Diabetes & Metabolism Journal

Editorial

Ideal Combination of Oral Hypoglycemic Agents for Patients with Type 2 Diabetes Mellitus: Hye Soon Kim; Diabetes Metab J. 2024;48(5):882-884. Published online September 1, 2024; DOI: https://doi.org/10.4093/dmj.2024.0479

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Financial burden of glycemic control: a single-center retrospective study of diabetes costs in South Korean patients
Han-Sang Baek, Sungju Kim, Dong-Jun Lim, Chul-Min Kim, Tae Seo Sohn, Sungrae Kim
The Korean Journal of Internal Medicine.2026; 41(4): 706. CrossRef
Clinical features, treatments, and outcomes of atezolizumab-induced diabetes mellitus in cancer patients
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Original Article

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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Ying Wang, Jiaxiang Ding, Dongmei Cheng, Yuzhou Ding, Tonghao Zhang, Wang Hu, Xiaoni Wang, Xu Zhu, Yunqiu Xie, Huan Zhou
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Combined Ursolic Acid and Rosuvastatin Treatment Mitigates Inflammation and Oxidative Stress in Diabetic Nephropathy Model Cells
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World Journal of Diabetes.2025;[Epub] CrossRef
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Yafeng Shi, Gemin Zhu, Jun Yan, Linxin Zhang, Yongku Du, Zhuoqiong Bian, Jing Fan
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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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Il Rae Park, Jun Sung Moon
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Response

Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease (Diabetes Metab J 2021;45:698-707): Eugene Han, Hye Soon Kim; Diabetes Metab J. 2021;45(6):972-973. Published online November 22, 2021; DOI: https://doi.org/10.4093/dmj.2021.0315

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EFFECT OF NON-ALCOHOLIC FATTY LIVER DISEASE ON THE COURSE OF DIABETIC POLYNEUROPATHY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Andriy Ya. Sabovchyk
Wiadomości Lekarskie.2023; 76(11): 2395. CrossRef

Original Article

Complications
Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease: Eugene Han, Mi Kyung Kim, Byoung Kuk Jang, Hye Soon Kim; Diabetes Metab J. 2021;45(5):698-707. Published online February 2, 2021; DOI: https://doi.org/10.4093/dmj.2020.0118

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Background
This study aimed to investigate the association between hepatic steatosis burden and albuminuria in Korean patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD).
Methods
We recruited 100 patients with both T2DM and NAFLD, but without chronic kidney disease. Albuminuria was defined as a spot urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. Transient elastography was performed, and the steatosis burden was quantified by controlled attenuation parameter (CAP) with significant steatosis defined as CAP >302 dB/m.
Results
The prevalence of significant steatosis and albuminuria was 56.0% and 21.0%, respectively. Subjects with significant steatosis were significantly younger and had a significantly shorter duration of T2DM, greater waist circumference, and higher body mass index, total cholesterol, triglyceride, and low density lipoprotein cholesterol levels, than subjects without severe NAFLD (all P<0.05). Albuminuria was higher in patients with significant steatosis than in patients without significant steatosis (32.1% vs. 6.8%, P=0.002). Urinary ACR showed a correlation with CAP (r=0.331, P=0.001), and multiple linear regression analysis revealed a significant association between a high degree of albuminuria and high CAP value (r=0.321, P=0.001). Additionally, multivariate logistic regression analysis demonstrated the independent association between urinary ACR and significant steatosis after adjustment for confounding factors including age, body mass index, duration of T2DM, low density lipoprotein level, and renin-angiotensin system blocker use (odds ratio, 1.88; 95% confidence interval, 1.31 to 2.71; P=0.001).
Conclusion
T2DM patients with NAFLD had a higher prevalence of albuminuria, which correlated with their steatosis burden.

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Non-alcoholic fatty liver disease and sarcopenia is associated with the risk of albuminuria independent of insulin resistance, and obesity
Eugene Han, Mi Kyung Kim, Seung-Soon Im, Byoung Kuk Jang, Hye Soon Kim
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Development and implementation of patient-level prediction models of end-stage renal disease for type 2 diabetes patients using fast healthcare interoperability resources
San Wang, Jieun Han, Se Young Jung, Tae Jung Oh, Sen Yao, Sanghee Lim, Hee Hwang, Ho-Young Lee, Haeun Lee
Scientific Reports.2022;[Epub] CrossRef
Beyond Liver Disease: Non-Alcoholic Fatty Liver Disease and Advanced Liver Fibrosis in Kidney Disease
Eugene Han
Diabetes & Metabolism Journal.2022; 46(4): 564. CrossRef
Muscle fat contents rather than muscle mass determines nonalcoholic steatohepatitis and liver fibrosis in patients with severe obesity
Eugene Han, Mi Kyung Kim, Hye Won Lee, Seungwan Ryu, Hye Soon Kim, Byoung Kuk Jang, Youngsung Suh
Obesity.2022; 30(12): 2440. CrossRef
Decreased Serum Osteocalcin is an Independent Risk Factor for Metabolic Dysfunction-Associated Fatty Liver Disease in Type 2 Diabetes
Yu-Jie Wang, Chun-Hua Jin, Jiang-Feng Ke, Jun-Wei Wang, Yi-Lin Ma, Jun-Xi Lu, Mei-Fang Li, Lian-Xi Li
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2022; Volume 15: 3717. CrossRef
Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease (Diabetes Metab J 2021;45:698-707)
Eugene Han, Hye Soon Kim
Diabetes & Metabolism Journal.2021; 45(6): 972. CrossRef
Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease (Diabetes Metab J 2021;45:698-707)
Mi-kyung Kim
Diabetes & Metabolism Journal.2021; 45(6): 968. CrossRef
Liver fibrosis indices are related to diabetic peripheral neuropathy in individuals with type 2 diabetes
Kyuho Kim, Tae Jung Oh, Hyen Chung Cho, Yun Kyung Lee, Chang Ho Ahn, Bo Kyung Koo, Jae Hoon Moon, Sung Hee Choi, Hak Chul Jang
Scientific Reports.2021;[Epub] CrossRef

Editorial

Obesity Degree and Glycemic Status: Factors That Should Be Considered in Heart Failure: Hye Soon Kim; Diabetes Metab J. 2020;44(4):529-531. Published online August 21, 2020; DOI: https://doi.org/10.4093/dmj.2020.0166

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Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure
Qingchun Zeng, Qing Zhou, Weitao Liu, Yutong Wang, Xingbo Xu, Dingli Xu
Frontiers in Cardiovascular Medicine.2021;[Epub] CrossRef

Original Articles

Drug/Regimen
Efficacy and Safety of Treatment with Quadruple Oral Hypoglycemic Agents in Uncontrolled Type 2 Diabetes Mellitus: A Multi-Center, Retrospective, Observational Study: Jun Sung Moon, Sunghwan Suh, Sang Soo Kim, Heung Yong Jin, Jeong Mi Kim, Min Hee Jang, Kyung Ae Lee, Ju Hyung Lee, Seung Min Chung, Young Sang Lyu, Jin Hwa Kim, Sang Yong Kim, Jung Eun Jang, Tae Nyun Kim, Sung Woo Kim, Eonju Jeon, Nan Hee Cho, Mi-Kyung Kim, Hye Soon Kim, Il Seong Nam-Goong, Eun Sook Kim, Jin Ook Chung, Dong-Hyeok Cho, Chang Won Lee, Young Il Kim, Dong Jin Chung, Kyu Chang Won, In Joo Kim, Tae Sun Park, Duk Kyu Kim, Hosang Shon; Diabetes Metab J. 2021;45(5):675-683. Published online August 12, 2020; DOI: https://doi.org/10.4093/dmj.2020.0107

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Background

Only few studies have shown the efficacy and safety of glucose-control strategies using the quadruple drug combination. Therefore, the aim of the present study was to investigate the usefulness of the quadruple combination therapy with oral hypoglycemic agents (OHAs) in patients with uncontrolled type 2 diabetes mellitus (T2DM).

Methods

From March 2014 to December 2018, data of patients with T2DM, who were treated with quadruple hypoglycemic medications for over 12 months in 11 hospitals in South Korea, were reviewed retrospectively. We compared glycosylated hemoglobin (HbA1c) levels before and 12 months after quadruple treatment with OHAs. The safety, maintenance rate, and therapeutic patterns after failure of the quadruple therapy were also evaluated.

Results

In total, 357 patients were enrolled for quadruple OHA therapy, and the baseline HbA1c level was 9.0%±1.3% (74.9±14.1 mmol/mol). After 12 months, 270 patients (75.6%) adhered to the quadruple therapy and HbA1c was significantly reduced from 8.9%±1.2% to 7.8%±1.3% (mean change, −1.1%±1.2%; P<0.001). The number of patients with HbA1c <7% increased significantly from 5 to 68 (P<0.005). In addition, lipid profiles and liver enzyme levels were also improved whereas no changes in body weight. There was no significant safety issue in patients treated with quadruple OHA therapy.

Conclusion

This study shows the therapeutic efficacy of the quadruple OHA regimen T2DM and demonstrates that it can be an option for the management of T2DM patients who cannot use insulin or reject injectable therapy.

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Efficacy and safety of adding a fourth oral antidiabetic drug versus metformin dose escalation in patients with type 2 diabetes inadequately controlled on triple oral combination therapy (EFFORT): A 24‐week, randomized, open‐label, multicenter trial
So Ra Kim, Jun Hwa Hong, Sin Gon Kim, Soo‐Kyung Kim, Hyuk‐Sang Kwon, Jun Sung Moon, Jung Hwan Park, Jae Myung Yu, Bong‐Soo Cha, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2026; 28(4): 3305. CrossRef
Empagliflozin-based quadruple oral therapy for type 2 diabetes: a prospective cohort study
Fatemeh Moosaie, Shiva Abedinzadeh, Soghra Rabizadeh, Kimia Daneshvar, Mohammadamin Noorafrooz, Fatemeh Alsadat Mojtahedi, Niloofar Deravi, Seyede Marzie Fatemi Abhari, Akam Ramezani, Alipasha Meysamie, Marzieh Hajibabaei, Sahar Karimpour Reyhan, Mahsa Ab
Scientific Reports.2025;[Epub] CrossRef
Estimating Type 2 Diabetes Prevalence: A Model of Drug Consumption Data
Rita Oliveira, Matilde Monteiro-Soares, José Pedro Guerreiro, Rúben Pereira, António Teixeira-Rodrigues
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Sevgi Demir Çam, Sevda Uzun
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Nadia Gul, Inayat Ur Rehman, Yasar shah, Arbab Muhammad Ali, Zahid Ali, Omer Shehzad, Khang Wen Goh, Long Chiau Ming, Amal K. Suleiman, Nimesh Lageju
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Diabetes, Obesity and Metabolism.2022; 24(6): 1105. CrossRef
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Soree Ryang, Sang Soo Kim, Ji Cheol Bae, Ji Min Han, Su Kyoung Kwon, Young Il Kim, Il Seong Nam‐Goong, Eun Sook Kim, Mi‐kyung Kim, Chang Won Lee, Soyeon Yoo, Gwanpyo Koh, Min Jeong Kwon, Jeong Hyun Park, In Joo Kim
Diabetes, Obesity and Metabolism.2022; 24(9): 1800. CrossRef
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Jaehyun Bae, Ji Hye Huh, Minyoung Lee, Yong‐Ho Lee, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2021; 23(2): 609. CrossRef

Epidemiology
Lower Leg Fat Depots Are Associated with Albuminuria Independently of Obesity, Insulin Resistance, and Metabolic Syndrome (Korea National Health and Nutrition Examination Surveys 2008 to 2011): Eugene Han, Nan Hee Cho, Mi Kyung Kim, Hye Soon Kim; Diabetes Metab J. 2019;43(4):461-473. Published online March 7, 2019; DOI: https://doi.org/10.4093/dmj.2018.0081

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Background

Although the involvement of obesity in metabolic disorders is well known, leg fat depot influences on albuminuria have not been determined.

Methods

This population-based, cross-sectional study used a nationally representative sample of 2,076 subjects aged ≥20 years from the Korea National Health and Nutrition Examination Surveys of 2008 to 2011. The ratio of leg fat to total fat (LF/TF ratio) was assessed by dual X-ray absorptiometry, and albuminuria was defined as more than one positive dipstick test or an albumin-to-creatinine ratio of ≥30 mg/g.

Results

Individuals whose LF/TF ratio was in the lowest tertile showed a higher proportion of albuminuria than those in the highest tertile (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.01 to 3.96; P<0.001). This association was observed in both sexes, all age groups, and all subgroups stratified by body mass index, waist circumference, homeostasis model assessments of insulin resistance, and the presence of metabolic syndrome (all, P<0.05). Multiple logistic regression analyses also demonstrated that the lowest LF/TF ratio was independently associated with albuminuria risk (OR, 1.55 to 2.16; all, P<0.05). In addition, the risk of albuminuria was higher in sarcopenic individuals with lower LF/TF ratios than in the highest LF/TF ratio subjects without sarcopenia (OR, 3.73; 95% CI, 2.26 to 6.13).

Conclusion

A lower LF/TF ratio was associated with an increased risk of albuminuria independent of obesity, insulin resistance, and metabolic syndrome, and when combined with sarcopenia, the albuminuria risk synergistically increased. Hence, our findings may have implications to improve risk stratification and recommendations on body fat distribution in the general population.

Citations

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Efficacy and safety of evogliptin in patients with type 2 diabetes and non‐alcoholic fatty liver disease: A multicentre, double‐blind, randomized, comparative trial
Eugene Han, Ji Hye Huh, Eun Y. Lee, Ji C. Bae, Sung W. Chun, Sung H. Yu, Soo H. Kwak, Kyong S. Park, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2022; 24(4): 752. CrossRef
Muscle fat contents rather than muscle mass determines nonalcoholic steatohepatitis and liver fibrosis in patients with severe obesity
Eugene Han, Mi Kyung Kim, Hye Won Lee, Seungwan Ryu, Hye Soon Kim, Byoung Kuk Jang, Youngsung Suh
Obesity.2022; 30(12): 2440. CrossRef
Albuminuria Is Associated with Steatosis Burden in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease
Eugene Han, Mi Kyung Kim, Byoung Kuk Jang, Hye Soon Kim
Diabetes & Metabolism Journal.2021; 45(5): 698. CrossRef

Letter

Letter: Association of Thigh Muscle Mass with Insulin Resistance and Incident Type 2 Diabetes Mellitus in Japanese Americans (Diabetes Metab J 2018;42:488–95): Nan Hee Cho, Hye Soon Kim; Diabetes Metab J. 2019;43(1):123-124. Published online February 19, 2019; DOI: https://doi.org/10.4093/dmj.2019.0026

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Response

Response: Patient Understanding of Hypoglycemia in Tertiary Referral Centers (Diabetes Metab J 2018;42:43-52): Nan Hee Cho, Hye Soon Kim; Diabetes Metab J. 2018;42(2):175-176. Published online April 19, 2018; DOI: https://doi.org/10.4093/dmj.2018.42.2.175

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Citations

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Factors associated with knowledge and hypoglycemia experience among patients with diabetes mellitus in Ghana: A cross‐sectional study
Samuel Asamoah Sakyi, Stephen Opoku, Ebenezer Senu, Emmanuel Ekow Korsah, Alfred Effah, Bright Takyi Baidoo, Eugene Ansah Arele, Emmanuel Frimpong, Emmanuel Naturinda, Kini Evans Kodzo, Anthony Amenuvor, Afia Agyapomaa Kwayie, Lydia Oppong Bannor, Ransfor
Public Health Challenges.2023;[Epub] CrossRef

Original Article

Clinical Care/Education
Patient Understanding of Hypoglycemia in Tertiary Referral Centers: Nan Hee Cho, Nam Kyung Kim, Eugene Han, Jun Hwa Hong, Eon Ju Jeon, Jun Sung Moon, Mi Hae Seo, Ji Eun Lee, Hyun-Ae Seo, Mi-Kyung Kim, Hye Soon Kim; Diabetes Metab J. 2018;42(1):43-52. Published online February 23, 2018; DOI: https://doi.org/10.4093/dmj.2018.42.1.43

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Background

Hypoglycemia is an important complication in the treatment of patients with diabetes. We surveyed the insight by patients with diabetes into hypoglycemia, their hypoglycemia avoidance behavior, and their level of worry regarding hypoglycemia.

Methods

A survey of patients with diabetes, who had visited seven tertiary referral centers in Daegu or Gyeongsangbuk-do, Korea, between June 2014 and June 2015, was conducted. The survey contained questions about personal history, symptoms, educational experience, self-management, and attitudes about hypoglycemia.

Results

Of 758 participants, 471 (62.1%) had experienced hypoglycemia, and 250 (32.9%) had experienced hypoglycemia at least once in the month immediately preceding the study. Two hundred and forty-two (31.8%) of the participants had received hypoglycemia education at least once, but only 148 (19.4%) knew the exact definition of hypoglycemia. Hypoglycemic symptoms identified by the participants were dizziness (55.0%), sweating (53.8%), and tremor (40.8%). They mostly chose candy (62.1%), chocolate (37.7%), or juice (36.8%) as food for recovering hypoglycemia. Participants who had experienced hypoglycemia had longer duration of diabetes and a higher proportion of insulin usage. The mean scores for hypoglycemia avoidance behavior and worry about hypoglycemia were 21.2±10.71 and 23.38±13.19, respectively. These scores tended to be higher for participants with higher than 8% of glycosylated hemoglobin, insulin use, and experience of emergency room visits.

Conclusion

Many patients had experienced hypoglycemia and worried about it. We recommend identifying patients that are anxious about hypoglycemia and educating them about what to do when they develop hypoglycemic symptoms, especially those who have a high risk of hypoglycemia.

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Letter

Letter: The Effect of 12 Weeks Aerobic, Resistance, and Combined Exercises on Omentin-1 Levels and Insulin Resistance among Type 2 Diabetic Middle-Aged Women (Diabetes Metab J 2017;41:205-12): Hye Soon Kim; Diabetes Metab J. 2017;41(4):322-323. Published online August 22, 2017; DOI: https://doi.org/10.4093/dmj.2017.41.4.322

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Blood Glucose Measurement: Is Serum Equal to Plasma?: Hye Soon Kim; Diabetes Metab J. 2016;40(5):365-366. Published online October 12, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.5.365

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Original Articles

Comparison of the Efficacy of Glimepiride, Metformin, and Rosiglitazone Monotherapy in Korean Drug-Naïve Type 2 Diabetic Patients: The Practical Evidence of Antidiabetic Monotherapy Study: Kun Ho Yoon, Jeong Ah Shin, Hyuk Sang Kwon, Seung Hwan Lee, Kyung Wan Min, Yu Bae Ahn, Soon Jib Yoo, Kyu Jeung Ahn, Sung Woo Park, Kwan Woo Lee, Yeon Ah Sung, Tae Sun Park, Min Seon Kim, Yong Ki Kim, Moon Suk Nam, Hye Soon Kim, Ie Byung Park, Jong Suk Park, Jeong Taek Woo, Ho Young Son; Diabetes Metab J. 2011;35(1):26-33. Published online February 28, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.1.26

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Background

Although many anti-diabetic drugs have been used to control hyperglycemia for decades, the efficacy of commonly-used oral glucose-lowering agents in Korean type 2 diabetic patients has yet to be clearly demonstrated.

Methods

We evaluated the efficacy of glimepiride, metformin, and rosiglitazone as initial treatment for drug-naïve type 2 diabetes mellitus patients in a 48-week, double-blind, randomized controlled study that included 349 Korean patients. Our primary goal was to determine the change in HbA1c levels from baseline to end point. Our secondary goal was to evaluate changes in fasting plasma glucose (FPG) levels, body weight, frequency of adverse events, and the proportion of participants achieving target HbA1c levels.

Results

HbA1c levels decreased from 7.8% to 6.9% in the glimepiride group (P<0.001), from 7.9% to 7.0% in the metformin group (P<0.001), and from 7.8% to 7.0% (P<0.001) in the rosiglitazone group. Glimepiride and rosiglitazone significantly increased body weight and metformin reduced body weight during the study period. Symptomatic hypoglycemia was more frequent in the glimepiride group and diarrhea was more frequent in the metformin group.

Conclusion

The efficacy of glimepiride, metformin, and rosiglitazone as antidiabetic monotherapies in drug-naïve Korean type 2 diabetic patients was similar in the three groups, with no statistical difference. This study is the first randomized controlled trial to evaluate the efficacy of commonly-used oral hypoglycemic agents in Korean type 2 diabetic patients. An additional subgroup analysis is recommended to obtain more detailed information.

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Background

The highly developed endoplasmic reticulum (ER) structure in pancreatic beta cells is heavily involved in insulin biosynthesis. Thus, any perturbation in ER function inevitably impacts insulin biosynthesis. Recent studies showed that the expression of tribbles-related protein 3 (TRB3), a mammalian homolog of Drosophilia tribbles, in various cell types is induced by ER stress. Here, we examined whether ER stress induces TRB3 expression in INS-1 cells and found that TRB3 mediates ER stress-induced suppression of insulin gene expression.

Methods

The effects of tunicamycin and thapsigargin on insulin and TRB3 expression in INS-1 cells were measured by Northern and Western blot analysis, respectively. The effects of adenovirus-mediated overexpression of TRB3 on insulin, PDX-1 and MafA gene expression in INS-1 cells were measured by Northern blot analysis. The effect of TRB3 on insulin promoter was measured by transient transfection study with constructs of human insulin promoter.

Results

The treatment of INS-1 cells with tunicamycin and thapsigargin decreased insulin mRNA expression, but increased TRB3 protein expression. Adenovirus-mediated overexpression of TRB3 decreased insulin gene expression in a dose-dependent manner. A transient transfection study showed that TRB3 inhibited insulin promoter activity, suggesting that TRB3 inhibited insulin gene expression at transcriptional level. Adenovirus-mediated overexpression of TRB3 also decreased PDX-1 mRNA expression, but did not influence MafA mRNA expression.

Conclusions

This study showed that ER stress induced TRB3 expression, but decreased both insulin and PDX-1 gene expression in INS-1 cells. Our data suggest that TRB3 plays an important role in ER stress-induced beta cell dysfunction.

Citations

Citations to this article as recorded by

Endoplasmic reticulum stress causes insulin resistance by inhibiting delivery of newly synthesized insulin receptors to the cell surface
Max Brown, Samantha Dainty, Natalie Strudwick, Adina D. Mihai, Jamie N. Watson, