulin Sensitivity and Vascular Inflammatory Response in Patients with Type 2 Diabetes Mellitus: Ji Hye Han, Kyong Hye Joung, Jun Choul Lee, Ok Soon Kim, Sorim Choung, Ji Min Kim, Yea Eun Kang, Hyon-Seung Yi, Ju Hee Lee, Bon Jeong Ku, Hyun Jin Kim; Diabetes Metab J. 2024;48(1):112-121. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0402

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Background
Type 2 diabetes mellitus (T2DM) induces endothelial dysfunction and inflammation, which are the main factors for atherosclerosis and cardiovascular disease. The present study aimed to compare the effects of rosuvastatin monotherapy and rosuvastatin/ezetimibe combination therapy on lipid profile, insulin sensitivity, and vascular inflammatory response in patients with T2DM.
Methods
A total of 101 patients with T2DM and dyslipidemia were randomized to either rosuvastatin monotherapy (5 mg/day, n=47) or rosuvastatin/ezetimibe combination therapy (5 mg/10 mg/day, n=45) and treated for 12 weeks. Serum lipids, glucose, insulin, soluble intercellular adhesion molecule-1 (sICAM-1), and peroxiredoxin 4 (PRDX4) levels were determined before and after 12 weeks of treatment.
Results
The reduction in low density lipoprotein cholesterol (LDL-C) by more than 50% from baseline after treatment was more in the combination therapy group. The serum sICAM-1 levels increased significantly in both groups, but there was no difference between the two groups. The significant changes in homeostasis model assessment of insulin resistance (HOMA-IR) and PRDX4 were confirmed only in the subgroup in which LDL-C was reduced by 50% or more in the combination therapy group. However, after adjusting for diabetes mellitus duration and hypertension, the changes in HOMA-IR and PRDX4 were not significant between the two groups.
Conclusion
Although rosuvastatin/ezetimibe combination therapy had a greater LDL-C reduction effect than rosuvastatin monotherapy, it had no additional effects on insulin sensitivity and vascular inflammatory response. Further studies are needed on the effect of long-term treatment with ezetimibe on insulin sensitivity and vascular inflammatory response.

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Risk factors for prediabetes in young adults: a study based on Korea National health and nutrition examination survey data
Sujung Lee, Dae-Soon Son, Jae-In Kim, Jungmin Lee
Scientific Reports.2025;[Epub] CrossRef
Effect of changes in the triglyceride-glucose index on atherogenic lipid profiles in coronary artery disease patients receiving lipid-lowering therapy: a prospective cohort study
Zhi-Fan Li, Zheng Yin, Xi Li, Meng-Ying Lu, Wen-Jia Zhang, Fang Luo, Yan-Lu Xu, Jian-Jun Li, Ke-Fei Dou, Xiao Wang, Hong Qiu, Na-Qiong Wu
Cardiovascular Diabetology.2025;[Epub] CrossRef
Angiopoietins: A potential therapeutic target in the treatment of diabetic nephropathy
Komal Thapa, Neha Kanojia, Heena Khan, Amarjot Kaur, Thakur Gurjeet Singh
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Pharmacokinetics of a single-pill combination of rosuvastatin and ezetimibe (2.5 mg/10 mg) in healthy Chinese subjects: an open-label, two-period, phase I study
Ying Wang, Jiaxiang Ding, Dongmei Cheng, Yuzhou Ding, Tonghao Zhang, Wang Hu, Xiaoni Wang, Xu Zhu, Yunqiu Xie, Huan Zhou
Naunyn-Schmiedeberg's Archives of Pharmacology.2025;[Epub] CrossRef
Combining Ezetimibe and Rosuvastatin: Impacts on Insulin Sensitivity and Vascular Inflammation in Patients with Type 2 Diabetes Mellitus
Eun Roh
Diabetes & Metabolism Journal.2024; 48(1): 55. CrossRef
Does Rosuvastatin/Ezetimibe Combination Therapy Offer Potential Benefits for Glucose Metabolism beyond Lipid-Lowering Efficacy in T2DM?
Il Rae Park, Jun Sung Moon
Diabetes & Metabolism Journal.2024; 48(3): 387. CrossRef
A Comparison of Rosuvastatin Monotherapy and Rosuvastatin Plus Ezetimibe Combination Therapy in Patients With Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials
Samuel K Dadzie, Godfrey Tabowei, Mandeep Kaur, Saeed Ahmed, Aayushi Thakur, Khaldoun Khreis, Monika Bai, Adil Amin
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The Pleiotropic Effects of Lipid-Modifying Interventions: Exploring Traditional and Emerging Hypolipidemic Therapies
Dimitris Kounatidis, Nikolaos Tentolouris, Natalia G. Vallianou, Iordanis Mourouzis, Irene Karampela, Theodora Stratigou, Eleni Rebelos, Marina Kouveletsou, Vasileios Stamatopoulos, Eleni Tsaroucha, Maria Dalamaga
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Basic Research
DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis: Dong-Keon Lee, Su Ho Jo, Eun Soo Lee, Kyung Bong Ha, Na Won Park, Deok-Hoon Kong, Sang-In Park, Joon Seok Park, Choon Hee Chung; Diabetes Metab J. 2024;48(1):97-111. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0367

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Background
Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression.
Methods
Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture.
Results
DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor β (TGFβ)-induced pro-fibrotic gene expression by suppressing TGFβ receptor 1 (TGFβR1)/Smad2/3 and TGFβR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis.
Conclusion
Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

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Ao Liu, Mengting Huang, Yuwen Xi, Xiaoling Deng, Keshu Xu
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Prolyl-tRNA synthetase inhibitor as a novel first-in-class keloid treatment: downregulation of de novo collagen synthesis and inflammatory cascade
Sally Min, Ki-Myo Kim, Joseph Hwang, Jaewoo Kim, Jun Ho Park, Joon Seok Park, Caroline H Lee, Ji-Ung Park
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Emmanuel Somm, Mahdi Rahman, Ildiko Szanto, Karim Gariani, François R. Jornayvaz
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EPRS1-mediated fibroblast activation and mitochondrial dysfunction promote kidney fibrosis
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Basic Research
Alantolactone Attenuates Renal Fibrosis via Inhibition of Transforming Growth Factor β/Smad3 Signaling Pathway: Kyeong-Min Lee, Yeo Jin Hwang, Gwon-Soo Jung; Diabetes Metab J. 2024;48(1):72-82. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0231

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Background
Renal fibrosis is characterized by the accumulation of extracellular matrix proteins and interstitial fibrosis. Alantolactone is known to exert anticancer, anti-inflammatory, antimicrobial and antifungal effects; however, its effects on renal fibrosis remains unknown. Here, we investigated whether alantolactone attenuates renal fibrosis in mice unilateral ureteral obstruction (UUO) and evaluated the effect of alantolactone on transforming growth factor (TGF) signaling pathway in renal cells.
Methods
To evaluate the therapeutic effect of alantolactone, cell counting kit-8 (CCK-8) assay, histological staining, Western blot analysis, and real-time quantitative polymerase chain reaction were performed in UUO kidneys in vivo and in TGF-β-treated renal cells in vitro.
Results
Alantolactone (0.25 to 4 µM) did not affect the viability of renal cells. Mice orally administered 5 mg/kg of alantolactone daily for 15 days did not show mortality or liver toxicity. Alantolactone decreased UUO-induced blood urea nitrogen and serum creatinine levels. In addition, it significantly alleviated renal tubulointerstitial damage and fibrosis and decreased collagen type I, fibronectin, and α-smooth muscle actin (α-SMA) expression in UUO kidneys. In NRK-49F cells, alantolactone inhibited TGF-βstimulated expression of fibronectin, collagen type I, plasminogen activator inhibitor-1 (PAI-1), and α-SMA. In HK-2 cells, alantolactone inhibited TGF-β-stimulated expression of collagen type I and PAI-1. Alantolactone inhibited UUO-induced phosphorylation of Smad3 in UUO kidneys. In addition, it not only decreased TGF-β secretion but also Smad3 phosphorylation and translocation to nucleus in both kidney cell lines.
Conclusion
Alantolactone improves renal fibrosis by inhibiting the TGF-β/Smad3 signaling pathway in obstructive nephropathy. Thus, alantolactone is a potential therapeutic agent for chronic kidney disease.

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Drug Regimen
The Efficacy and Safety of Moderate-Intensity Rosuvastatin with Ezetimibe versus High-Intensity Rosuvastatin in High Atherosclerotic Cardiovascular Disease Risk Patients with Type 2 Diabetes Mellitus: A Randomized, Multicenter, Open, Parallel, Phase 4 Study: Jun Sung Moon, Il Rae Park, Sang Soo Kim, Hye Soon Kim, Nam Hoon Kim, Sin Gon Kim, Seung Hyun Ko, Ji Hyun Lee, Inkyu Lee, Bo Kyeong Lee, Kyu Chang Won; Diabetes Metab J. 2023;47(6):818-825. Published online November 24, 2023; DOI: https://doi.org/10.4093/dmj.2023.0171

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Background
To investigate the efficacy and safety of moderate-intensity rosuvastatin/ezetimibe combination compared to highintensity rosuvastatin in high atherosclerotic cardiovascular disease (ASCVD) risk patients with type 2 diabetes mellitus (T2DM).
Methods
This study was a randomized, multicenter, open, parallel phase 4 study, and enrolled T2DM subjects with an estimated 10-year ASCVD risk ≥7.5%. The primary endpoint was the low-density lipoprotein cholesterol (LDL-C) change rate after 24-week rosuvastatin 10 mg/ezetimibe 10 mg treatment was non-inferior to that of rosuvastatin 20 mg. The achievement proportion of 10-year ASCVD risk <7.5% or comprehensive lipid target (LDL-C <70 mg/dL, non-high-density lipoprotein cholesterol <100 mg/dL, and apolipoprotein B <80 mg/dL) without discontinuation, and several metabolic parameters were explored as secondary endpoints.
Results
A hundred and six participants were assigned to each group. Both groups showed significant reduction in % change of LDL-C from baseline at week 24 (–63.90±6.89 vs. –55.44±6.85, combination vs. monotherapy, p=0.0378; respectively), but the combination treatment was superior to high-intensity monotherapy in LDL-C change (%) from baseline (least square [LS] mean difference, –8.47; 95% confidence interval, –16.44 to –0.49; p=0.0378). The combination treatment showed a higher proportion of achieved comprehensive lipid targets rather than monotherapy (85.36% vs. 62.22% in monotherapy, p=0.015). The ezetimibe combination significantly improved homeostasis model assessment of β-cell function even without A1c changes (LS mean difference, 17.13; p=0.0185).
Conclusion
In high ASCVD risk patients with T2DM, the combination of moderate-intensity rosuvastatin and ezetimibe was not only non-inferior but also superior to improving dyslipidemia with additional benefits compared to high-intensity rosuvastatin monotherapy.

