Diabetes & Metabolism Journal

Original Articles

Metabolic Risk/Epidemiology
Obesity Transitions by Age, Period, and Cohort: A Population-Based Application of the Lancet Commission Framework in the United States and Korea: Garam Jo, Dahyun Park, Shieon Kim, Hee Ju Jun, Faidon Magkos, Jordi Merino, Qi Sun, Rockli Kim, S.V. Subramanian, Paul W. Franks, Min-Jeong Shin; Received September 19, 2025 Accepted February 6, 2026 Published online April 10, 2026; DOI: https://doi.org/10.4093/dmj.2025.0918 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
While emerging global classification frameworks highlight the need to redefine obesity beyond body mass index (BMI) to improve prevention strategies and public health policy, population-level applications remain scarce. We examined trends in BMI-based and newly proposed Lancet Commission definitions of obesity in the United States and South Korea, two countries with contrasting obesity trends.
Methods
Using representative data from the United States National Health and Nutrition Examination Survey (NHANES, 2003–2016) and the Korea National Health and Nutrition Examination Survey (KNHANES, 2007–2023), we conducted age-standardized and age-period-cohort (APC) analyses to compare obesity trends.
Results
Newly defined obesity phenotypes demonstrated a greater proportion of at-risk individuals than BMI alone, particularly among United States women and Korean men. Excess adiposity in the United States showed early increases from 55.6% to over 75%, followed by stabilization, while Korea exhibited a sustained upward trend. APC analyses revealed more divergent patterns. These sex-specific patterns align with differences in visceral adiposity by sex and in East Asian populations. Period effects on obesity were characterized by a high and sustained burden in the United States, but a more gradual yet persistent upward trend in Korea. Preclinical obesity displayed a U-shaped cohort effect in the United States, with higher prevalence in cohorts born after 1975, whereas clinical obesity continued to rise in Korea’s recent birth cohorts, especially among men.
Conclusion
Our findings emphasize the utility of expanded obesity definitions and APC analysis in capturing sex-specific and generational patterns of obesity and related complications. They support adopting life-course, cohort-informed approaches in obesity prevention.

Metabolic Risk/Epidemiology
Predictive Models for Type 2 Diabetes Mellitus in Han Chinese with Insights into Cross-Population Applicability and Demographic Specific Risk Factors: Ying-Erh Chen, Djeane Debora Onthoni, Shao-Yuan Chuang, Guo-Hung Li, Yong-Sheng Zhuang, Hung-Yi Chiou, Wayne Huey-Herng Sheu, Ren-Hua Chung; Diabetes Metab J. 2025;49(6):1272-1286. Published online May 21, 2025; DOI: https://doi.org/10.4093/dmj.2024.0319

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Background
The rising global incidence of type 2 diabetes mellitus (T2DM) underscores the need for predictive models that enhance early detection and prevention across diverse populations. This study aimed to identify predictors of incident T2DM within a Han Chinese population, assess their impact across various age and sex demographics, and explore their applicability to European populations.
Methods
Using data from about 65,000 participants in the Taiwan Biobank (TWB), we developed a predictive model, achieving an area under the receiver operating characteristic curve of 90.58%. Key predictors were identified through LASSO regression within the TWB cohort and validated using over 4 million records from Taiwan’s Adult Preventive Healthcare Services (APHS) program and the UK Biobank (UKB).
Results
Our analysis highlighted 13 significant predictors, including established factors like glycosylated hemoglobin (HbA1c) and blood glucose levels, and less conventionally considered variables such as peak expiratory flow. Notable differences in the effects of HbA1c levels and polygenic risk scores between the TWB and UKB cohorts were observed. Additionally, age and sex-specific impacts of these predictors, detailed through APHS data, revealed significant variances; for instance, waist circumference and diagnosed mixed hyperlipidemia showed greater impacts in younger females than in males, while effects remained uniform across male age groups.
Conclusion
Our findings offer novel insights into the diagnosis and management of diabetes for the Han Chinese and potentially for broader East Asian populations, highlighting the importance of ethnic and demographic diversity in developing predictive models for early detection and personalized intervention strategies.

Citations

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Plasminogen activator inhibitor-1, vaspin, and dietary inflammatory index in relation to cardiometabolic health in diabetic women
Sule Kocabas, Nevin Sanlier
Frontiers in Nutrition.2026;[Epub] CrossRef
The Relationship Between High-Density Lipoprotein (HDL) and Glycated Hemoglobin (HbA1C) in Type 2 Diabetes Mellitus Patients: Implications for Cardiovascular Risk
Setyoadi Setyoadi, Dina Dewi Sartika Lestari Ismail, Annisa Wuri Kartika, Dewi Purnama Sari, Angel Dwi Septian, Adelina Stefanie Lallo, Rara Kurniasari
Journal of Rural Community Nursing Practice.2025; 3(2): 234. CrossRef

Pathophysiology
Deficiency of ASGR1 Alleviates Diet-Induced Systemic Insulin Resistance via Improved Hepatic Insulin Sensitivity: Xiaorui Yu, Jiawang Tao, Yuhang Wu, Yan Chen, Penghui Li, Fan Yang, Miaoxiu Tang, Abdul Sammad, Yu Tao, Yingying Xu, Yin-Xiong Li; Diabetes Metab J. 2024;48(4):802-815. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0124

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Background
Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown.
Methods
The constructed ASGR1 knockout mice and ASGR1^-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro.
Results
ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1^-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis.
Conclusion
The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.

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Increased Asialoglycoprotein Receptor 1 Level in Granulosa Cell as a Potential Biomarker for Polycystic Ovary Syndrome
Xitong Liu, Rongxia Xie, Yang Cai, Hui Lan, Jing Mu, Chen Zhang, Bo Li
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Valerie K. Sullivan, Jingsha Chen, Lawrence J. Appel, Sarah Schrauben, Ana C. Ricardo, Panduranga Rao, Mirela Dobre, Nishigandha Pradhan, Jing Chen, Jiang He, Hernan Rincon-Choles, Paul L. Kimmel, Casey M. Rebholz
Clinical Journal of the American Society of Nephrology.2026; 21(4): 553. CrossRef
Serum soluble ASGR1 concentration is elevated in patients with metabolic dysfunction-associated steatotic liver disease and is associated with adiponectin
Jing-Ming Wang, Li-Yan Jiang, Yu-Ting Deng, Jiao-Yang Li, Heng Sun, Li Ran, Xinhua Xiao
BMJ Open Diabetes Research & Care.2026; 14(1): e005638. CrossRef
Association Analysis of the Circulating Proteome With Sarcopenia‐Related Traits Reveals Potential Drug Targets for Sarcopenia
Simin Wen, Siqi Xu, Xizeng Zong, Shifeng Wen, Wende Xiao, Weipeng Zheng, Han Cen, Zhaohua Zhu, Jingyu Xie, Yan Zhang, Changhai Ding, Guangfeng Ruan
Journal of Cachexia, Sarcopenia and Muscle.2025;[Epub] CrossRef
Serum Soluble Asialoglycoprotein Receptor 1: A Potential Predictor Marker Linked to Type 2 Diabetes Mellitus, Demonstrating Positive Correlation With High Sensitive C-Reactive Protein
Haifeng Zhu, Ziyi Zhong, Gaonian Zhao, Yuan Cao, Wei Liu, Yawen Guo, Jing Jin
Diabetes, Metabolic Syndrome and Obesity.2025; Volume 18: 663. CrossRef
Cross-sectional, interventional, and causal investigation of insulin sensitivity using plasma proteomics in diverse populations
Pik Fang Kho, Neil Wary, Daniela Zanetti, Fahim Abbasi, Joshua W. Knowles, Daniel J. Panyard, Katie T. Watson, Laurel Stell, Laura C. Lazzeroni, Stefan Gustafsson, Lars Lind, John R. Petrie, Themistocles L. Assimes
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Fangfang Zhou, Yuanyuan Wang, Youjun Xu, Lailiang Wang, Jinxia Ge, Qun Luo, Hongpeng Sun
Renal Failure.2025;[Epub] CrossRef
Experimental cell models of insulin resistance: overview and appraisal
Ying Yang, Ting-ting Wang, Hu-ai Xie, Ping Ping Hu, Pan Li
Frontiers in Endocrinology.2024;[Epub] CrossRef

Review

Metabolic Risk/Epidemiology
Role of Fenofibrate Use in Dyslipidemia and Related Comorbidities in the Asian Population: A Narrative Review: Chaicharn Deerochanawong, Sin Gon Kim, Yu-Cheng Chang; Diabetes Metab J. 2024;48(2):184-195. Published online January 26, 2024; DOI: https://doi.org/10.4093/dmj.2023.0168

