Diabetes & Metabolism Journal

Original Articles

Metabolic Risk/Epidemiology
2023 Diabetic Kidney Disease Fact Sheet in Korea: Nam Hoon Kim, Mi-Hae Seo, Jin Hyung Jung, Kyung Do Han, Mi Kyung Kim, Nan Hee Kim, on Behalf of Diabetic Kidney Disease Research Group of the Korean Diabetes Association; Received July 30, 2023 Accepted January 26, 2024 Published online March 19, 2024; DOI: https://doi.org/10.4093/dmj.2023.0310 [Epub ahead of print]

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Background
To investigate the prevalence, incidence, comorbidities, and management status of diabetic kidney disease (DKD) and diabetes-related end-stage kidney disease (ESKD) in South Korea.
Methods
We used the Korea National Health and Nutrition Examination Survey data (2019 to 2021, n=2,665) for the evaluation of prevalence, comorbidities, control rate of glycemia and comorbidities in DKD, and the Korean Health Insurance Service-customized database (2008 to 2019, n=3,950,857) for the evaluation of trends in the incidence and prevalence rate of diabetes-related ESKD, renin-angiotensin system (RAS) blockers and sodium glucose cotransporter 2 (SGLT2) inhibitors use for DKD, and the risk of atherosclerotic cardiovascular disease (ASCVD) and mortality according to DKD stages. DKD was defined as albuminuria or low estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² in patients with diabetes mellitus.
Results
The prevalence of DKD was 25.4% (albuminuria, 22.0%; low eGFR, 6.73%) in patients with diabetes mellitus aged ≥30 years. Patients with DKD had a higher rate of comorbidities, including hypertension, dyslipidemia, and central obesity; however, their control rates were lower than those without DKD. Prescription rate of SGLT2 inhibitors with reduced eGFR increased steadily, reaching 5.94% in 2019. Approximately 70% of DKD patients were treated with RAS blockers. The prevalence rate of diabetesrelated ESKD has been steadily increasing, with a higher rate in older adults. ASCVD and mortality were significantly associated with an in increase in DKD stage.
Conclusion
DKD is prevalent among Korean patients with diabetes and is an independent risk factor for cardiovascular morbidity and mortality, which requiring intensive management of diabetes and comorbidities. The prevalence of diabetes-related ESKD has been increasing, especially in the older adults, during past decade.

Citations

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Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes
Karin A. M. Jandeleit-Dahm, Haritha R. Kankanamalage, Aozhi Dai, Jaroslawna Meister, Sara Lopez-Trevino, Mark E. Cooper, Rhian M. Touyz, Christopher R. J. Kennedy, Jay C. Jha
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Cardiovascular Risk/Epidemiology
Two-Year Changes in Diabetic Kidney Disease Phenotype and the Risk of Heart Failure: A Nationwide Population-Based Study in Korea: Seung Eun Lee, Juhwan Yoo, Han Seok Choi, Kyungdo Han, Kyoung-Ah Kim; Diabetes Metab J. 2023;47(4):523-534. Published online April 25, 2023; DOI: https://doi.org/10.4093/dmj.2022.0096

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Abstract PDF Supplementary Material PubReader ePub: Background
Diabetic kidney disease (DKD) is a risk factor for hospitalization for heart failure (HHF). DKD could be classified into four phenotypes by estimated glomerular filtration rate (eGFR, normal vs. low) and proteinuria (PU, negative vs. positive). Also, the phenotype often changes dynamically. This study examined HHF risk according to the DKD phenotype changes across 2-year assessments.
Methods
The study included 1,343,116 patients with type 2 diabetes mellitus (T2DM) from the Korean National Health Insurance Service database after excluding a very high-risk phenotype (eGFR <30 mL/min/1.73 m2) at baseline, who underwent two cycles of medical checkups between 2009 and 2014. From the baseline and 2-year eGFR and PU results, participants were divided into 10 DKD phenotypic change categories.
Results
During an average of 6.5 years of follow-up, 7,874 subjects developed HHF. The cumulative incidence of HHF from index date was highest in the eGFR^lowPU– phenotype, followed by eGFR^norPU⁺ and eGFR^norPU^–. Changes in DKD phenotype differently affect HHF risk. When the persistent eGFR^norPU^– category was the reference, hazard ratios for HHF were 3.10 (95% confidence interval [CI], 2.73 to 3.52) in persistent eGFR^norPU⁺ and 1.86 (95% CI, 1.73 to 1.99) in persistent eGFR^lowPU^–. Among altered phenotypes, the category converted to eGFR^lowPU⁺ showed the highest risk. In the normal eGFR category at the second examination, those who converted from PU^– to PU⁺ showed a higher risk of HHF than those who converted from PU⁺ to PU^–.
Conclusion
Changes in DKD phenotype, particularly with the presence of PU, are more likely to reflect the risk of HHF, compared with DKD phenotype based on a single time point in patients with T2DM.

Review

Complications
Pathophysiologic Mechanisms and Potential Biomarkers in Diabetic Kidney Disease: Chan-Young Jung, Tae-Hyun Yoo; Diabetes Metab J. 2022;46(2):181-197. Published online March 24, 2022; DOI: https://doi.org/10.4093/dmj.2021.0329

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Although diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease eventually requiring chronic kidney replacement therapy, the prevalence of DKD has failed to decline over the past 30 years. In order to reduce disease prevalence, extensive research has been ongoing to improve prediction of DKD onset and progression. Although the most commonly used markers of DKD are albuminuria and estimated glomerular filtration rate, their limitations have encouraged researchers to search for novel biomarkers that could improve risk stratification. Considering that DKD is a complex disease process that involves several pathophysiologic mechanisms such as hyperglycemia induced inflammation, oxidative stress, tubular damage, eventually leading to kidney damage and fibrosis, many novel biomarkers that capture one specific mechanism of the disease have been developed. Moreover, the increasing use of high-throughput omic approaches to analyze biological samples that include proteomics, metabolomics, and transcriptomics has emerged as a strong tool in biomarker discovery. This review will first describe recent advances in the understanding of the pathophysiology of DKD, and second, describe the current clinical biomarkers for DKD, as well as the current status of multiple potential novel biomarkers with respect to protein biomarkers, proteomics, metabolomics, and transcriptomics.

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Original Articles

Type 1 Diabetes
Association between Metabolic Syndrome and Microvascular Complications in Chinese Adults with Type 1 Diabetes Mellitus: Qianwen Huang, Daizhi Yang, Hongrong Deng, Hua Liang, Xueying Zheng, Jinhua Yan, Wen Xu, Xiangwen Liu, Bin Yao, Sihui Luo, Jianping Weng; Diabetes Metab J. 2022;46(1):93-103. Published online August 31, 2021; DOI: https://doi.org/10.4093/dmj.2020.0240

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Background
Both type 1 diabetes mellitus (T1DM) and metabolic syndrome (MetS) are associated with an elevated risk of morbidity and mortality yet with increasing heterogeneity. This study primarily aimed to evaluate the prevalence of MetS among adult patients with T1DM in China and investigate its associated risk factors, and relationship with microvascular complications.
Methods
We included adult patients who had been enrolled in the Guangdong T1DM Translational Medicine Study conducted from June 2010 to June 2015. MetS was defined according to the updated National Cholesterol Education Program criterion. Logistic regression models were used to estimate the odds ratio (OR) for the association between MetS and the risk of diabetic kidney disease (DKD) and diabetic retinopathy (DR).
Results
Among the 569 eligible patients enrolled, the prevalence of MetS was 15.1%. While female gender, longer diabetes duration, higher body mass index, and glycosylated hemoglobin A1c (HbA1c) were risk factors associated with MetS (OR, 2.86, 1.04, 1.14, and 1.23, respectively), received nutrition therapy education was a protective factor (OR, 0.46). After adjustment for gender, age, diabetes duration, HbA1c, socioeconomic and lifestyle variables, MetS status was associated with an increased risk of DKD and DR (OR, 2.14 and 3.72, respectively; both P<0.05).
Conclusion
Although the prevalence of MetS in adult patients with T1DM in China was relatively low, patients with MetS were more likely to have DKD and DR. A comprehensive management including lifestyle modification might reduce their risk of microvascular complications in adults with T1DM.

Citations

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Prevalence of Metabolic Syndrome and Its Risk Factors Influence on Microvascular Complications in Patients With Type 1 and Type 2 Diabetes Mellitus
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Association between Metabolic Syndrome and Microvascular Complications in Chinese Adults with Type 1 Diabetes Mellitus (Diabetes Metab J 2022;46:93-103)
Qianwen Huang, Sihui Luo
Diabetes & Metabolism Journal.2022; 46(3): 515. CrossRef
Association between Metabolic Syndrome and Microvascular Complications in Chinese Adults with Type 1 Diabetes Mellitus (Diabetes Metab J 2022;46:93-103)
Gyuri Kim
Diabetes & Metabolism Journal.2022; 46(3): 512. CrossRef
Metabolic syndrome associated with higher glycemic variability in type 1 diabetes: A multicenter cross-sectional study in china
Keyu Guo, Liyin Zhang, Jianan Ye, Xiaohong Niu, Hongwei Jiang, Shenglian Gan, Jian Zhou, Lin Yang, Zhiguang Zhou
Frontiers in Endocrinology.2022;[Epub] CrossRef

Basic Research
Sulforaphane Ameliorates Diabetes-Induced Renal Fibrosis through Epigenetic Up-Regulation of BMP-7: Lili Kong, Hongyue Wang, Chenhao Li, Huiyan Cheng, Yan Cui, Li Liu, Ying Zhao; Diabetes Metab J. 2021;45(6):909-920. Published online June 4, 2021; DOI: https://doi.org/10.4093/dmj.2020.0168

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Background
The dietary agent sulforaphane (SFN) has been reported to reduce diabetes-induced renal fibrosis, as well as inhibit histone deacetylase (HDAC) activity. Bone morphologic protein 7 (BMP-7) has been shown to reduce renal fibrosis induced by transforming growth factor-beta1. The aim of this study was to investigate the epigenetic effect of SFN on BMP-7 expression in diabetes-induced renal fibrosis.
Methods
Streptozotocin (STZ)-induced diabetic mice and age-matched controls were subcutaneously injected with SFN or vehicle for 4 months to measure the in vivo effects of SFN on the kidneys. The human renal proximal tubular (HK11) cell line was used to mimic diabetic conditions in vitro. HK11 cells were transfected to over-express HDAC2 and treated with high glucose/palmitate (HG/Pal) to explore the epigenetic modulation of BMP-7 in SFN-mediated protection against HG/Pal-induced renal fibrosis.
Results
SFN significantly attenuated diabetes-induced renal fibrosis in vivo. Among all of the HDACs we detected, HDAC2 activity was markedly elevated in the STZ-induced diabetic kidneys and HG/Pal-treated HK11 cells. SFN inhibited the diabetes-induced increase in HDAC2 activity which was associated with histone acetylation and transcriptional activation of the BMP-7 promoter. HDAC2 over-expression reduced BMP-7 expression and abolished the SFN-mediated protection against HG/Pal-induced fibrosis in vitro.
Conclusion
Our study demonstrates that the HDAC inhibitor SFN protects against diabetes-induced renal fibrosis through epigenetic up-regulation of BMP-7.