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Overcoming β-Cell Dysfunction in Type 2 Diabetes Mellitus: CD36 Inhibition and Antioxidant System
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Ezetimibe plus statin combination versus double-dose statin in patients with dyslipidemia and atherosclerotic cardiovascular disease risk: a comprehensive systematic review and meta-analysis of 47 randomized controlled trials
Abdelrahman Mahmoud, Hazem Mohamed Salamah, Hazem Rezq, Yazan Al-Mohtasib, Ali Ashraf Salah Ahmed, Mohamed R. Abdelraouf, Ahmed Mazen Amin, Ahmed A. Ibrahim, Yasmine Adel Mohammed, Omar Ahmed Abdelwahab, Majd M. AlBarakat, Salem Elshenawy, Husam Abu Suili
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Shujie Zhang, Tingting Sun, Lina Song, Xiaodong Jin, Bo Li
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Basic Research
Beneficial Effects of a Curcumin Derivative and Transforming Growth Factor-β Receptor I Inhibitor Combination on Nonalcoholic Steatohepatitis: Kyung Bong Ha, Eun Soo Lee, Na Won Park, Su Ho Jo, Soyeon Shim, Dae-Kee Kim, Chan Mug Ahn, Choon Hee Chung; Diabetes Metab J. 2023;47(4):500-513. Published online April 25, 2023; DOI: https://doi.org/10.4093/dmj.2022.0110

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Background
Curcumin 2005-8 (Cur5-8), a derivative of curcumin, improves fatty liver disease via AMP-activated protein kinase activation and autophagy regulation. EW-7197 (vactosertib) is a small molecule inhibitor of transforming growth factor β (TGF-β) receptor I and may scavenge reactive oxygen species and ameliorate fibrosis through the SMAD2/3 canonical pathway. This study aimed to determine whether co-administering these two drugs having different mechanisms is beneficial.
Methods
Hepatocellular fibrosis was induced in mouse hepatocytes (alpha mouse liver 12 [AML12]) and human hepatic stellate cells (LX-2) using TGF-β (2 ng/mL). The cells were then treated with Cur5-8 (1 μM), EW-7197 (0.5 μM), or both. In animal experiments were also conducted during which, methionine-choline deficient diet, Cur5-8 (100 mg/kg), and EW-7197 (20 mg/kg) were administered orally to 8-week-old C57BL/6J mice for 6 weeks.
Results
TGF-β-induced cell morphological changes were improved by EW-7197, and lipid accumulation was restored on the administration of EW-7197 in combination with Cur5-8. In a nonalcoholic steatohepatitis (NASH)-induced mouse model, 6 weeks of EW-7197 and Cur5-8 co-administration alleviated liver fibrosis and improved the nonalcoholic fatty liver disease (NAFLD) activity score.
Conclusion
Co-administering Cur5-8 and EW-7197 to NASH-induced mice and fibrotic hepatocytes reduced liver fibrosis and steatohepatitis while maintaining the advantages of both drugs. This is the first study to show the effect of the drug combination against NASH and NAFLD. Similar effects in other animal models will confirm its potential as a new therapeutic agent.

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Xing Wan, Jingyuan Ma, He Bai, Xuyang Hu, Yanna Ma, Mingjian Zhao, Jifeng Liu, Zhijun Duan
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Drug/Regimen
Risk of Diabetic Retinopathy between Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists: Tzu-Yi Lin, Eugene Yu-Chuan Kang, Shih-Chieh Shao, Edward Chia-Cheng Lai, Sunir J. Garg, Kuan-Jen Chen, Je-Ho Kang, Wei-Chi Wu, Chi-Chun Lai, Yih-Shiou Hwang; Diabetes Metab J. 2023;47(3):394-404. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0221

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Background
To compare risk of diabetic retinopathy (DR) between patients taking sodium-glucose cotransporter-2 inhibitors (SGLT2is) and those taking glucagon-like peptide-1 receptor agonists (GLP1-RAs) in routine care.
Methods
This retrospective cohort study emulating a target trial included patient data from the multi-institutional Chang Gung Research Database in Taiwan. Totally, 33,021 patients with type 2 diabetes mellitus using SGLT2is and GLP1-RAs between 2016 and 2019 were identified. 3,249 patients were excluded due to missing demographics, age <40 years, prior use of any study drug, a diagnosis of retinal disorders, a history of receiving vitreoretinal procedure, no baseline glycosylated hemoglobin, or no follow-up data. Baseline characteristics were balanced using inverse probability of treatment weighting with propensity scores. DR diagnoses and vitreoretinal interventions served as the primary outcomes. Occurrence of proliferative DR and DR receiving vitreoretinal interventions were regarded as vision-threatening DR.
Results
There were 21,491 SGLT2i and 1,887 GLP1-RA users included for the analysis. Patients receiving SGLT2is and GLP-1 RAs exhibited comparable rate of any DR (subdistribution hazard ratio [SHR], 0.90; 95% confidence interval [CI], 0.79 to 1.03), whereas the rate of proliferative DR (SHR, 0.53; 95% CI, 0.42 to 0.68) was significantly lower in the SGLT2i group. Also, SGLT2i users showed significantly reduced risk of composite surgical outcome (SHR, 0.58; 95% CI, 0.48 to 0.70).
Conclusion
Compared to those taking GLP1-RAs, patients receiving SGLT2is had a lower risk of proliferative DR and vitreoretinal interventions, although the rate of any DR was comparable between the SGLT2i and GLP1-RA groups. Thus, SGLT2is may be associated with a lower risk of vision-threatening DR but not DR development.

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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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Different ways of diagnosing selective glomerular hypofiltration syndromes such as shrunken pore syndrome and the associated increase in mortality
Anna Åkesson, Linnea Malmgren, Felicia Leion, Ulf Nyman, Anders Christensson, Jonas Björk, Anders Grubb
Journal of Internal Medicine.2025; 297(1): 79. CrossRef
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Yue Song, Changqiang Yang
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Identification of cystatin C as a new marker of glomerular filtration rate, and of shrunken pore syndrome – a new kidney disorder defining selective glomerular hypofiltration syndromes – calls for expansion of the international KDIGO guidelines
Anna Åkesson, Carl Öberg, Linnea Malmgren, Christopher Nilsson, Yoshi Itoh, Søren Blirup-Jensen, Veronica Lindström, Magnus Abrahamson, Felicia Leion, Isleifur Olafsson, Henrik Bjursten, David Grubb, Erik Herou, Alain Dardashti, Johann Sigurjonsson, Liana
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Xunliang Li, Li Zhao, Wenman Zhao, Tongxin Sun, Haifeng Pan, Deguang Wang
American Journal of Nephrology.2025; : 1. CrossRef
Intraindividual difference in estimated GFR by creatinine and cystatin C, cognitive trajectories and motoric cognitive risk syndrome
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广智杨
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Technology/Device
Glycemia according to the Use of Continuous Glucose Monitoring among Adults with Type 1 Diabetes Mellitus in Korea: A Real-World Study: You-Bin Lee, Minjee Kim, Jae Hyeon Kim; Diabetes Metab J. 2023;47(3):405-414. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0032

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Background
We explored the association between continuous glucose monitoring (CGM) use and glycemia among adults with type 1 diabetes mellitus (T1DM) and determined the status of CGM metrics among adults with T1DM using CGM in the real-world.
Methods
For this propensity-matched cross-sectional study, individuals with T1DM who visited the outpatient clinic of the Endocrinology Department of Samsung Medical Center between March 2018 and February 2020 were screened. Among them, 111 CGM users (for ≥9 months) were matched based on propensity score considering age, sex, and diabetes duration in a 1:2 ratio with 203 CGM never-users. The association between CGM use and glycemic measures was explored. In a subpopulation of CGM users who had been using official applications (not “do-it-yourself” software) such that Ambulatory Glucose Profile data for ≥1 month were available (n=87), standardized CGM metrics were summarized.
Results
Linear regression analyses identified CGM use as a determining factor for log-transformed glycosylated hemoglobin. The fully-adjusted odds ratio (OR) and 95% confidence interval (CI) for uncontrolled glycosylated hemoglobin (>8%) were 0.365 (95% CI, 0.190 to 0.703) in CGM users compared to never-users. The fully-adjusted OR for controlled glycosylated hemoglobin (<7%) was 1.861 (95% CI, 1.119 to 3.096) in CGM users compared to never-users. Among individuals who had been using official applications for CGM, time in range (TIR) values within recent 30- and 90-day periods were 62.45%±16.63% and 63.08%±15.32%, respectively.
Conclusion
CGM use was associated with glycemic control status among Korean adults with T1DM in the real-world, although CGM metrics including TIR might require further improvement among CGM users.

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Complications
Non-Alcoholic Fatty Liver Disease with Sarcopenia and Carotid Plaque Progression Risk in Patients with Type 2 Diabetes Mellitus: Yongin Cho, Hye-Sun Park, Byung Wook Huh, Yong-ho Lee, Seong Ha Seo, Da Hea Seo, Seong Hee Ahn, Seongbin Hong, So Hun Kim; Diabetes Metab J. 2023;47(2):232-241. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2021.0355

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Background
We aimed to evaluate whether non-alcoholic fatty liver disease (NAFLD) with or without sarcopenia is associated with progression of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM).
Methods
We investigated 852 T2DM patients who underwent abdominal ultrasonography, bioelectrical impedance analysis, and carotid artery ultrasonography at baseline and repeated carotid ultrasonography after 6 to 8 years. NAFLD was confirmed by abdominal ultrasonography, and sarcopenia was defined as a sex-specific skeletal muscle mass index (SMI) value <2 standard deviations below the mean for healthy young adults. SMI was calculated by dividing the sum of appendicular skeletal mass by body weight. We investigated the association between NAFLD with or without sarcopenia and the progression of carotid atherosclerosis.
Results
Of the 852 patients, 333 (39.1%) were classified as NAFLD without sarcopenia, 66 (7.7%) were classified as sarcopenia without NAFLD, and 123 (14.4%) had NAFLD with sarcopenia at baseline. After 6 to 8 years, patients with both NAFLD and sarcopenia had a higher risk of atherosclerosis progression (adjusted odds ratio, 2.20; P<0.009) than controls without NAFLD and sarcopenia. When a subgroup analysis was performed on only patients with NAFLD, female sex, absence of central obesity, and non-obesity were significant factors related to increased risk of plaque progression risk in sarcopenic patients.
Conclusion
NAFLD with sarcopenia was significantly associated with the progression of carotid atherosclerosis in T2DM patients.