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Hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) persist despite statin therapy, contributing to residual atherosclerotic cardiovascular disease (ASCVD) risk. Asian subjects are metabolically more susceptible to hypertriglyceridemia than other ethnicities. Fenofibrate regulates hypertriglyceridemia, raises HDL-C levels, and is a recommended treatment for dyslipidemia. However, data on fenofibrate use across different Asian regions are limited. This narrative review summarizes the efficacy and safety data of fenofibrate in Asian subjects with dyslipidemia and related comorbidities (diabetes, metabolic syndrome, diabetic retinopathy, and diabetic nephropathy). Long-term fenofibrate use resulted in fewer cardiovascular (CV) events and reduced the composite of heart failure hospitalizations or CV mortality in type 2 diabetes mellitus. Fenofibrate plays a significant role in improving irisin resistance and microalbuminuria, inhibiting inflammatory responses, and reducing retinopathy incidence. Fenofibrate plus statin combination significantly reduced composite CV events risk in patients with metabolic syndrome and demonstrated decreased triglyceride and increased HDL-C levels with an acceptable safety profile in those with high CV or ASCVD risk. Nevertheless, care is necessary with fenofibrate use due to possible hepatic and renal toxicities in vulnerable individuals. Long-term trials and real-world studies are needed to confirm the clinical benefits of fenofibrate in the heterogeneous Asian population with dyslipidemia.

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Original Articles

Drug/Regimen
Real-World Prescription Patterns and Barriers Related to the Use of Sodium-Glucose Cotransporter 2 Inhibitors among Korean Patients with Type 2 Diabetes Mellitus and Cardiovascular Disease: Jong Ha Baek, Ye Seul Yang, Seung-Hyun Ko, Kyung Do Han, Jae Hyeon Kim, Min Kyong Moon, Jong Suk Park, Byung-Wan Lee, Tae Jung Oh, Suk Chon, Jong Han Choi, Kyu Yeon Hur, Committee of Clinical Practice Guidelines, Korean Diabetes Association; Diabetes Metab J. 2022;46(5):701-712. Published online June 3, 2022; DOI: https://doi.org/10.4093/dmj.2022.0002

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Background
To evaluate prescription trends and clinical factors of the sodium-glucose cotransporter 2 inhibitors (SGLT2i) use according to the presence of atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF) in Korean patients with type 2 diabetes mellitus (T2DM).
Methods
Prescription patterns of SGLT2i use between 2015 and 2019 were determined using the Korean National Health Insurance Service database of claims.
Results
Of all patients with T2DM (n=4,736,493), the annual prescription rate of SGLT2i increased every year in patients with ASCVD (from 2.2% to 10.7%) or HF (from 2.0% to 11.1%). After the first hospitalization for ASCVD (n=518,572), 13.7% (n=71,259) of patients initiated SGLT2i with a median of 10.6 months. After hospitalization for HF (n=372,853), 11.2% (n=41,717) of patients initiated SGLT2i after a median of 8.8 months. In multivariate regression for hospitalization, older age (per 10 years, odds ratio [OR], 0.57; 95% confidence interval [CI], 0.56 to 0.57), lower household income (OR, 0.93; 95% CI, 0.92 to 0.95), rural residents (OR, 0.95; 95% CI, 0.93 to 0.97), and dipeptidyl peptidase-4 inhibitor (DPP-4i) users (OR, 0.82; 95% CI, 0.81 to 0.84) were associated with lesser initiation of SGLT2i in ASCVD. Additionally, female gender (OR, 0.97; 95% CI, 0.95 to 0.99) was associated with lesser initiation of SGLT2i in HF.
Conclusion
The prescription rate of SGLT2i increased gradually up to 2019 but was suboptimal in patients with ASCVD or HF. After the first hospitalization for ASCVD or HF, older age, female gender, low household income, rural residents, and DPP-4i users were less likely to initiate SGLT2i.