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Mengjiao Wang, Min Chen, Rui Guo, Yangyang Ding, Haihui Zhang, Yuanqing He
Trends in Food Science & Technology.2022; 129: 397. CrossRef
Defining therapeutic targets for renal fibrosis: Exploiting the biology of pathogenesis
Hao Yan, Jiangxin Xu, Zhifei Xu, Bo Yang, Peihua Luo, Qiaojun He
Biomedicine & Pharmacotherapy.2021; 143: 112115. CrossRef

Complications
Screening Tools Based on Nomogram for Diabetic Kidney Diseases in Chinese Type 2 Diabetes Mellitus Patients: Ganyi Wang, Biyao Wang, Gaoxing Qiao, Hao Lou, Fei Xu, Zhan Chen, Shiwei Chen; Diabetes Metab J. 2021;45(5):708-718. Published online April 13, 2021; DOI: https://doi.org/10.4093/dmj.2020.0117

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Background
The influencing factors of diabetic kidney disease (DKD) in Chinese patients with type 2 diabetes mellitus (T2DM) were explored to develop and validate a DKD diagnostic tool based on nomogram approach for patients with T2DM.
Methods
A total of 2,163 in-hospital patients with diabetes diagnosed from March 2015 to March 2017 were enrolled. Specified logistic regression models were used to screen the factors and establish four different diagnostic tools based on nomogram according to the final included variables. Discrimination and calibration were used to assess the performance of screening tools.
Results
Among the 2,163 participants with diabetes (1,227 men and 949 women), 313 patients (194 men and 120 women) were diagnosed with DKD. Four different screening equations (full model, laboratory-based model 1 [LBM1], laboratory-based model 2 [LBM2], and simplified model) showed good discriminations and calibrations. The C-indexes were 0.8450 (95% confidence interval [CI], 0.8202 to 0.8690) for full model, 0.8149 (95% CI, 0.7892 to 0.8405) for LBM1, 0.8171 (95% CI, 0.7912 to 0.8430) for LBM2, and 0.8083 (95% CI, 0.7824 to 0.8342) for simplified model. According to Hosmer-Lemeshow goodness-of-fit test, good agreement between the predicted and observed DKD events in patients with diabetes was observed for full model (χ²=3.2756, P=0.9159), LBM1 (χ²=7.749, P=0.4584), LBM2 (χ²=10.023, P=0.2634), and simplified model (χ²=12.294, P=0.1387).
Conclusion
LBM1, LBM2, and simplified model exhibited excellent predictive performance and availability and could be recommended for screening DKD cases among Chinese patients with diabetes.

Citations

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Development of Serum Lactate Level-Based Nomograms for Predicting Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients
Chunxia Jiang, Xiumei Ma, Jiao Chen, Yan Zeng, Man Guo, Xiaozhen Tan, Yuping Wang, Peng Wang, Pijun Yan, Yi Lei, Yang Long, Betty Yuen Kwan Law, Yong Xu
Diabetes, Metabolic Syndrome and Obesity.2024; Volume 17: 1051. CrossRef
Changes in urinary exosomal protein CALM1 may serve as an early noninvasive biomarker for diagnosing diabetic kidney disease
Tao Li, Tian ci Liu, Na Liu, Man Zhang
Clinica Chimica Acta.2023; 547: 117466. CrossRef
Developing screening tools to estimate the risk of diabetic kidney disease in patients with type 2 diabetes mellitus
Xu Cao, Xiaomei Pei
Technology and Health Care.2023; : 1. CrossRef
Development and validation of a novel nomogram to predict diabetic kidney disease in patients with type 2 diabetic mellitus and proteinuric kidney disease
Hui Zhuan Tan, Jason Chon Jun Choo, Stephanie Fook-Chong, Yok Mooi Chin, Choong Meng Chan, Chieh Suai Tan, Keng Thye Woo, Jia Liang Kwek
International Urology and Nephrology.2022; 55(1): 191. CrossRef
Nomogram-Based Chronic Kidney Disease Prediction Model for Type 1 Diabetes Mellitus Patients Using Routine Pathological Data
Nakib Hayat Chowdhury, Mamun Bin Ibne Reaz, Sawal Hamid Md Ali, Shamim Ahmad, María Liz Crespo, Andrés Cicuttin, Fahmida Haque, Ahmad Ashrif A. Bakar, Mohammad Arif Sobhan Bhuiyan
Journal of Personalized Medicine.2022; 12(9): 1507. CrossRef
Development and assessment of diabetic nephropathy prediction model using hub genes identified by weighted correlation network analysis
Xuelian Zhang, Yao Wang, Zhaojun Yang, Xiaoping Chen, Jinping Zhang, Xin Wang, Xian Jin, Lili Wu, Xiaoyan Xing, Wenying Yang, Bo Zhang
Aging.2022; 14(19): 8095. CrossRef

Complications
Associations of Plasma Glucagon Levels with Estimated Glomerular Filtration Rate, Albuminuria and Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus: Hua-Xing Huang, Liang-Lan Shen, Hai-Yan Huang, Li-Hua Zhao, Feng Xu, Dong-Mei Zhang, Xiu-Lin Zhang, Tong Chen, Xue-Qin Wang, Yan Xie, Jian-Bin Su; Diabetes Metab J. 2021;45(6):868-879. Published online March 23, 2021; DOI: https://doi.org/10.4093/dmj.2020.0149

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Background
Type 2 diabetes mellitus (T2DM) is characterized by elevated fasting glucagon and impaired suppression of postprandial glucagon secretion, which may participate in diabetic complications. Therefore, we investigated the associations of plasma glucagon with estimated glomerular filtration rate (eGFR), albuminuria and diabetic kidney disease (DKD) in T2DM patients.
Methods
Fasting glucagon and postchallenge glucagon (assessed by area under the glucagon curve [AUC_gla]) levels were determined during oral glucose tolerance tests. Patients with an eGFR <60 mL/min/1.73 m² and/or a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g who presented with diabetic retinopathy were identified as having DKD.
Results
Of the 2,436 recruited patients, fasting glucagon was correlated with eGFR and UACR (r=–0.112 and r=0.157, respectively; P<0.001), and AUC_gla was also correlated with eGFR and UACR (r=–0.267 and r=0.234, respectively; P<0.001). Moreover, 31.7% (n=771) presented with DKD; the prevalence of DKD was 27.3%, 27.6%, 32.5%, and 39.2% in the first (Q1), second (Q2), third (Q3), and fourth quartile (Q4) of fasting glucagon, respectively; and the corresponding prevalence for AUC_gla was 25.9%, 22.7%, 33.7%, and 44.4%, respectively. Furthermore, after adjusting for other clinical covariates, the adjusted odds ratios (ORs; 95% confidence intervals) for DKD in Q2, Q3, and Q4 versus Q1 of fasting glucagon were 0.946 (0.697 to 1.284), 1.209 (0.895 to 1.634), and 1.521 (1.129 to 2.049), respectively; the corresponding ORs of AUC_gla were 0.825 (0.611 to 1.114), 1.323 (0.989 to 1.769), and 2.066 (1.546 to 2.760), respectively. Additionally, when we restricted our analysis in patients with glycosylated hemoglobin <7.0% (n=471), we found fasting glucagon and AUC_gla were still independently associated with DKD.
Conclusion
Both increased fasting and postchallenge glucagon levels were independently associated with DKD in T2DM patients.

Citations

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Glucagon in type 2 diabetes: Friend or foe?
Irene Caruso, Nicola Marrano, Giuseppina Biondi, Valentina Annamaria Genchi, Rossella D'Oria, Gian Pio Sorice, Sebastio Perrini, Angelo Cignarelli, Annalisa Natalicchio, Luigi Laviola, Francesco Giorgino
Diabetes/Metabolism Research and Reviews.2023;[Epub] CrossRef

Complications
Association of Urinary N-Acetyl-β-D-Glucosaminidase with Cardiovascular Autonomic Neuropathy in Type 1 Diabetes Mellitus without Nephropathy: Min Sun Choi, Ji Eun Jun, Sung Woon Park, Jee Hee Yoo, Jiyeon Ahn, Gyuri Kim, Sang-Man Jin, Kyu Yeon Hur, Moon-Kyu Lee, Jae Hyeon Kim; Diabetes Metab J. 2021;45(3):349-357. Published online February 2, 2021; DOI: https://doi.org/10.4093/dmj.2019.0211

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Background
Cardiovascular autonomic neuropathy (CAN) is a common microvascular complication of diabetes and related to albuminuria in diabetic nephropathy (DN). Urinary N-acetyl-β-D-glucosaminidase (uNAG) is a renal tubular injury marker which has been reported as an early marker of DN even in patients with normoalbuminuria. This study evaluated whether uNAG is associated with the presence and severity of CAN in patients with type 1 diabetes mellitus (T1DM) without nephropathy.
Methods
This cross-sectional study comprised 247 subjects with T1DM without chronic kidney disease and albuminuria who had results for both uNAG and autonomic function tests within 3 months. The presence of CAN was assessed by age-dependent reference values for four autonomic function tests. Total CAN score was assessed as the sum of the partial points of five cardiovascular reflex tests and was used to estimatethe severity of CAN. The correlations between uNAG and heart rate variability (HRV) parameters were analyzed.
Results
The association between log-uNAG and presence of CAN was significant in a multivariate logistic regression model (adjusted odds ratio, 2.39; 95% confidence interval [CI], 1.08 to 5.28; P=0.031). Total CAN score was positively associated with loguNAG (β=0.261, P=0.026) in the multivariate linear regression model. Log-uNAG was inversely correlated with frequency-domain and time-domain indices of HRV.
Conclusion
This study verified the association of uNAG with presence and severity of CAN and changes in HRV in T1DM patients without nephropathy. The potential role of uNAG should be further assessed for high-risk patients for CAN in T1DM patients without nephropathy.

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Determination of Diabetes-associated Cardiovascular Autonomic Neuropathy Risk Factors among Insulin and Non-insulin Dependent Diabetics
Ibrahim Abdulsada, Zain Alabdeen Obaid, Farah Almerza, Mays Alwaeli, Anmar Al-Elayawi, Taha Al-Dayyeni, Harir Al-Tuhafy
The Journal of Medical Research.2023; 9(6): 141. CrossRef
Association between carotid atherosclerosis and presence of intracranial atherosclerosis using three-dimensional high-resolution vessel wall magnetic resonance imaging in asymptomatic patients with type 2 diabetes
Ji Eun Jun, You-Cheol Hwang, Kyu Jeong Ahn, Ho Yeon Chung, Geon-Ho Jahng, Soonchan Park, In-Kyung Jeong, Chang-Woo Ryu
Diabetes Research and Clinical Practice.2022; 191: 110067. CrossRef

Review

Complications
Treatment of Diabetic Kidney Disease: Current and Future: Tomotaka Yamazaki, Imari Mimura, Tetsuhiro Tanaka, Masaomi Nangaku; Diabetes Metab J. 2021;45(1):11-26. Published online January 22, 2021; DOI: https://doi.org/10.4093/dmj.2020.0217

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Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. However, only renin-angiotensin system inhibitor with multidisciplinary treatments is effective for DKD. In 2019, sodium-glucose cotransporter 2 (SGLT2) inhibitor showed efficacy against DKD in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, adding a new treatment option. However, the progression of DKD has not been completely controlled. The patients with transient exposure to hyperglycemia develop diabetic complications, including DKD, even after normalization of their blood glucose. Temporary hyperglycemia causes advanced glycation end product (AGE) accumulations and epigenetic changes as metabolic memory. The drugs that improve metabolic memory are awaited, and AGE inhibitors and histone modification inhibitors are the focus of clinical and basic research. In addition, incretin-related drugs showed a renoprotective ability in many clinical trials, and these trials with renal outcome as their primary endpoint are currently ongoing. Hypoxia-inducible factor prolyl hydroxylase inhibitors recently approved for renal anemia may be renoprotective since they improve tubulointerstitial hypoxia. Furthermore, NF-E2–related factor 2 activators improved the glomerular filtration rate of DKD patients in Bardoxolone Methyl Treatment: Renal Function in chronic kidney disease/Type 2 Diabetes (BEAM) trial and Phase II Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI) trial. Thus, following SGLT2 inhibitor, numerous novel drugs could be utilized in treating DKD. Future studies are expected to provide new insights.

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Original Articles

Complications
Serum Levels of Adipocyte Fatty Acid-Binding Protein Are Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes Mellitus and Preserved Renal Function: Da Hea Seo, Moonsuk Nam, Mihye Jung, Young Ju Suh, Seong Hee Ahn, Seongbin Hong, So Hun Kim; Diabetes Metab J. 2020;44(6):875-886. Published online July 10, 2020; DOI: https://doi.org/10.4093/dmj.2019.0221

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Background

Recent studies have demonstrated that the levels of adipocyte fatty acid-binding protein (A-FABP) are closely associated with diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). This study aimed to examine the association between serum A-FABP level and rapid renal function decline in patients with T2DM and preserved renal function.

Methods

This was a prospective observational study of 452 patients with T2DM and preserved renal function who had serial measurements of estimated glomerular filtration rate (eGFR). Rapid renal function decline was defined as an eGFR decline of >4% per year. The association between baseline serum A-FABP level and rapid renal function decline was investigated.

Results

Over a median follow-up of 7 years, 82 participants (18.1%) experienced rapid renal function decline. Median A-FABP levels were significantly higher in patients with rapid renal function decline, compared to non-decliners (20.2 ng/mL vs. 17.2 ng/mL, P=0.005). A higher baseline level of A-FABP was associated with a greater risk of developing rapid renal function decline, independent of age, sex, duration of diabetes, body mass index, systolic blood pressure, history of cardiovascular disease, baseline eGFR, urine albumin creatinine ratio, total cholesterol, glycosylated hemoglobin, high-sensitivity C-reactive protein and use of thiazolidinedione, insulin, angiotensin-converting-enzyme inhibitors and angiotensin II-receptor blockers and statin (odds ratio, 3.10; 95% confidence interval, 1.53 to 6.29; P=0.002).

Conclusion

A high level of serum A-FABP is associated with an increased risk of rapid renal function decline in patients with T2DM and preserved renal function. This suggests that A-FABP could play a role in the progression of DKD in the early stages.