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Complications
Advanced Liver Fibrosis Is Associated with Chronic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease: Da Hea Seo, Young Ju Suh, Yongin Cho, Seong Hee Ahn, Seongha Seo, Seongbin Hong, Yong-ho Lee, Young Ju Choi, Eunjig Lee, So Hun Kim; Diabetes Metab J. 2022;46(4):630-639. Published online January 26, 2022; DOI: https://doi.org/10.4093/dmj.2021.0130

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Background
Nonalcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). However, the causal relationship between NAFLD and CKD is uncertain, particularly in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the association between the presence and severity of NAFLD and incident CKD in patients with T2DM.
Methods
In this longitudinal cohort study of patients with T2DM, 3,188 patients with preserved renal function were followed up for the occurrence of incident CKD. NAFLD was defined as the presence of hepatic steatosis on ultrasonography, without any other causes of chronic liver disease. Advanced liver fibrosis of NAFLD was defined as a fibrosis-4 index ≥2.67. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m².
Results
At baseline, 1,729 (54.2%) patients had NAFLD, of whom 94 (5.4%) had advanced liver fibrosis. During the follow-up of 8.3±3.6 years, 472 (14.8%) patients developed incident CKD: 220 (15.1%) in the non-NAFLD group, 231 (14.1%) in the NAFLD without advanced fibrosis group and 28 (31.1%) in the NAFLD with advanced fibrosis group. There was no increased risk of incident CKD in the NAFLD group compared to the non-NAFLD group (P=0.435). However, among patients with NAFLD, advanced liver fibrosis was associated with an increased risk of CKD (adjusted hazard ratio, 1.75; 95% confidence interval, 1.15 to 2.66; P=0.009).
Conclusion
Advanced liver fibrosis in patients with NAFLD is independently associated with an increased risk of incident CKD in patients with T2DM.

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Basic Research
The Effects of Exercise and Restriction of Sugar-Sweetened Beverages on Muscle Function and Autophagy Regulation in High-Fat High-Sucrose-Fed Obesity Mice: Didi Zhang, Ji Hyun Lee, Hyung Eun Shin, Seong Eun Kwak, Jun Hyun Bae, Liang Tang, Wook Song; Diabetes Metab J. 2021;45(5):773-786. Published online March 25, 2021; DOI: https://doi.org/10.4093/dmj.2020.0157

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Background
Autophagy maintains muscle mass and healthy skeletal muscles. Several recent studies have associated sugar-sweetened beverage (SSB) consumption with diseases. We investigated whether muscle dysfunction due to obesity could be restored by SSB restriction (SR) alone or in combination with exercise (EX) training.
Methods
Obese mice were subjected to SR combined with treadmill EX. Intraperitoneal glucose tolerance test, grip strength test, hanging time test, and body composition analysis were performed. Triglyceride (TG) and total cholesterol (TC) serum concentrations and TG concentrations in quadriceps muscles were analyzed. Western blot and reverse transcription-quantitative polymerase chain reaction helped analyze autophagy-related protein and mRNA expression, respectively.
Results
SR alone had no significant effect on fasting blood glucose levels, glucose tolerance, and muscle function. However, it had effect on serum TC, serum TG, and BCL2 interacting protein 3 expression. SR+EX improved glucose tolerance and muscle function and increased serum TC utilization than SR alone. SR+EX reduced P62 levels, increased glucose transporter type 4 and peroxisome proliferator-activated receptor γ coactivator-1α protein expression, and improved grip strength relative to the high-fat and high-sucrose liquid (HFHS) group, and this was not observed in the HFHS+EX group.
Conclusion
SR induced mitophagy-related protein expression in quadriceps, without affecting muscle function. And, the combination of SR and EX activated mitophagy-related proteins and improved muscle function.

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Mitochondrial Dysfunction, Oxidative Stress, and Inter-Organ Miscommunications in T2D Progression
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Metabolic Risk/Epidemiology
Fetal Abdominal Obesity Detected At 24 to 28 Weeks of Gestation Persists Until Delivery Despite Management of Gestational Diabetes Mellitus: Wonjin Kim, Soo Kyung Park, Yoo Lee Kim; Diabetes Metab J. 2021;45(4):547-557. Published online March 5, 2021; DOI: https://doi.org/10.4093/dmj.2020.0078

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Background
Fetal abdominal obesity (FAO) has been reported to be affected at gestational diabetes mellitus (GDM) diagnosis at 24 to 28 weeks of gestation in older and/or obese women. This study investigated whether the management of GDM improves FAO in GDM subjects near term.
Methods
Medical records of 7,099 singleton pregnant women delivering at CHA Gangnam Medical Center were reviewed retrospectively. GDM was diagnosed by 100-g oral glucose tolerance test after 50-g glucose challenge test based on Carpenter–Coustan criteria. GDM subjects were divided into four study groups according to maternal age and obesity. FAO was defined as ≥90th percentile of fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference per actual GA by the last menstruation period, biparietal diameter, or femur length, respectively.
Results
As compared with normal glucose tolerance (NGT) subjects near term, FAORs and odds ratio for FAO were significantly higher in old and/or obese women with GDM but not in young and nonobese women with GDM. For fetuses of GDM subjects with FAO at the time of GDM diagnosis, the odds ratio for exhibiting FAO near term and being large for GA at birth were 7.87 (95% confidence interval [CI], 4.38 to 14.15) and 10.96 (95% CI, 5.58 to 20.53) compared with fetuses of NGT subjects without FAO at GDM diagnosis.
Conclusion
Despite treatment, FAO detected at the time of GDM diagnosis persisted until delivery. Early diagnosis and treatment might be necessary to prevent near term FAO in high-risk older and/or obese women.

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Review

Complications
Lost in Translation? Measuring Diabetic Neuropathy in Humans and Animals: Heung Yong Jin, Seong-Su Moon, Nigel A. Calcutt; Diabetes Metab J. 2021;45(1):27-42. Published online December 15, 2020; DOI: https://doi.org/10.4093/dmj.2020.0216

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The worldwide diabetes epidemic is estimated to currently afflict almost 500 million persons. Long-term diabetes damages multiple organ systems with the blood vessels, eyes, kidneys and nervous systems being particularly vulnerable. These complications of diabetes reduce lifespan, impede quality of life and impose a huge social and economic burden on both the individual and society. Peripheral neuropathy is a debilitating complication that will impact over half of all persons with diabetes. There is no treatment for diabetic neuropathy and a disturbingly long history of therapeutic approaches showing promise in preclinical studies but failing to translate to the clinic. These failures have prompted re-examination of both the animal models and clinical trial design. This review focuses on the functional and structural parameters used as indices of peripheral neuropathy in preclinical and clinical studies and the extent to which they share a common pathogenesis and presentation. Nerve conduction studies in large myelinated fibers have long been the mainstay of preclinical efficacy screening programs and clinical trials, supplemented by quantitative sensory tests. However, a more refined approach is emerging that incorporates measures of small fiber density in the skin and cornea alongside these traditional assays at both preclinical and clinical phases.

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Original Article

Drug/Regimen
Cardiovascular Safety of Sodium Glucose Cotransporter 2 Inhibitors as Add-on to Metformin Monotherapy in Patients with Type 2 Diabetes Mellitus: Ja Young Jeon, Kyoung Hwa Ha, Dae Jung Kim; Diabetes Metab J. 2021;45(4):505-514. Published online October 30, 2020; DOI: https://doi.org/10.4093/dmj.2020.0057

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Background
Using real-world data, cardiovascular safety was investigated in metformin users newly starting sodium glucose cotransporter 2 (SGLT2) inhibitors compared with other glucose-lowering drugs in Korea.
Methods
This was a retrospective observational study using the National Health Insurance Service claims database in Korea. The study period was from September 2014 to December 2016. The study included subjects who were newly prescribed SGLT2 inhibitors or other glucose-lowering drugs while on metformin monotherapy; cohort 1 was composed of new users of SGLT2 inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors and cohort 2 included new users of SGLT2 inhibitors versus sulfonylureas. To balance the patient characteristics, propensity score matching was performed at a 1:1 ratio. Cardiovascular outcomes included hospitalization for heart failure (HHF), all-cause mortality, HHF plus all-cause mortality, myocardial infarction (MI), stroke, and modified major adverse cardiovascular events (MACEs).
Results
After propensity score matching, each cohort group was well balanced at baseline (21,688 pairs in cohort 1 and 20,120 pairs in cohort 2). As the second-line treatment, use of SGLT2 inhibitors was associated with a lower risk of HHF and HHF plus all-cause mortality compared with DPP-4 inhibitors. In addition, use of SGLT2 inhibitors versus sulfonylurea as add-on therapy to metformin was associated with decreased risks of HHF, all-cause mortality, HHF plus all-cause mortality, MI, stroke, and modified MACEs.
Conclusion
SGLT2 inhibitors can be a good second-line drug to reduce the incidence of cardiovascular diseases compared with DPP-4 inhibitors or sulfonylureas in people with type 2 diabetes mellitus.

Citations

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Jui Wang, Hon-Yen Wu, Kuo-Liong Chien
Diabetes & Metabolism.2022; 48(3): 101299. CrossRef
Cardiovascular disease in patients with type 2 diabetes
Ja Young Jeon, Dae Jung Kim
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Israel Mazin, Fernando Chernomordik, Paul Fefer, Shlomi Matetzky, Roy Beigel
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Chang Hee Kwon, Ye-Jee Kim, Min-Ju Kim, Myung-Jin Cha, Min Soo Cho, Gi-Byoung Nam, Kee-Joon Choi, Jun Kim
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Review

Metabolic Risk/Epidemiology
Nonalcoholic Fatty Liver Disease: A Drug Revolution Is Coming: Soung Won Jeong; Diabetes Metab J. 2020;44(5):640-657. Published online October 21, 2020; DOI: https://doi.org/10.4093/dmj.2020.0115

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The worldwide prevalence of non-alcoholic fatty liver disease is around 25%, and that of nonalcoholic steatohepatitis (NASH) ranges from 1.5% to 6.45%. Patients with NASH, especially those with fibrosis, are at higher risk for adverse outcomes such as cirrhosis and liver-related mortality. Although vitamin E, pioglitazone, and liraglutide improved liver histology in randomized trials, there are currently no Food and Drug Administration-approved drugs for NASH. Five pharmacologic agents—obeticholic acid, elafibranor, cenicriviroc, resmetirom, and aramchol—are being evaluated in large, histology-based phase 3 trials. Within 2 to 4 years, new and effective drugs for the treatment of NASH are expected. Additionally, many phase 2 trials are ongoing for various agents. Based on the results of phase 2 and 3 trials, combination treatments are also being investigated. Future treatment strategies will comprise drug combinations and precision medicine based on the different phenotypes of NASH and treatment response of the individual patient.

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Original Articles

Complications
Therapeutic Effects of Fibroblast Growth Factor-21 on Diabetic Nephropathy and the Possible Mechanism in Type 1 Diabetes Mellitus Mice: Wenya Weng, Tingwen Ge, Yi Wang, Lulu He, Tinghao Liu, Wanning Wang, Zongyu Zheng, Lechu Yu, Chi Zhang, Xuemian Lu; Diabetes Metab J. 2020;44(4):566-580. Published online May 15, 2020; DOI: https://doi.org/10.4093/dmj.2019.0089

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Background

Fibroblast growth factor 21 (FGF21) has been only reported to prevent type 1 diabetic nephropathy (DN) in the streptozotocin-induced type 1 diabetes mellitus (T1DM) mouse model. However, the FVB (Cg)-Tg (Cryaa-Tag, Ins2-CALM1) 26OVE/PneJ (OVE26) transgenic mouse is a widely recommended mouse model to recapture the most important features of T1DM nephropathy that often occurs in diabetic patients. In addition, most previous studies focused on exploring the preventive effect of FGF21 on the development of DN. However, in clinic, development of therapeutic strategy has much more realistic value compared with preventive strategy since the onset time of DN is difficult to be accurately predicted. Therefore, in the present study OVE26 mice were used to investigate the potential therapeutic effects of FGF21 on DN.

Methods

Four-month-old female OVE26 mice were intraperitoneally treated with recombinant FGF21 at a dose of 100 µg/kg/day for 3 months. The diabetic and non-diabetic control mice were treated with phosphate-buffered saline at the same volume. Renal functions, pathological changes, inflammation, apoptosis, oxidative stress and fibrosis were examined in mice of all groups.

Results

The results showed that severe renal dysfunction, morphological changes, inflammation, apoptosis, and fibrosis were observed in OVE26 mice. However, all the renal abnormalities above in OVE26 mice were significantly attenuated by 3-month FGF21 treatment associated with improvement of renal adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) activity and sirtuin 1 (SIRT1) expression.

Conclusion

Therefore, this study demonstrated that FGF21 might exert therapeutic effects on DN through AMPK-SIRT1 pathway.

Citations

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David M. Ornitz, Nobuyuki Itoh
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Wenxiu Qi, Cheng Hu, Daqing Zhao, Xiangyan Li
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Min-Qi Jia, Cha-Xiang Guan, Jia-Hao Tao, Yong Zhou, Liang-Jun Yan
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Metabolic-associated fatty liver disease increases the risk of end-stage renal disease in patients with biopsy-confirmed diabetic nephropathy: a propensity-matched cohort study
Yutong Zou, Lijun Zhao, Junlin Zhang, Yiting Wang, Yucheng Wu, Honghong Ren, Tingli Wang, Yuancheng Zhao, Huan Xu, Lin Li, Nanwei Tong, Fang Liu
Acta Diabetologica.2022; 60(2): 225. CrossRef
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João Victor Salgado, Miguel Angelo Goes, Natalino Salgado Filho
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Junyu Deng, Ye Liu, Yiqiu Liu, Wei Li, Xuqiang Nie
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Fanrui Meng, Yukai Cao, Mir Hassan Khoso, Kai Kang, Guiping Ren, Wei Xiao, Deshan Li
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Cardiovascular Risk/Epidemiology
Validation of Risk Prediction Models for Atherosclerotic Cardiovascular Disease in a Prospective Korean Community-Based Cohort: Jae Hyun Bae, Min Kyong Moon, Sohee Oh, Bo Kyung Koo, Nam Han Cho, Moon-Kyu Lee; Diabetes Metab J. 2020;44(3):458-469. Published online January 13, 2020; DOI: https://doi.org/10.4093/dmj.2019.0061

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Background

To investigate the performance of the 2013 American College of Cardiology/American Heart Association Pooled Cohort Equations (PCE) in a large, prospective, community-based cohort in Korea and to compare it with that of the Framingham Global Cardiovascular Disease Risk Score (FRS-CVD) and the Korean Risk Prediction Model (KRPM).

Methods

In the Korean Genome and Epidemiology Study (KOGES)-Ansan and Ansung study, we evaluated calibration and discrimination of the PCE for non-Hispanic whites (PCE-WH) and for African Americans (PCE-AA) and compared their predictive abilities with the FRS-CVD and the KRPM.

Results

The present study included 7,932 individuals (3,778 men and 4,154 women). The PCE-WH and PCE-AA moderately overestimated the risk of atherosclerotic cardiovascular disease (ASCVD) for men (6% and 13%, respectively) but underestimated the risk for women (−49% and −25%, respectively). The FRS-CVD overestimated ASCVD risk for men (91%) but provided a good risk prediction for women (3%). The KRPM underestimated ASCVD risk for men (−31%) and women (−31%). All the risk prediction models showed good discrimination in both men (C-statistic 0.730 to 0.735) and women (C-statistic 0.726 to 0.732). Recalibration of the PCE using data from the KOGES-Ansan and Ansung study substantially improved the predictive accuracy in men.

Conclusion

In the KOGES-Ansan and Ansung study, the PCE overestimated ASCVD risk for men and underestimated the risk for women. The PCE-WH and the FRS-CVD provided an accurate prediction of ASCVD in men and women, respectively.

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Cardiovascular Risk/Epidemiology
Impact of Diabetes Control on Subclinical Atherosclerosis: Analysis from Coronary Computed Tomographic Angiography Registry: Gyung-Min Park, Chang Hoon Lee, Seung-Whan Lee, Sung-Cheol Yun, Young-Hak Kim, Yong-Giun Kim, Ki-Bum Won, Soe Hee Ann, Shin-Jae Kim, Dong Hyun Yang, Joon-Won Kang, Tae-Hwan Lim, Eun Hee Koh, Woo Je Lee, Min-Seon Kim, Joong-Yeol Park, Hong-Kyu Kim, Jaewon Choe, Sang-Gon Lee; Diabetes Metab J. 2020;44(3):470-479. Published online November 22, 2019; DOI: https://doi.org/10.4093/dmj.2019.0073

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Background

There are limited data on the impact of diabetes control on the risk of subclinical coronary atherosclerosis.

Methods

We analyzed 6,434 consecutive asymptomatic individuals without previous history of coronary artery disease who underwent coronary computed tomographic angiography (CCTA) (mean age, 53.7±7.6 years and 4,694 men [73.0%]). The degree and extent of subclinical coronary atherosclerosis were assessed by CCTA, and ≥50% diameter stenosis was defined as significant. A cardiac event was defined as a composite of all-cause death, myocardial infarction, unstable angina, or coronary revascularization. Study participants were categorized as normal (n=5,319), controlled diabetes (glycosylated hemoglobin [HbA1c] <7%, n=747), or uncontrolled diabetes (HbA1c ≥7%, n=368), respectively.

Results

Compared with normal individuals, there were no statistically significant differences in the risk of for any atherosclerotic plaque (odds ratio [OR], 1.16; 95% confidence interval [CI], 0.98 to 1.38; P=0.086) and significant coronary artery stenosis (OR, 1.08; 95% CI, 0.82 to 1.42; P=0.583) in controlled diabetic individuals. In contrast, uncontrolled diabetic individuals had consistently higher risks of any atherosclerotic plaque (OR, 2.16; 95% CI, 1.70 to 2.75; P<0.001) and significant coronary artery stenosis (OR, 3.34; 95% CI, 2.52 to 4.43; P<0.001) than normal individuals. During a follow-up of median 5.4 years, there was no significant difference in cardiac events between normal and controlled diabetic individuals (P=0.365). However, uncontrolled diabetes was associated with an increased risk of cardiac events compared with normal individuals (P<0.001) and controlled diabetic individuals (P=0.023).

Conclusion

Asymptomatic uncontrolled diabetes was associated with significant subclinical coronary atherosclerosis with subsequent high risk for cardiac events.

Citations

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Basic Research
Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT: Sundong Lin, Lechu Yu, Yongqing Ni, Lulu He, Xiaolu Weng, Xuemian Lu, Chi Zhang; Diabetes Metab J. 2020;44(1):158-172. Published online October 28, 2019; DOI: https://doi.org/10.4093/dmj.2018.0235

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Background

Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study.

Methods

Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4′-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months.

Results

DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2).

Conclusion

FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.

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Metabolic Risk/Epidemiology
Plasma CD36 and Incident Diabetes: A Case-Cohort Study in Danish Men and Women: Yeli Wang, Jingwen Zhu, Sarah Aroner, Kim Overvad, Tianxi Cai, Ming Yang, Anne Tjønneland, Aase Handberg, Majken K. Jensen; Diabetes Metab J. 2020;44(1):134-142. Published online October 18, 2019; DOI: https://doi.org/10.4093/dmj.2018.0273

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Background

Membrane CD36 is a fatty acid transporter implicated in the pathogenesis of metabolic disease. We aimed to evaluate the association between plasma CD36 levels and diabetes risk and to examine if the association was independent of adiposity among Danish population.

Methods

We conducted a case-cohort study nested within the Danish Diet, Cancer and Health study among participants free of cardiovascular disease, diabetes and cancer and with blood samples and anthropometric measurements (height, weight, waist circumference, and body fat percentage) at baseline (1993 to 1997). CD36 levels were measured in 647 incident diabetes cases that occurred before December 2011 and a total of 3,515 case-cohort participants (236 cases overlap).

Results

Higher plasma CD36 levels were associated with higher diabetes risk after adjusting for age, sex and other lifestyle factors. The hazard ratio (HR) comparing high versus low tertile of plasma CD36 levels was 1.36 (95% confidence interval [CI], 1.00 to 1.86). However, the association lost its significance after further adjustment for different adiposity indices such as body mass index (HR, 1.23; 95% CI, 0.87 to 1.73), waist circumference (HR, 1.21; 95% CI, 0.88 to 1.68) or body fat percentage (HR, 1.20; 95% CI, 0.86 to 1.66). Moreover, raised plasma CD36 levels were moderately associated with diabetes risk among lean participants, but the association was not present among overweight/obese individuals.

Conclusion

Higher plasma CD36 levels were associated with higher diabetes risk, but the association was not independent of adiposity. In this Danish population, the association of CD36 with diabetes risk could be either mediated or confounded by adiposity.

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Monika Rac
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Genetics
Severity of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus: Relationship between Nongenetic Factors and PNPLA3/HSD17B13 Polymorphisms: Mattia Bellan, Cosimo Colletta, Matteo Nazzareno Barbaglia, Livia Salmi, Roberto Clerici, Venkata Ramana Mallela, Luigi Mario Castello, Giuseppe Saglietti, Gian Piero Carnevale Schianca, Rosalba Minisini, Mario Pirisi; Diabetes Metab J. 2019;43(5):700-710. Published online July 29, 2019; DOI: https://doi.org/10.4093/dmj.2018.0201

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Background

The prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is high, though its severity is often underestimated. Our aim is to provide an estimate of the prevalence of severe NAFLD in T2DM and identify its major predictors.

Methods

T2DM patients (n=328) not previously known to have NAFLD underwent clinical assessment, transient elastography with measure of liver stiffness (LS) and controlled attenuation parameter (CAP), and genotyping for patatin like phospholipase domain containing 3 (PNPLA3) and 17β-hydroxysteroid-dehydrogenase type 13 (HSD17B13).

Results

Median LS was 6.1 kPa (4.9 to 8.6). More than one-fourth patients had advanced liver disease, defined as LS ≥7.9 kPa (n=94/238, 29%), and had a higher body mass index (BMI) than those with a LS <7.9 kPa. Carriage of the G allele in the PNPLA3 gene was associated with higher LS, being 5.9 kPa (4.7 to 7.7) in C/C homozygotes, 6.1 kPa (5.2 to 8.7) in C/G heterozygotes, and 6.8 kPa (5.8 to 9.2) in G/G homozygotes (P=0.01). This trend was absent in patients with ≥1 mutated HSD17B13 allele. In a multiple linear regression model, BMI and PNPLA3 genotype predicted LS, while age, gender, disease duration, and glycosylated hemoglobin did not fit into the model. None of these variables was confirmed to be predictive among carriers of at least one HSD17B13 mutated allele. There was no association between CAP and polymorphisms of PNPLA3 or HSD17B13.

Conclusion

Advanced NAFLD is common among T2DM patients. LS is predicted by both BMI and PNPLA3 polymorphism, the effect of the latter being modulated by mutated HSD17B13.

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Brief Report

Basic Research
A Novel Pancreatic Imaging Window for Stabilized Longitudinal In Vivo Observation of Pancreatic Islets in Murine Model: Inwon Park, Sujung Hong, Yoonha Hwang, Pilhan Kim; Diabetes Metab J. 2020;44(1):193-198. Published online May 29, 2019; DOI: https://doi.org/10.4093/dmj.2018.0268

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Longitudinal imaging of murine pancreas is technically challenging due to the mechanical softness of the tissue influenced by peristalsis. Here, we report a novel pancreatic imaging window for long-term stabilized cellular-level observation of the islets in the pancreas in vivo. By spatially separating the pancreas from the bowel movement and physiologic respiration with a metal plate integrated in the imaging window, we successfully tracked the pancreatic islets up to three weeks and visualized the dumbbell-shape transformation from the single islet. This window can be a useful tool for long-term cellular-level visualization of the microstructure in the pancreas.

Citations

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SWIP—a stabilized window for intravital imaging of the murine pancreas
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Original Articles

Obesity and Metabolic Syndrome
Increased Serum Angiopoietin-Like 6 Ahead of Metabolic Syndrome in a Prospective Cohort Study: Jun Namkung, Joon Hyung Sohn, Jae Seung Chang, Sang-Wook Park, Jang-Young Kim, Sang-Baek Koh, In Deok Kong, Kyu-Sang Park; Diabetes Metab J. 2019;43(4):521-529. Published online March 29, 2019; DOI: https://doi.org/10.4093/dmj.2018.0080

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Background

Despite being an anti-obesity hepatokine, the levels of serum angiopoietin-like 6 (ANGPTL6) are elevated in various metabolic diseases. Thus, ANGPTL6 expression may reflect metabolic burden and may have compensatory roles. This study investigated the association between serum ANGPTL6 levels and new-onset metabolic syndrome.

Methods

In total, 221 participants without metabolic syndrome were randomly selected from a rural cohort in Korea. Baseline serum ANGPTL6 levels were measured using an enzyme-linked immunosorbent assay. Anthropometric and biochemical markers were analyzed before and after follow-up examinations.

Results

During an average follow-up period of 2.75 (interquartile range, 0.76) years, 82 participants (37.1%) presented new-onset metabolic syndrome and had higher ANGPTL6 levels before onset than those without metabolic syndrome (48.03±18.84 ng/mL vs. 64.75±43.35 ng/mL, P=0.001). In the multivariable adjusted models, the odds ratio for the development of metabolic syndrome in the highest quartile of ANGPTL6 levels was 3.61 (95% confidence interval, 1.27 to 10.26). The use of ANGPTL6 levels in addition to the conventional components improved the prediction of new-onset metabolic syndrome (area under the receiver operating characteristic curve: 0.775 vs. 0.807, P=0.036).

Conclusion

Increased serum ANGPTL6 levels precede the development of metabolic syndrome and its components, including low high density lipoprotein, high triglyceride, and high glucose levels, which have an independent predictive value for metabolic syndrome.

Citations

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Circulating Angiopoietin-like Protein 6 Levels and Clinical Features in Patients with Type 2 Diabetes
Kohzo Takebayashi, Tatsuhiko Suzuki, Mototaka Yamauchi, Kenji Hara, Takafumi Tsuchiya, Toshihiko Inukai, Koshi Hashimoto
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Effects of Accumulated and Continuous High-Intensity Aerobic Exercise on Cardiorespiratory Fitness and Circulating ANGPTL6 Levels in Obese Adolescents
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High serum EDA concentration is associated with metabolic syndrome and its determinants
Xia Deng, Yanyan Li, Tian Gu, Xunan Wu, Ziyan Sun, Haoxiang Li, Ling Yang, Guoyue Yuan
Acta Diabetologica.2024; 62(6): 915. CrossRef
Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases
Eric Thorin, Pauline Labbé, Mélanie Lambert, Pauline Mury, Olina Dagher, Géraldine Miquel, Nathalie Thorin-Trescases
Canadian Journal of Cardiology.2023; 39(12): 1736. CrossRef
Hyperlipidemia and hypothyroidism
Xin Su, Hua Peng, Xiang Chen, Xijie Wu, Bin Wang
Clinica Chimica Acta.2022; 527: 61. CrossRef
Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease
Eunha Chang, Jae Seung Chang, In Deok Kong, Soon Koo Baik, Moon Young Kim, Kyu-Sang Park
Gut and Liver.2022; 16(2): 171. CrossRef
Triglyceride and Triglyceride-Rich Lipoproteins in Atherosclerosis
Bai-Hui Zhang, Fan Yin, Ya-Nan Qiao, Shou-Dong Guo
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Relationship of ANGPTL6 With Neonatal Glucose Homeostasis and Fat Mass Is Disrupted in Gestational Diabetic Pregnancies
Abel Valencia-Martínez, Ute Schaefer-Graf, Encarnación Amusquivar, Emilio Herrera, Henar Ortega-Senovilla
The Journal of Clinical Endocrinology & Metabolism.2022; 107(10): e4078. CrossRef
Update on dyslipidemia in hypothyroidism: the mechanism of dyslipidemia in hypothyroidism
Huixing Liu, Daoquan Peng
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RETRACTED ARTICLE: Relationship between the development of hyperlipidemia in hypothyroidism patients
Xin Su, Xiang Chen, Bin Wang
Molecular Biology Reports.2022; 49(11): 11025. CrossRef
Effects of Exercise Intervention on Mitochondrial Stress Biomarkers in Metabolic Syndrome Patients: A Randomized Controlled Trial
Jae Seung Chang, Jun Namkung
International Journal of Environmental Research and Public Health.2021; 18(5): 2242. CrossRef
Angiopoietin-like proteins in atherosclerosis
Yi-Zhang Liu, Chi Zhang, Jie-Feng Jiang, Zhe-Bin Cheng, Zheng-Yang Zhou, Mu-Yao Tang, Jia-Xiang Sun, Liang Huang
Clinica Chimica Acta.2021; 521: 19. CrossRef
Effects of Bariatric Surgeries on Fetuin-A, Selenoprotein P, Angiopoietin-Like Protein 6, and Fibroblast Growth Factor 21 Concentration
Jakub Poloczek, Wojciech Kazura, Ewa Kwaśnicka, Janusz Gumprecht, Jerzy Jochem, Dominika Stygar, Munmun Chattopadhyay
Journal of Diabetes Research.2021; 2021: 1. CrossRef
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Tae Hyun Kim, Dong-Gyun Hong, Yoon Mee Yang
Biomedicines.2021; 9(12): 1903. CrossRef
Serum levels of angiopoietin-related growth factor in diabetes mellitus and chronic hemodialysis
Semra ÖZKAN ÖZTÜRK, Hilmi ATASEVEN
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ANGPTL6 Level in Patient with Coronary Heart Disease and Its Relationship with the Severity of Coronary Artery Lesions
蕾任
Advances in Clinical Medicine.2020; 10(05): 714. CrossRef
Investigating the Role of Myeloperoxidase and Angiopoietin-like Protein 6 in Obesity and Diabetes
Mohammad G. Qaddoumi, Muath Alanbaei, Maha M. Hammad, Irina Al Khairi, Preethi Cherian, Arshad Channanath, Thangavel Alphonse Thanaraj, Fahd Al-Mulla, Mohamed Abu-Farha, Jehad Abubaker
Scientific Reports.2020;[Epub] CrossRef
Letter: Increased Serum Angiopoietin-Like 6 Ahead of Metabolic Syndrome in a Prospective Cohort Study (Diabetes Metab J 2019;43:521-9)
Jin Hwa Kim
Diabetes & Metabolism Journal.2019; 43(5): 727. CrossRef
Response: Increased Serum Angiopoietin-Like 6 Ahead of Metabolic Syndrome in a Prospective Cohort Study (Diabetes Metab J 2019;43:521-9)
Jun Namkung, Kyu-Sang Park
Diabetes & Metabolism Journal.2019; 43(5): 729. CrossRef

Complications
Gemigliptin Attenuates Renal Fibrosis Through Down-Regulation of the NLRP3 Inflammasome: Jung Beom Seo, Yeon-Kyung Choi, Hye-In Woo, Yun-A Jung, Sungwoo Lee, Seunghyeong Lee, Mihyang Park, In-Kyu Lee, Gwon-Soo Jung, Keun-Gyu Park; Diabetes Metab J. 2019;43(6):830-839. Published online March 5, 2019; DOI: https://doi.org/10.4093/dmj.2018.0181

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Background

The hypoglycemic drugs dipeptidyl peptidase-4 (DPP-4) inhibitors have proven protective effects on diabetic kidney disease, including renal fibrosis. Although NOD-like receptor protein 3 (NLRP3) inflammasome activation is known to play an important role in the progression of renal fibrosis, the impact of DPP-4 inhibition on NLRP3-mediated inflammation while ameliorating renal fibrosis has not been fully elucidated. Here, we report that the renoprotective effect of gemigliptin is associated with a reduction in NLRP3-mediated inflammation in a murine model of renal fibrosis.

Methods

We examined the effects of gemigliptin on renal tubulointerstitial fibrosis induced in mice by unilateral ureteral obstruction (UUO). Using immunohistochemical and Western blot analysis, we quantitated components of the NLRP3 inflammasome in kidneys with and without gemigliptin treatment, and in vitro in human kidney tubular epithelial human renal proximal tubule cells (HK-2) cells, we further analyzed the effect of gemigliptin on transforming growth factor-β (TGF-β)-stimulated production of profibrotic proteins.

Results

Immunohistological examination revealed that gemigliptin ameliorated UUO-induced tubular atrophy and renal fibrosis. Gemigliptin-treated kidneys showed a reduction in levels of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-1β, which had all been markedly increased by UUO. In line with the in vivo results, TGF-β markedly increased NLRP3 inflammasome markers, which were attenuated by gemigliptin treatment. Furthermore, gemigliptin treatment attenuated phosphorylated nuclear factor-κB levels, which had been increased in the UUO kidney as well as in TGF-β-treated cultured renal cells.

Conclusion

The present study shows that activation of the NLRP3 inflammasome contributes to UUO-induced renal fibrosis and the renoprotective effect of gemigliptin is associated with attenuation of NLRP3 inflammasome activation.

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Clinical Diabetes & Therapeutics
Comparison of the Efficacy of Rosuvastatin Monotherapy 20 mg with Rosuvastatin 5 mg and Ezetimibe 10 mg Combination Therapy on Lipid Parameters in Patients with Type 2 Diabetes Mellitus: You-Cheol Hwang, Ji Eun Jun, In-Kyung Jeong, Kyu Jeung Ahn, Ho Yeon Chung; Diabetes Metab J. 2019;43(5):582-589. Published online January 16, 2019; DOI: https://doi.org/10.4093/dmj.2018.0124

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Background

The apolipoprotein B/A1 (apoB/A1) ratio is a stronger predictor of future cardiovascular disease than is the level of conventional lipids. Statin and ezetimibe combination therapy have shown additional cardioprotective effects over statin monotherapy.

Methods

This was a single-center, randomized, open-label, active-controlled study in Korea. A total of 36 patients with type 2 diabetes mellitus were randomized to either rosuvastatin monotherapy (20 mg/day, n=20) or rosuvastatin/ezetimibe (5 mg/10 mg/day, n=16) combination therapy for 6 weeks.

Results

After the 6-week treatment, low density lipoprotein cholesterol (LDL-C) and apoB reduction were comparable between the two groups (−94.3±15.4 and −62.0±20.9 mg/dL in the rosuvastatin group, −89.9±22.7 and −66.8±21.6 mg/dL in the rosuvastatin/ezetimibe group, P=0.54 and P=0.86, respectively). In addition, change in apoB/A1 ratio (−0.44±0.16 in the rosuvastatin group and −0.47±0.25 in the rosuvastatin/ezetimibe group, P=0.58) did not differ between the two groups. On the other hand, triglyceride and free fatty acid (FFA) reductions were greater in the rosuvastatin/ezetimibe group than in the rosuvastatin group (−10.5 mg/dL [interquartile range (IQR), −37.5 to 29.5] and 0.0 µEq/L [IQR, −136.8 to 146.0] in the rosuvastatin group, −49.5 mg/dL [IQR, −108.5 to −27.5] and −170.5 µEq/L [IQR, −353.0 to 0.8] in the rosuvastatin/ezetimibe group, P=0.010 and P=0.049, respectively). Both treatments were generally well tolerated, and there were no differences in muscle or liver enzyme elevation.

Conclusion

A 6-week combination therapy of low-dose rosuvastatin and ezetimibe showed LDL-C, apoB, and apoB/A1 ratio reduction comparable to that of high-dose rosuvastatin monotherapy in patients with type 2 diabetes mellitus. Triglyceride and FFA reductions were greater with the combination therapy than with rosuvastatin monotherapy.

Citations

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Review

Clinical Diabetes & Therapeutics
Diabetes and Subclinical Coronary Atherosclerosis: Chang Hoon Lee, Seung-Whan Lee, Seong-Wook Park; Diabetes Metab J. 2018;42(5):355-363. Published online October 22, 2018; DOI: https://doi.org/10.4093/dmj.2018.0041

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It is well known that diabetic patients have a high risk of cardiovascular events, and although there has been a tremendous effort to reduce these cardiovascular risks, the incidence of cardiovascular morbidity and mortality in diabetic patients remains high. Therefore, the early detection of coronary artery disease (CAD) is necessary in those diabetic patients who are at risk of cardiovascular events. Significant medical and radiological advancements, including coronary computed tomography angiography (CCTA), mean that it is now possible to investigate the characteristics of plaques, instead of solely evaluating the calcium level of the coronary artery. Recently, several studies reported that the prevalence of subclinical coronary atherosclerosis (SCA) is higher than expected, and this could impact on CAD progression in asymptomatic diabetic patients. In addition, several reports suggest the potential benefit of using CCTA for screening for SCA in asymptomatic diabetic patients, which might dramatically decrease the incidence of cardiovascular events. For these reasons, the medical interest in SCA in diabetic patients is increasing. In this article, we sought to review the results of studies on CAD in asymptomatic diabetic patients and discuss the clinical significance and possibility of using CCTA to screen for SCA.

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Original Article

Clinical Diabetes and Therapeutics
Cardio-Ankle Vascular Index as a Surrogate Marker of Early Atherosclerotic Cardiovascular Disease in Koreans with Type 2 Diabetes Mellitus: So Young Park, Sang Ook Chin, Sang Youl Rhee, Seungjoon Oh, Jeong-Taek Woo, Sung Woon Kim, Suk Chon; Diabetes Metab J. 2018;42(4):285-295. Published online July 27, 2018; DOI: https://doi.org/10.4093/dmj.2017.0080

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Background

Carotid artery intima medial thickness (IMT), brachial-ankle pulse wave velocity (baPWV), and ankle-brachial index (ABI) are commonly used surrogate markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The cardio-ankle vascular index (CAVI) is a complement to the baPWV, which is affected by blood pressure. However, it is unclear which marker is the most sensitive predictor of atherosclerotic cardiovascular disease (ASCVD).

Methods

This was a retrospective non-interventional study that enrolled 219 patients with T2DM. The correlations among IMT, ABI, and CAVI as well as the relationship of these tests to the 10-year ASCVD risk were also analyzed.

Results

Among the 219 patients, 39 (17.8%) had ASCVD. In the non-ASCVD group, CAVI correlated significantly with IMT after adjusting for confounding variables, but ABI was not associated with CAVI or IMT. The analyses after dividing the non-ASCVD group into three subgroups according to the CAVI score (<8, ≥8 and <9, and ≥9) demonstrated the significant increase in the mean IMT, 10-year ASCVD risk and number of metabolic syndrome risk factors, and decrease in the mean ABI in the high-CAVI group. A high CAVI was an independent risk factor in the non-ASCVD group for both a high 10-year ASCVD risk (≥7.5%; odds ratio [OR], 2.42; P<0.001) and atherosclerosis (mean IMT ≥1 mm; OR, 1.53; P=0.007).

Conclusion

In Korean patients with T2DM without ASCVD, CAVI was the most sensitive of several surrogate markers for the detection of subclinical atherosclerosis.

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Review

Obesity and Metabolic Syndrome
Non-Alcoholic Fatty Liver Disease: The Emerging Burden in Cardiometabolic and Renal Diseases: Eugene Han, Yong-ho Lee; Diabetes Metab J. 2017;41(6):430-437. Published online November 17, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.6.430

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As the number of individuals with non-alcoholic fatty liver disease (NAFLD) has increased, the influence of NAFLD on other metabolic diseases has been highlighted. Accumulating epidemiologic evidence indicates that NAFLD not only affects the liver but also increases the risk of extra-hepatic diseases such as type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, hypertension, cardiovascular or cerebrovascular diseases, and chronic kidney disease. Non-alcoholic steatohepatitis, an advanced type of NAFLD, can aggravate these inter-organ relationships and lead to poorer outcomes. NAFLD induces insulin resistance and exacerbates systemic chronic inflammation and oxidative stress, which leads to organ dysfunction in extra-hepatic tissues. Although more research is needed to identify the pathophysiological mechanisms and causal relationship between NAFLD and cardiometabolic and renal diseases, screening for heart, brain, and kidney diseases, risk assessment for diabetes, and a multidisciplinary approach for managing these patients should be highly encouraged.

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Original Articles

Obesity and Metabolic Syndrome
Beneficial Effects of Aerobic Exercise Training Combined with Rosiglitazone on Glucose Metabolism in Otsuka Long Evans Tokushima Fatty Rats: Shan-Ji Piao, So Hun Kim, Young Ju Suh, Seong-Bin Hong, Seong Hee Ahn, Da Hae Seo, In-Sun Park, Moonsuk Nam; Diabetes Metab J. 2017;41(6):474-485. Published online November 15, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.6.474

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Abstract PDF PubReader ePub

Background

Regular aerobic exercise is essential for the prevention and management of type 2 diabetes mellitus and may be particularly beneficial for those treated with thiazolidinediones, since it may prevent associated weight gain. This study aimed to evaluate the effect of combined exercise and rosiglitazone treatment on body composition and glucose metabolism in obese diabetes-prone animals.

Methods

We analyzed metabolic parameters, body composition, and islet profiles in Otsuka Long Evans Tokushima Fatty rats after 28 weeks of aerobic exercise, rosiglitazone treatment, and combined exercise and rosiglitazone treatment.

Results

Combined exercise with rosiglitazone showed significantly less increase in weight and epididymal fat compared to rosiglitazone treatment. Aerobic exercise alone and combined rosiglitazone and exercise treatment led to similar retention of lean body mass. All experimental groups showed a decrease in fasting glucose. However, the combined exercise and rosiglitazone therapy group showed prominent improvement in glucose tolerance compared to the other groups. Rescue of islet destruction was observed in all experimental groups, but was most prominent in the combined therapy group.

Conclusion

Regular aerobic exercise combined with rosiglitazone treatment can compensate for the adverse effect of rosiglitazone treatment and has benefit for islet preservation.

Citations

Citations to this article as recorded by

A Review of Animal Models for Studying Bone Health in Type-2 Diabetes Mellitus (T2DM) and Obesity
Saiful Iqbal Norazman, Anis Syauqina Mohd Zaffarin, Ahmad Nazrun Shuid, Haniza Hassan, Ima Nirwana Soleiman, Wong Sok Kuan, Ekram Alias
International Journal of Molecular Sciences.2024; 25(17): 9399. CrossRef
Impacts of an Exercise Intervention on the Health of Pancreatic Beta-Cells: A Review
Shuang Zhang, Yaru Wei, Chunxiao Wang
International Journal of Environmental Research and Public Health.2022; 19(12): 7229. CrossRef
Molecular mechanisms by which aerobic exercise induces insulin sensitivity
Habib Yaribeygi, Stephen L. Atkin, Luis E. Simental‐Mendía, Amirhossein Sahebkar
Journal of Cellular Physiology.2019; 234(8): 12385. CrossRef

Epidemiology
Application of the 2013 American College of Cardiology/American Heart Association Cholesterol Guideline to the Korean National Health and Nutrition Examination Surveys from 1998 to 2012: Young Shin Song, Tae Jung Oh, Kyoung Min Kim, Jae Hoon Moon, Sung Hee Choi, Hak Chul Jang, Kyong Soo Park, Soo Lim; Diabetes Metab J. 2017;41(1):38-50. Published online December 16, 2016; DOI: https://doi.org/10.4093/dmj.2017.41.1.38

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Background

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the treatment of blood cholesterol recommends statin therapy for individuals at high risk of atherosclerotic cardiovascular disease (ASCVD). The aim of this study was to investigate serial trends in the percentages of Korean adults considered eligible for statin therapy according to the new ACC/AHA cholesterol guideline.