Citations

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Young Sang Lyu, Seok Oh, Jin Hwa Kim, Sang Yong Kim, Myung Ho Jeong
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Severe hypoglycemia as a risk factor for cardiovascular outcomes in patients with type 2 diabetes: is it preventable?
Seung-Hyun Ko
Cardiovascular Prevention and Pharmacotherapy.2022; 4(3): 106. CrossRef
Association between the Diabetes Drug Cost and Cardiovascular Events and Death in Korea: A National Health Insurance Service Database Analysis
Seung Min Chung, Ji-In Lee, Eugene Han, Hyun-Ae Seo, Eonju Jeon, Hye Soon Kim, Ji Sung Yoon
Endocrinology and Metabolism.2022; 37(5): 759. CrossRef

Obesity and Metabolic Syndrome
Higher High Density Lipoprotein 2 (HDL2) to Total HDL Cholesterol Ratio Is Associated with a Lower Risk for Incident Hypertension: You-Cheol Hwang, Wilfred Y. Fujimoto, Steven E. Kahn, Donna L. Leonetti, Edward J. Boyko; Diabetes Metab J. 2019;43(1):114-122. Published online September 28, 2018; DOI: https://doi.org/10.4093/dmj.2018.0053

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Background

Recent studies have suggested that high density lipoprotein (HDL) cholesterol is inversely associated with the development of hypertension. We aimed to determine the association between different HDL cholesterol subclasses and risk of future hypertension.

Methods

A total of 270 Japanese Americans (130 men, 140 women) without hypertension between the ages of 34 to 75 years were enrolled. Blood pressure was measured with a mercury sphygmomanometer, and average blood pressure was calculated. Incident hypertension was determined 5 to 6 and 10 to 11 years after enrollment. HDL2, HDL3, and total HDL cholesterol were measured at baseline.

Results

During 10 years of follow-up, the cumulative incidence of hypertension was 28.1% (76/270). In univariate analysis, age, diabetes, waist circumference, systolic and diastolic blood pressure, fasting glucose, insulin resistance index, total and low density lipoprotein cholesterol, and visceral adipose tissue were significant predictors for incident hypertension. Among the HDL cholesterol subclass, HDL2 cholesterol was inversely associated with hypertension incidence, but both total and HDL3 cholesterol were not. In addition, HDL2/HDL cholesterol was inversely associated with future hypertension risk. In multivariate analysis, age (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26 to 2.31; P=0.001), systolic blood pressure (OR, 1.83; 95% CI, 1.31 to 2.56; P<0.001), and HDL2/HDL cholesterol (OR, 0.71; 95% CI, 0.52 to 0.98; P=0.035), were associated with future development of hypertension.

Conclusion

A higher proportion of HDL2 cholesterol among total HDL cholesterol predicted a lower risk for incident hypertension. However, concentrations of total HDL, HDL2, and HDL3 cholesterol were not independent predictors of incident hypertension.

Citations

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Elham Sharifi‐Zahabi, Zahra Dastafkan, Amirhossein Asadi, Fatemeh Sadat Hosseini‐Baharanchi, Nayebali Rezvani, Saba Yari, Farzad Shidfar
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Epidemiology
Predictors of Incident Type 2 Diabetes Mellitus in Japanese Americans with Normal Fasting Glucose Level: You-Cheol Hwang, Wilfred Y. Fujimoto, Steven E. Kahn, Donna L. Leonetti, Edward J. Boyko; Diabetes Metab J. 2018;42(3):198-206. Published online April 25, 2018; DOI: https://doi.org/10.4093/dmj.2017.0100

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Background

Little is known about the natural course of normal fasting glucose (NFG) in Asians and the risk factors for future diabetes.

Methods

A total of 370 Japanese Americans (163 men, 207 women) with NFG levels and no history of diabetes, aged 34 to 75 years, were enrolled. Oral glucose tolerance tests were performed at baseline, 2.5, 5, and 10 years after enrollment.

Results

During 10 years of follow-up, 16.1% of participants met criteria for diabetes diagnosis, and 39.6% of subjects still had NFG levels at the time of diabetes diagnosis. During 5 years of follow-up, age (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.01 to 1.10; P=0.026) and family history of diabetes (OR, 3.24; 95% CI, 1.42 to 7.40; P=0.005) were independently associated with future diabetes diagnosis; however, fasting glucose level was not an independent predictor. During 10 years of follow-up, family history of diabetes (OR, 2.76; 95% CI, 1.37 to 5.54; P=0.004), fasting insulin level (OR, 1.01; 95% CI, 1.00 to 1.02; P=0.037), and fasting glucose level (OR, 3.69; 95% CI, 1.13 to 12.01; P=0.030) were associated with diabetes diagnosis independent of conventional risk factors for diabetes.