Citations

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Serum fatty acid-binding protein 4 as a biomarker for early detection of diabetic nephropathy in type 2 diabetes
Amr M. Shaker, Maggie E. Mohamed, Tarek Ramzy, Mayssa I. Ali
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Circulating thrombospondin-2 level for identifying individuals with rapidly declining kidney function trajectory in type 2 diabetes: a prospective study of the Hong Kong West Diabetes Registry
Chi-Ho Lee, David Tak-Wai Lui, Chloe Yu-Yan Cheung, Carol Ho-Yi Fong, Michele Mae-Ann Yuen, Wing-Sun Chow, Aimin Xu, Karen Siu-Ling Lam
Nephrology Dialysis Transplantation.2023;[Epub] CrossRef
Analysis of inflammatory cytokines and estimated glomerular filtration rate decline in Japanese patients with diabetic kidney disease: a pilot study
Yuka Sugawara, Yosuke Hirakawa, Koki Mise, Kosuke Kashiwabara, Ko Hanai, Satoshi Yamaguchi, Akihiro Katayama, Yasuhiro Onishi, Yui Yoshida, Naoki Kashihara, Yutaka Matsuyama, Tetsuya Babazono, Masaomi Nangaku, Jun Wada
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Serum Adipocyte Fatty-Acid Binding Protein as an Independent Marker of Peripheral Artery Disease in Patients with Type-2 Diabetes Mellitus
Bang-Gee Hsu, Chin-Yee Mah, Du-An Wu, Ming-Chun Chen
International Journal of Environmental Research and Public Health.2022; 19(15): 9459. CrossRef
Fatty acid-binding protein 4 in kidney diseases: From mechanisms to clinics
Weijing Lai, Min Shi, Rongshuang Huang, Ping Fu, Liang Ma
European Journal of Pharmacology.2022; 931: 175224. CrossRef
Serum fatty acid-binding protein 4 levels and responses of pancreatic islet β-cells and α-cells in patients with type 2 diabetes
Hong Wang, Jie Cao, Jian-bin Su, Xue-qin Wang, Xing Wang, Dong-mei Zhang, Xiao-hua Wang
Diabetology & Metabolic Syndrome.2021;[Epub] CrossRef
The Low-Expression Variant of FABP4 Is Associated With Cardiovascular Disease in Type 1 Diabetes
Emma H. Dahlström, Jani Saksi, Carol Forsblom, Nicoline Uglebjerg, Nina Mars, Lena M. Thorn, Valma Harjutsalo, Peter Rossing, Tarunveer S. Ahluwalia, Perttu J. Lindsberg, Niina Sandholm, Per-Henrik Groop
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White adipocyte-targeted dual gene silencing of FABP4/5 for anti-obesity, anti-inflammation and reversal of insulin resistance: Efficacy and comparison of administration routes
Jee Young Chung, Juhyeong Hong, Hyung-Jin Kim, Yoonsung Song, Seok-Beom Yong, Jieun Lee, Yong-Hee Kim
Biomaterials.2021; 279: 121209. CrossRef

Type 1 Diabetes
Age at Diagnosis and the Risk of Diabetic Nephropathy in Young Patients with Type 1 Diabetes Mellitus: Jong Ha Baek, Woo Je Lee, Byung-Wan Lee, Soo Kyoung Kim, Gyuri Kim, Sang-Man Jin, Jae Hyeon Kim; Diabetes Metab J. 2021;45(1):46-54. Published online July 10, 2020; DOI: https://doi.org/10.4093/dmj.2019.0134

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Background

The aim of this study was to evaluate characteristics and risk of diabetic complications according to age at diagnosis among young adults with type 1 diabetes mellitus (T1DM).

Methods

A total of 255 T1DM patients aged less than 40 years were included. Patients were categorized into three groups (<20, 20 to 29, and 30 to 40 years) according to age at diagnosis. Diabetic nephropathy (DN) was defined when spot urine-albumin creatinine ratio was 300 mg/g or more and/or estimated glomerular filtration ratio (eGFR) level was 60 mL/min/1.73 m² or less.

Results

Median age at diagnosis was 25 years and disease duration was 14 years. Individuals diagnosed with T1DM at childhood/adolescent (age <20 years) had lower stimulated C-peptide levels. They received more intensive insulin treatment with higher total daily insulin doses compared to older onset groups. The prevalence of DN was higher in the childhood/adolescent-onset group than in older onset groups (25.3% vs. 15.3% vs. 9.6%, P=0.022). The eGFR was inversely associated with disease duration whilst the degree of decrease was more prominent in the childhood/adolescent-onset group than in the later onset group (aged 30 to 40 years; P<0.001). Childhood/adolescent-onset group was independently associated with the risk of DN compared to the older onset group (aged 30 to 40 years; odds ratio, 3.47; 95% confidence interval, 1.45 to 8.33; P=0.005).

Conclusion

In individuals with childhood/adolescent-onset T1DM, the reduction in renal function is more prominent with disease duration. Early age-onset T1DM is an independent risk of DN.

Citations

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Age at onset of type 1 diabetes between puberty and 30 years old is associated with increased diabetic nephropathy risk
Yen-Bo Lin, Wayne Huey-Herng Sheu, Su-Huey Lo, Yen-Po Yeh, Chien-Ning Huang, Chii-Min Hwu, Chang-Hsun Hsieh, Horng-Yi Ou, Lee-Ming Chuang, Jung-Fu Chen, Yu-Cheng Chen, Yun-Hsing Peng, Szu-Tah Chen, Shang-Ren Hsu, Yi-Ling Hsieh, Chih-Hsun Chu, Chieg-Hsiang
Scientific Reports.2024;[Epub] CrossRef
Targeted mapping and utilization of the perihepatic surface for therapeutic beta cell replacement and retrieval in diabetic non-human primates
David J. Leishman, Scott H. Oppler, Laura L. Hocum Stone, Timothy D. O’Brien, Sabarinathan Ramachandran, Bradley J. Willenberg, Andrew B. Adams, Bernhard J. Hering, Melanie L. Graham
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Comparison between a tubeless, on-body automated insulin delivery system and a tubeless, on-body sensor-augmented pump in type 1 diabetes: a multicentre randomised controlled trial
Ji Yoon Kim, Sang-Man Jin, Eun Seok Kang, Soo Heon Kwak, Yeoree Yang, Jee Hee Yoo, Jae Hyun Bae, Jun Sung Moon, Chang Hee Jung, Ji Cheol Bae, Sunghwan Suh, Sun Joon Moon, Sun Ok Song, Suk Chon, Jae Hyeon Kim
Diabetologia.2024;[Epub] CrossRef
Continuous glucose monitoring with structured education in adults with type 2 diabetes managed by multiple daily insulin injections: a multicentre randomised controlled trial
Ji Yoon Kim, Sang-Man Jin, Kang Hee Sim, Bo-Yeon Kim, Jae Hyoung Cho, Jun Sung Moon, Soo Lim, Eun Seok Kang, Cheol-Young Park, Sin Gon Kim, Jae Hyeon Kim
Diabetologia.2024;[Epub] CrossRef
Network-based identification and prioritization of key transcriptional factors of diabetic kidney disease
Ikhlak Ahmed, Mubarak Ziab, Sahar Da’as, Waseem Hasan, Sujitha P. Jeya, Elbay Aliyev, Sabah Nisar, Ajaz A. Bhat, Khalid Adnan Fakhro, Ammira S. Alshabeeb Akil
Computational and Structural Biotechnology Journal.2023; 21: 716. CrossRef
Comparison of diabetes distress and depression screening results of emerging adults with type 1 diabetes onset at different ages: findings from the German early-onset T1D study and the German Diabetes Study (GDS)
Anna Stahl-Pehe, Christina Bächle, Kálmán Bódis, Oana-Patricia Zaharia, Karin Lange, Reinhard W. Holl, Michael Roden, Joachim Rosenbauer, M. Roden, H. Al-Hasani, B Belgardt, GJ. Bönhof, V Burkart, A. E. Buyken, G. Geerling, C. Herder, A. Icks, K. Jandelei
Diabetology & Metabolic Syndrome.2023;[Epub] CrossRef
Hemoperfusion and functional state of the macula after simultaneous pancreas and kidney transplantation
IV Vorobyeva, EV Bulava, LK Moshetova, AV Pinchuk
Bulletin of Russian State Medical University.2022;[Epub] CrossRef
Sigesbeckia orientalis Extract Ameliorates the Experimental Diabetic Nephropathy by Downregulating the Inflammatory and Oxidative Stress Signaling Pathways
Chung-Ming Chen, Jer-Yiing Houng, Tsui-Ling Ko, Shu-Hui Juan, Hsiu-Chu Chou, Xing Li
Evidence-Based Complementary and Alternative Medicine.2022; 2022: 1. CrossRef
Impact of low-protein diet on cardiovascular risk factors and kidney function in diabetic nephropathy: A systematic review and meta-analysis of randomized-controlled trials
Mohammad Hassan Sohouli, Parvin Mirmiran, Shaikh Sanjid Seraj, Emad Kutbi, Hadil Ali Mohammed Alkahmous, Faisal Almuqayyid, Omar Ahnaf Arafah, Abdul Rahman Riad Barakeh, Ahmed Abu-Zaid
Diabetes Research and Clinical Practice.2022; 191: 110068. CrossRef
Age at Diagnosis and the Risk of Diabetic Nephropathy in Young Patients with Type 1 Diabetes Mellitus (Diabetes Metab J 2021;45:46-54)
Jong Ha Baek, Jae Hyeon Kim
Diabetes & Metabolism Journal.2021; 45(2): 281. CrossRef
Age at Diagnosis and the Risk of Diabetic Nephropathy in Young Patients with Type 1 Diabetes Mellitus (Diabetes Metab J 2021;45:46-54)
Ye Seul Yang, Tae Seo Sohn
Diabetes & Metabolism Journal.2021; 45(2): 277. CrossRef
Role of magnetic resonance diffusion weighted imaging in diagnosis of diabetic nephropathy in children living with type 1 diabetes mellitus
Eman Nabil Wahba, Ashraf Elsharkawy, Mohammad Hosny Awad, Ashraf Abdel Rahman, Amr Sarhan
Journal of Pediatric Endocrinology and Metabolism.2021; 34(12): 1585. CrossRef

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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Wenhui Zhong, Yuheng Jiang, Huizhen Wang, Xiang Luo, Tao Zeng, Huimi Huang, Ling Xiao, Nan Jia, Aiqing Li
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Urinary Excretion of Biomolecules Related to Cell Cycle, Proliferation, and Autophagy in Subjects with Type 2 Diabetes and Chronic Kidney Disease
Anton I. Korbut, Vyacheslav V. Romanov, Vadim V. Klimontov
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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
FGF21 and Chronic Kidney Disease
João Victor Salgado, Miguel Angelo Goes, Natalino Salgado Filho
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The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy
Junyu Deng, Ye Liu, Yiqiu Liu, Wei Li, Xuqiang Nie
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Therapeutic effect and mechanism of combined use of FGF21 and insulin on diabetic nephropathy
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Basic Research
Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy: Chang-Yun Woo, Ji Yeon Baek, Ah-Ram Kim, Chung Hwan Hong, Ji Eun Yoon, Hyoun Sik Kim, Hyun Ju Yoo, Tae-Sik Park, Ranjan Kc, Ki-Up Lee, Eun Hee Koh; Diabetes Metab J. 2020;44(4):581-591. Published online November 4, 2019; DOI: https://doi.org/10.4093/dmj.2019.0063