Methods

Data from the Korean National Health and Nutrition Examination Survey (KNHANES) I (1998, n=7,698), II (2001, n=5,654), III (2005, n=5,269), IV (2007 to 2009, n=15,727), and V (2010 to 2012, n=16,304), which used a stratified, multistage, probability sampling design, were used as representative of the entire Korean population.

Results

The percentage of adults eligible for statin therapy according to the ACC/AHA cholesterol guideline increased with time: 17.0%, 19.0%, 20.8%, 20.2%, and 22.0% in KNHANES I, II, III, IV, and V, respectively (P=0.022). The prevalence of ASCVD was 1.4% in KNHANES I and increased to 3.3% in KNHANES V. The percentage of diabetic patients aged 40 to 75 years with a low density lipoprotein cholesterol levels of 70 to 189 mg/dL increased from 4.8% in KNHANES I to 6.1% in KNHANES V. People with an estimated 10-year ASCVD risk ≥7.5% and aged 40 to 75 years accounted for the largest percentage among the four statin benefit groups: 9.1% in KNHANES I and 11.0% in KNHANES V.

Conclusion

Application of the 2013 ACC/AHA guideline has found that the percentage of Korean adults in the statin benefit groups has increased over the past 15 years.

Citations

Citations to this article as recorded by

Sex differences in risk factors for subclinical hypothyroidism
Jeonghoon Ha, Jeongmin Lee, Kwanhoon Jo, Dong-Jun Lim, Moo Il Kang, Bong Yun Cha, Min-Hee Kim
Endocrine Connections.2018; 7(4): 511. CrossRef

Complications
Renoprotective Effect of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Streptozotocin-Induced Type 1 Diabetic Mice: Gwon-Soo Jung, Jae-Han Jeon, Mi Sun Choe, Sung-Woo Kim, In-Kyu Lee, Mi-Kyung Kim, Keun-Gyu Park; Diabetes Metab J. 2016;40(3):211-221. Published online March 31, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.3.211

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Background

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice.

Methods

Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis.

Results

Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation.

Conclusion

Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.

Citations

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Adili Tuersun, Munire Mohetaer, Guanxin Hou, Gang Cheng
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Pattern of Thyroid Dysfunction in Patients with Metabolic Syndrome and Its Relationship with Components of Metabolic Syndrome: Prabin Gyawali, Jyoti Shrestha Takanche, Raj Kumar Shrestha, Prem Bhattarai, Kishor Khanal, Prabodh Risal, Rajendra Koju; Diabetes Metab J. 2015;39(1):66-73. Published online February 16, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.1.66

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Background

Thyroid dysfunction (TD) and metabolic syndrome (MetS) are known risk factors for atherosclerotic cardiovascular disease (ASCVD). TD is risk factor for ASCVD mediated by the effects of thyroid hormones on lipid metabolism and blood pressure hence the components of MetS. It is possible that coexistence of these two disease entities and unrecognized TD in patients with MetS might substantially increase ASCVD risk. Moreover, little is known about the relationship between TD and the components of MetS. Thus, the purpose of this study was to evaluate the pattern of TD in patients with MetS and its relationship with components of the MetS.

Methods

A total of 358 previously diagnosed patients with MetS were recruited in the study. The thyroid function test parameters were measured to classify TD at Dhulikhel Hospital-Kathmandu University Hospital, Dhulikhel, Nepal. Statistical analyses were performed using SPSS version 16.0 to evaluate pattern and relationship.

Results

The overall prevalence of TD in patients with MetS was 31.84% with high prevalence of subclinical hypothyroidism (29.32%). We found no evidence of a relationship between TD and components of MetS, although there was significant difference in waist circumference between four groups of TD.

Conclusion

Patients with MetS had subclinical hypothyroidism greatly. Although there was no evidence of any relationship between thyroid status and all components of MetS, TD should be taken into account when evaluating and treating patients with MetS to reduce the impending risk.

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Review

Resistin in Rodents and Humans: Hyeong Kyu Park, Rexford S. Ahima; Diabetes Metab J. 2013;37(6):404-414. Published online December 12, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.6.404

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Abstract PDF PubReader ePub

Obesity is characterized by excess accumulation of lipids in adipose tissue and other organs, and chronic inflammation associated with insulin resistance and an increased risk of type 2 diabetes. Obesity, type 2 diabetes, and cardiovascular diseases are major health concerns. Resistin was first discovered as an adipose-secreted hormone (adipokine) linked to obesity and insulin resistance in rodents. Adipocyte-derived resistin is increased in obese rodents and strongly related to insulin resistance. However, in contrast to rodents, resistin is expressed and secreted from macrophages in humans and is increased in inflammatory conditions. Some studies have also suggested an association between increased resistin levels and insulin resistance, diabetes and cardiovascular disease. Genetic studies have provided additional evidence for a role of resistin in insulin resistance and inflammation. Resistin appears to mediate the pathogenesis of atherosclerosis by promoting endothelial dysfunction, vascular smooth muscle cell proliferation, arterial inflammation, and formation of foam cells. Indeed, resistin is predictive of atherosclerosis and poor clinical outcomes in patients with coronary artery disease and ischemic stroke. There is also growing evidence that elevated resistin is associated with the development of heart failure. This review will focus on the biology of resistin in rodents and humans, and evidence linking resistin with type 2 diabetes, atherosclerosis, and cardiovascular disease.

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Original Articles

Risk Factors for the Progression of Intima-Media Thickness of Carotid Arteries: A 2-Year Follow-Up Study in Patients with Newly Diagnosed Type 2 Diabetes: Sang Ouk Chin, Jin Kyung Hwang, Sang Youl Rhee, Suk Chon, You-Cheol Hwang, Seungjoon Oh, Kyu Jeung Ahn, Ho Yeon Chung, Jeong-taek Woo, Sung-Woon Kim, Young Seol Kim, Ja-Heon Kang, In-Kyung Jeong; Diabetes Metab J. 2013;37(5):365-374. Published online October 17, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.5.365

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Abstract PDF Supplementary Material PubReader ePub

Background

Intima-media thickness (IMT) of the carotid arteries is known to have a positive correlation with the risk of cardiovascular disease. This study was designed to identify risk factors affecting the progression of carotid IMT in patients with type 2 diabetes mellitus (T2DM).

Methods

Patients with newly diagnosed T2DM with carotid IMT measurements were enrolled, and their clinical data and carotid IMT results at baseline and 2 years later were compared.

Results

Of the 171 patients, 67.2% of males and 50.8% of females had abnormal baseline IMT of the left common carotid artery. At baseline, systolic blood pressure, body mass index and smoking in male participants, and fasting plasma glucose and glycated hemoglobin levels in females were significantly higher in patients with abnormal IMT than in those with normal IMT. Low density lipoprotein cholesterol (LDL-C) levels in males and high density lipoprotein cholesterol (HDL-C) levels in females at the 2-year follow-up were significantly different between the nonprogression and the progression groups. Reduction of the United Kingdom Prospective Diabetes Study (UKPDS) 10-year coronary heart disease (CHD) risk score after 2 years was generally higher in the nonprogression group than the progression group.

Conclusion

LDL-C levels in males and HDL-C levels in females at the 2-year follow-up were significantly different between participants with and without progression of carotid IMT. Furthermore, a reduction in the UKPDS 10-year CHD risk score appeared to delay the advancement of atherosclerosis. Therefore, the importance of establishing the therapeutic goal of lipid profiles should be emphasized to prevent the progression of carotid IMT in newly diagnosed T2DM patients.

Citations

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Comparison of the Effectiveness of Low Carbohydrate Versus Low Fat Diets, in Type 2 Diabetes: Systematic Review and Meta-Analysis of Randomized Controlled Trials
Tanefa A. Apekey, Maria J. Maynard, Monia Kittana, Setor K. Kunutsor
Nutrients.2022; 14(20): 4391. CrossRef
Nomogram Based on Risk Factors for Type 2 Diabetes Mellitus Patients with Coronary Heart Disease

Rong Shi, Birong Wu, Zheyun Niu, Hui Sun, Fan Hu
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2020; Volume 13: 5025. CrossRef
HMGA1 Mediated High-Glucose-Induced Vascular Smooth Muscle Cell Proliferation in Diabetes Mellitus: Association Between PI3K/Akt Signaling and HMGA1 Expression
Qinghai Zhang, Ling Chen, Zhibo Zhao, Ying Wu, Jing Zhong, Gebo Wen, Renxian Cao, Xuyu Zu, Jianghua Liu
DNA and Cell Biology.2018; 37(4): 389. CrossRef
Relationship between frequency of hypoglycemic episodes and changes in carotid atherosclerosis in insulin-treated patients with type 2 diabetes mellitus
Tomoya Mita, Naoto Katakami, Toshihiko Shiraiwa, Hidenori Yoshii, Nobuichi Kuribayashi, Takeshi Osonoi, Hideaki Kaneto, Keisuke Kosugi, Yutaka Umayahara, Masahiko Gosho, Iichiro Shimomura, Hirotaka Watada
Scientific Reports.2017;[Epub] CrossRef
Impact of carotid atherosclerosis detection on physician and patient behavior in the management of type 2 diabetes mellitus: a prospective, observational, multicenter study
In-Kyung Jeong, Sin-Gon Kim, Dong Hyeok Cho, Chong Hwa Kim, Chul Sik Kim, Won-Young Lee, Kyu-Chang Won, Doo-Man Kim
BMC Cardiovascular Disorders.2016;[Epub] CrossRef
The effect of fibroblast growth factors and advanced glycation end-products on the intima-media complex thickness in patients with coronary heart disease and type 2 diabetes
Ekaterina Vladimirovna Ivannikova, Victor Yurievich Kalashnikov, Olga Mikhailovna Smirnova, Alexander Borisovich Kuznetsov, Сергей Anatolievich Terekhin, Alexander Viktorovich Il'in
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Fracture Incidence and Risk of Osteoporosis in Female Type 2 Diabetic Patients in Korea: Jong Kwan Jung, Hyo Jeong Kim, Hong Kyu Lee, Sang Soo Kim, Chan Soo Shin, Jin Taek Kim; Diabetes Metab J. 2012;36(2):144-150. Published online April 17, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.2.144

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Background

There are no published data regarding fracture risk in type 2 diabetic patients in Korea. In this study, we compared the fracture incidence and risk of osteoporosis of type 2 diabetic female patients with those in a non-diabetic hypertensive cohort.

Methods

The incidence of fracture in a type 2 diabetic cohort was compared with that in a non-diabetic hypertensive cohort over the course of 7 years. Female type 2 diabetic and non-diabetic hypertensive patients who visited Eulji General Hospital outpatient clinic from January 2004 to April 2004 were assigned to the diabetic cohort and the non-diabetic hypertensive cohort, respectively. Surveys on fracture event, use of anti-osteoporosis medications, and bone mineral density were performed.

Results

The number of fractures was 88 in the female diabetic cohort (n=1,268, 60.6±11.5 years) and 57 in the female non-diabetic hypertensive cohort (n=1,014, 61.4±11.7 years). The RR in the diabetic cohort was 1.38 (P=0.064; 95% confidence interval [CI], 0.98 to 1.94) when adjusted for age. Diabetic patients with microvascular complications (61.0%) showed a higher RR of 1.81 (P=0.014; 95% CI, 1.13 to 2.92) compared with those without these complications. The prevalence of osteoporosis was comparable between the groups, while use of anti-osteoporosis medication was more common in the diabetic cohort (12.8%) than in the hypertensive cohort (4.5%) (P<0.001).

Conclusion

In our study, a higher fracture risk was observed in female type 2 diabetics with microvascular complications. Special concern for this risk group is warranted.

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Risk of low-energy fracture in type 2 diabetes patients: a meta-analysis of observational studies
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Osteoporosis International.2017; 28(11): 3113. CrossRef
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Kwang Joon Kim, Yong-Ki Min, Jung-Min Koh, Yoon-Sok Chung, Kyoung Min Kim, Dong-Won Byun, In Joo Kim, Mikyung Kim, Sung-Soo Kim, Kyung Wan Min, Ki Ok Han, Hyoung Moo Park, Chan Soo Shin, Sung Hee Choi, Jong Suk Park, Dong Jin Chung, Ji Oh Mok, Hong Sun Ba
Yonsei Medical Journal.2014; 55(3): 715. CrossRef
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Chien-Chang Liao, Chao-Shun Lin, Chun-Chuan Shih, Chun-Chieh Yeh, Yi-Cheng Chang, Yuan-Wen Lee, Ta-Liang Chen
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Calcified Tissue International.2012; 91(6): 370. CrossRef

Cardiovascular Risk Assessment with Vascular Function, Carotid Atherosclerosis and the UKPDS Risk Engine in Korean Patients with Newly Diagnosed Type 2 Diabetes: Choon Sik Seon, Kyung Wan Min, Seung Yup Lee, Kyoung Woo Nho, Se Hwan Park, Bo Kyung Koo, Kyung Ah Han; Diabetes Metab J. 2011;35(6):619-627. Published online December 26, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.6.619

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Background

Patients with type 2 diabetes have an increased risk of cardiovascular disease. Few studies have evaluated the cardiovascular disease (CVD) risk simultaneously using the United Kingdom Prospective Diabetes Study (UKPDS) risk engine and non-invasive vascular tests in patients with newly diagnosed type 2 diabetes.

Methods

Participants (n=380; aged 20 to 81 years) with newly diagnosed type 2 diabetes were free of clinical evidence of CVD. The 10-year coronary heart disease (CHD) and stroke risks were calculated for each patient using the UKPDS risk engine. Carotid intima media thickness (CIMT), flow mediated dilation (FMD), pulse wave velocity (PWV) and augmentation index (AI) were measured. The correlations between the UKPDS risk engine and the non-invasive vascular tests were assessed using partial correlation analysis, after adjusting for age, and multiple regression analysis.

Results

The mean 10-year CHD and 10-year stroke risks were 14.92±11.53% and 4.03±3.95%, respectively. The 10-year CHD risk correlated with CIMT (P<0.001), FMD (P=0.017), and PWV (P=0.35) after adjusting for age. The 10-year stroke risk correlated only with the mean CIMT (P<0.001) after adjusting for age. FMD correlated with age (P<0.01) and systolic blood pressure (P=0.09). CIMT correlated with age (P<0.01), HbA1c (P=0.05), and gender (P<0.01).

Conclusion

The CVD risk is increased at the onset of type 2 diabetes. CIMT, FMD, and PWV along with the UKPDS risk engine should be considered to evaluate cardiovascular disease risk in patients with newly diagnosed type 2 diabetes.

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Mashkura Riyazuddeen, AliHasan Faiz Karnam, L Gopinath, Nayyar Iqbal
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Carotid atherosclerosis and its relationship to coronary heart disease and stroke risk in patients with type 2 diabetes mellitus
Yan Wu, Jie He, Xue Sun, Yi-Ming Zhao, Han-Yu Lou, Xiao-li Ji, Xiao-Hong Pang, Li-Zhen Shan, Ying-Xiu Kang, Jun Xu, Song-Zhao Zhang, Yong-Jian Wang, Yue-Zhong Ren, Peng-Fei Shan
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Carotid Intimal-Medial Thickness Is Not Increased in Women with Previous Gestational Diabetes Mellitus: Yun Hyi Ku, Sung Hee Choi, Soo Lim, Young Min Cho, Young Joo Park, Kyong Soo Park, Seong Yeon Kim, Hak Chul Jang; Diabetes Metab J. 2011;35(5):497-503. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.497

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Background

Gestational diabetes mellitus (GDM) is known to increase the risk of cardiovascular diseases. Measuring the carotid artery intimal-medial thickness (CIMT) is a non-invasive technique used to evaluate early atherosclerosis and to predict future cardiovascular diseases. We examined the association between CIMT and cardiovascular risk factors in young Korean women with previous GDM.

Methods

One hundred one women with previous GDM and 19 women who had normal pregnancies (NP) were recruited between 1999 and 2002. At one year postpartum, CIMT was measured using high-resolution B-mode ultrasonography, and oral glucose tolerance tests were performed. Fasting glucose, glycated hemoglobin A1c (HbA1c), insulin levels and lipid profiles were also measured. CIMTs in the GDM and NP groups were compared, and the associations between CIMT and cardiovascular risk factors were analyzed in the GDM group.

Results

CIMT results of the GDM group were not significantly different from those of the NP group (GDM, 0.435±0.054 mm; NP, 0.460±0.046 mm; P=0.069). In the GDM group, a higher HbA1c was associated with an increase in CIMT after age adjustment (P=0.011). CIMT results in the group with HbA1c >6.0% were higher than those of the normal HbA1c (HbA1c ≤6.0%) (P=0.010). Nine of the patients who are type 2 diabetes mellitus converters within one year postpartum but showed no significant difference in CIMT results compared to NP group.

Conclusion

Higher HbA1c is associated with an increase in CIMT in women with previous GDM. However, CIMT at one year postpartum was not increased in these women compared to that in NP women.

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Review

Fuel-Stimulated Insulin Secretion Depends upon Mitochondria Activation and the Integration of Mitochondrial and Cytosolic Substrate Cycles: Gary W. Cline; Diabetes Metab J. 2011;35(5):458-465. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.458

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The pancreatic islet β-cell is uniquely specialized to couple its metabolism and rates of insulin secretion with the levels of circulating nutrient fuels, with the mitochondrial playing a central regulatory role in this process. In the β-cell, mitochondrial activation generates an integrated signal reflecting rates of oxidativephosphorylation, Kreb's cycle flux, and anaplerosis that ultimately determines the rate of insulin exocytosis. Mitochondrial activation can be regulated by proton leak and mediated by UCP2, and by alkalinization to utilize the pH gradient to drive substrate and ion transport. Converging lines of evidence support the hypothesis that substrate cycles driven by rates of Kreb's cycle flux and by anaplerosis play an integral role in coupling responsive changes in mitochondrial metabolism with insulin secretion. The components and mechanisms that account for the integrated signal of ATP production, substrate cycling, the regulation of cellular redox state, and the production of other secondary signaling intermediates are operative in both rodent and human islet β-cells.

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Original Article

Basal C-peptide Level as a Surrogate Marker of Subclinical Atherosclerosis in Type 2 Diabetic Patients: Sung-Tae Kim, Byung-Joon Kim, Dong-Mee Lim, In-Geol Song, Jang-Han Jung, Kang-Woo Lee, Keun-Young Park, Youn-Zoo Cho, Dae-Ho Lee, Gwan-Pyo Koh; Diabetes Metab J. 2011;35(1):41-49. Published online February 28, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.1.41

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Background

Recent studies have revealed that C-peptide induces smooth muscle cell proliferation and causes human atherosclerotic lesions in diabetic patients. The present study was designed to examine whether the basal C-peptide levels correlate with cardiovascular risk in type 2 diabetes mellitus (T2DM) patients.

Methods

Data was obtained from 467 patients with T2DM from two institutions who were followed for four years. The medical findings of all patients were reviewed, and patients with creatinine >1.4 mg/dL, any inflammation or infection, hepatitis, or type 1 DM were excluded. The relationships between basal C-peptide and other clinical values were statistically analyzed.

Results

A simple correlation was found between basal C-peptide and components of metabolic syndrome (MS). Statistically basal C-peptide levels were significantly higher than the three different MS criteria used in the present study, the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program's (NCEP's), World Health Organization (WHO), and the International Diabetes Federation (IDF) criteria (NCEP-ATP III, P=0.001; IDF, P<0.001; WHO, P=0.029). The multiple regression analysis between intima-media thickness (IMT) and clinical values showed that basal C-peptide significantly correlated with IMT (P=0.043), while the analysis between the 10-year coronary heart disease risk by the United Kingdom Prospective Diabetes Study risk engine and clinical values showed that basal C-peptide did not correlate with IMT (P=0.226).

Conclusion

Basal C-peptide is related to cardiovascular predictors (IMT) of T2DM, suggesting that basal C-peptide does provide a further indication of cardiovascular disease.

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Biomarker potential of C-peptide for screening of insulin resistance in diabetic and non-diabetic individuals
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Saudi Journal of Biological Sciences.2018; 25(8): 1729. CrossRef
SERUM C-PEPTIDE LEVEL IN OBESE AND NON-OBESE PATIENTS WITH TYPE 2 DIABETES MELLITUS
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Hemolysis Affects C‐Peptide Immunoassay
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C-Peptide Is Independently Associated with an Increased Risk of Coronary Artery Disease in T2DM Subjects: A Cross-Sectional Study
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C-peptide as a risk factor of coronary artery disease in the general population
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Susan Costantini, Francesca Capone, Eliana Guerriero, Raffaele Marfella, Angela Sorice, Patrizia Maio, Michele Di Stasio, Giuseppe Paolisso, Giuseppe Castello, Giovanni Colonna, Patricia Fitzgerald-Bocarsly
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Serum glycated albumin predicts the progression of carotid arterial atherosclerosis
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Diabetes & Metabolism Journal.2011; 35(2): 188. CrossRef
Response: Basal C-peptide Level as a Surrogate Marker of Subclinical Atherosclerosis in Type 2 Diabetic Patients (Diabetes Metab J 2011;35:41-9)
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