Conclusion

A substantial number of subjects with NFG at baseline still remained in the NFG range at the time of diabetes diagnosis. A family history of diabetes and fasting insulin and glucose levels were associated with diabetes diagnosis during 10 years of follow-up; however, fasting glucose level was not associated with diabetes risk within the relatively short-term follow-up period of 5 years in subjects with NFG.

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Others
Addition of Ipragliflozin to Metformin Treatment in Korean Patients with Type 2 Diabetes Mellitus: Subgroup Analysis of a Phase 3 Trial: Kyung-Wan Min, Bon Jeong Ku, Ji-Hyun Lee, Min-Seon Kim, Kyu-Jeung Ahn, Moon-Kyu Lee, Satoshi Kokubo, Satoshi Yoshida, Hyun-Ji Cho, Bong-Soo Cha; Diabetes Metab J. 2017;41(2):135-145. Published online January 11, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.2.135

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Background

This is a subgroup analysis of Korean patients from a phase 3 clinical trial investigating the efficacy and safety of ipragliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin.

Methods

This multicenter, placebo-controlled, double-blind, parallel-group study was carried out between November 2011 and January 2013. Patients entered a 2-week placebo pretreatment period, followed by a 24-week treatment period with either ipragliflozin (50 mg/day) or placebo, while continuing metformin. Efficacy outcomes (glycosylated hemoglobin [HbA1c], fasting plasma glucose [FPG], and body weight) and safety outcomes (treatment-emergent adverse events [TEAEs]) were measured and compared between the two treatment groups for patients enrolled in all 18 study sites in Korea.

Results

Eighty-two Korean patients received ipragliflozin (n=43) or placebo (n=39) during the study period. Mean changes in HbA1c levels from baseline to the end of treatment were –0.97% in the ipragliflozin group and –0.31% in the placebo group, with an adjusted between-group difference of –0.60% (P<0.001). Compared to placebo, FPG and body weight also decreased significantly (both P<0.001) from baseline after treatment in the ipragliflozin group, with between-group differences of –21.4 mg/dL and –1.53 kg, respectively. Decreased weight was the most common TEAE in the ipragliflozin group (7.0%); there were no reports of genital and urinary tract infection.

Conclusion

Ipragliflozin treatment in addition to metformin led to significant improvement in glycemic outcomes and reduction in body weight in Korean patients with type 2 diabetes mellitus, compared with metformin treatment alone; the safety profile was comparable in both groups.

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Review

Obesity and Metabolic Syndrome
Metabolic Surgery for Type 2 Diabetes Mellitus: Experience from Asia: Wei-Jei Lee, Lwin Aung; Diabetes Metab J. 2016;40(6):433-443. Published online December 2, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.6.433

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Type 2 diabetes mellitus (T2DM) is a current global health priority and Asia is the epicenter of this epidemic disease. Unlike in the west, where older population is most affected, the burden of diabetes in Asian countries is disproportionately high in young to middle-age adults. The incidence of diabetic nephropathy is alarmingly high in patients with early onset T2DM, especially in those with poor glycemic control. How to control this chronic and debilitating disease is currently a very important health issue in Asia. Bariatric surgery has proven successful in treating not just obesity but also T2DM in morbid obese patients (body mass index [BMI] >35 kg/m²). Gastrointestinal metabolic surgery recently has been proposed as a new treatment modality for obesity related T2DM for patients with BMI <35 kg/m². Many studies from Asia reported promising results of metabolic surgery to treat obese patients with T2DM which is not well controlled. It has been demonstrated that changes in gastrointestinal hormone secretion after gastrointestinal surgery would favor an early improvement of T2DM in Asians. New procedures have also been designed and proposed specifically for the treatment of diabetes in Asia. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of metabolic surgery for the treatment of T2DM in the Asia. We propose a systematic approach to surgical treatment, addressing current evidences, patient selection, procedure of choice, and timing and guideline for new procedures.

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Original Articles

An In Vitro Model to Probe the Regulation of Adipocyte Differentiation under Hyperglycemia: Kusampudi Shilpa, Thangaraj Dinesh, Baddireddi Subhadra Lakshmi; Diabetes Metab J. 2013;37(3):176-180. Published online June 14, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.3.176

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Background

The aim of this study was an in vitro investigation of the effect of high glucose concentration on adipogenesis, as prolonged hyperglycemia alters adipocyte differentiation.

Methods

3T3-L1 preadipocytes differentiated in the presence of varying concentrations of glucose (25, 45, 65, 85, and 105 mM) were assessed for adipogenesis using AdipoRed (Lonza) assay. Cell viability and proliferation were measured using MTT reduction and [³H] thymidine incorporation assay. The extent of glucose uptake and glycogen synthesis were measured using radiolabelled 2-deoxy-D-[1-³H] glucose and [¹⁴C]-UDP-glucose. The gene level expression was evaluated using reverse transcription-polymerase chain reaction and protein expression was studied using Western blot analysis.

Results

Glucose at 105 mM concentration was observed to inhibit adipogenesis through inhibition of CCAAT-enhancer-binding proteins, sterol regulatory element-binding protein, peroxisome proliferator-activated receptor and adiponectin. High concentration of glucose induced stress by increasing levels of toll-like receptor 4, nuclear factor κB and tumor necrosis factor α thereby generating activated preadipocytes. These cells entered the state of hyperplasia through inhibition of p27 and proliferation was found to increase through activation of protein kinase B via phosphoinositide 3 kinase dependent pathway. This condition inhibited insulin signaling through decrease in insulin receptor β. Although the glucose transporter 4 (GLUT4) protein remained unaltered with the glycogen synthesis inhibited, the cells were found to exhibit an increase in glucose uptake via GLUT1.

Conclusion

Adipogenesis in the presence of 105 mM glucose leads to an uncontrolled proliferation of activated preadipocytes providing an insight towards understanding obesity.

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The Effect of alpha-Lipoic Acid on Vascular Smooth Muscle Cell Proliferation, Migration, Neointimal Formation and PAI-1 Expression.: Dong Woo Shin, Dong Wook Lee, Sang Jun Lee, Hye Soon Kim, Hyo Gyoung Kang, Jong Deok Ahn, In Kyu Lee; Korean Diabetes J. 2001;25(6):446-459. Published online December 1, 2001

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Abstract PDF: BACKGROUND
Exposure to large amounts of glucose causes a characteristic dysfunction and morphologic changes of the endothelium by an increased production of reactive oxygen species (ROS) in diabetes. The plasminogen activator inhibitor-1 (PAI-1), which modulates fibrinolysis and cell migration, may influence proteolysis and neointimal formation in vascular smooth muscle cells (VSMC). Antioxidants have been proposed to inhibit multiple proatherogenic events. This study investigated the effect of (alpha)-Lipoic acid on PAI-1 expression and VSMC proliferation and migration both in vivo and in vitro. METHODS: In the in vitro study, cultured rat aortic smooth muscle cells (RASMC) were incubated in a medium containing high glucose (22 mM) and 100 nM angiotensin II for 4 hour. After (alpha)-Lipoic acidtreatment, a -migration and growth assay of the RASMC, and a gel mobility shift assay and reporter gene analysis for nuclear factor- B (NF-kappa B) and northern blot analysis for PAI-1 were performed. In the in vivo study, the effect of (alpha)-Lipoic acid on neointimal hyperplasia in a rat carotid balloon injury model was evaluated. RESULTS: RASMC migration was inhibited significantly by (alpha)-Lipoic acid (p<0.01), but their proliferation was not inhibited. The NF-kappa B DNA binding activity and NF-kappa B promoter activity was inhibited by (alpha)-Lipoic acid significantly (p<0.01). (alpha)-Lipoic acid inhibited PAI-1 mRNA expression by high glucose and angiotensin II in dose dependent manner (p<0.05). In the rat carotid artery balloon injury model, neointimal formation was reduced by (alpha)-Lipoic acid treatment in a dose dependent manner significantly (p<0.01). CONCLUSION: (alpha)-Lipoic acid suppresses migration, but not proliferation in RASMC. (alpha)-Lipoic acid also reduce neointima formation in a rat carotid balloon injured model. This effect might be related to the blocking of NF-kappa B which increase the expression of the genes associated with atherosclerosis including TNF-alpha, IL-1, IL-6, endothelin-1, MCP-1, VCAM-1, ICAM-1, E-selectin, tissue factor.

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