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Background

Ceramides are associated with metabolic complications including diabetic nephropathy in patients with diabetes. Recent studies have reported that podocytes play a pivotal role in the progression of diabetic nephropathy. Also, mitochondrial dysfunction is known to be an early event in podocyte injury. Thus, we tested the hypothesis that ceramide accumulation in podocytes induces mitochondrial damage through reactive oxygen species (ROS) production in patients with diabetic nephropathy.

Methods

We used Otsuka Long Evans Tokushima Fatty (OLETF) rats and high-fat diet (HFD)-fed mice. We fed the animals either a control- or a myriocin-containing diet to evaluate the effects of the ceramide. Also, we assessed the effects of ceramide on intracellular ROS generation and on podocyte autophagy in cultured podocytes.

Results

OLETF rats and HFD-fed mice showed albuminuria, histologic features of diabetic nephropathy, and podocyte injury, whereas myriocin treatment effectively treated these abnormalities. Cultured podocytes exposed to agents predicted to be risk factors (high glucose, high free fatty acid, and angiotensin II in combination [GFA]) showed an increase in ceramide accumulation and ROS generation in podocyte mitochondria. Pretreatment with myriocin reversed GFA-induced mitochondrial ROS generation and prevented cell death. Myriocin-pretreated cells were protected from GFA-induced disruption of mitochondrial integrity.

Conclusion

We showed that mitochondrial ceramide accumulation may result in podocyte damage through ROS production. Therefore, this signaling pathway could become a pharmacological target to abate the development of diabetic kidney disease.

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Complications
Presence of Carotid Plaque Is Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes Mellitus and Normal Renal Function: Da Hea Seo, So Hun Kim, Joon Ho Song, Seongbin Hong, Young Ju Suh, Seong Hee Ahn, Jeong-Taek Woo, Sei Hyun Baik, Yongsoo Park, Kwan Woo Lee, Young Seol Kim, Moonsuk Nam; Diabetes Metab J. 2019;43(6):840-853. Published online March 12, 2019; DOI: https://doi.org/10.4093/dmj.2018.0186

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Abstract PDF Supplementary Material PubReader

Background

Recent evidences indicate that early rapid renal function decline is closely associated with the development and progression of diabetic kidney disease. We have investigated the association between carotid atherosclerosis and rapid renal function decline in patients with type 2 diabetes mellitus and preserved renal function.

Methods

In a prospective, multicenter cohort, a total of 967 patients with type 2 diabetes mellitus and preserved renal function were followed for 6 years with serial estimated glomerular filtration rate (eGFR) measurements. Common carotid intima-media thickness (CIMT) and presence of carotid plaque were assessed at baseline. Rapid renal function decline was defined as an eGFR decline >3.3% per year.

Results

Over a median follow-up of 6 years, 158 participants (16.3%) developed rapid renal function decline. While there was no difference in CIMT, the presence of carotid plaque in rapid decliners was significantly higher than in non-decliners (23.2% vs. 12.2%, P<0.001). In multivariable logistic regression analysis, presence of carotid plaque was an independent predictor of rapid renal function decline (odds ratio, 2.33; 95% confidence interval, 1.48 to 3.68; P<0.0001) after adjustment for established risk factors. The model including the carotid plaque had better performance for discrimination of rapid renal function decline than the model without carotid plaque (area under the receiver operating characteristic curve 0.772 vs. 0.744, P=0.016).

Conclusion

Close monitoring of renal function and early intensive management may be beneficial in patients with type 2 diabetes mellitus and carotid plaques.

Citations

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Response: Presence of Carotid Plaque Is Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes Mellitus and Normal Renal Function (Diabetes Metab J 2019;43:840–53)
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Brief Report

Complications
Effect of Empagliflozin, a Selective Sodium-Glucose Cotransporter 2 Inhibitor, on Kidney and Peripheral Nerves in Streptozotocin-Induced Diabetic Rats: Kyung Ae Lee, Heung Yong Jin, Na Young Lee, Yu Ji Kim, Tae Sun Park; Diabetes Metab J. 2018;42(4):338-342. Published online April 25, 2018; DOI: https://doi.org/10.4093/dmj.2017.0095

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Abstract PDF PubReader

The effect of sodium-glucose cotransporter 2 inhibitors on peripheral nerves and kidneys in diabetes mellitus (DM) remains unexplored. Therefore, this study aimed to explore the effect of empagliflozin in diabetic rats. DM in rats was induced by streptozotocin injection, and diabetic rats were treated with empagliflozin 3 or 10 mg/kg. Following 24-week treatment, response thresholds to four different stimuli were tested and found to be lower in diabetic rats than in normal rats. Empagliflozin significantly prevented hypersensitivity (P<0.05) and the loss of skin intraepidermal nerve fibers, and mesangial matrix expansion in diabetic rats. Results of this study demonstrate the potential therapeutic effects of empagliflozin for the treatment of diabetic peripheral neuropathy and nephropathy.

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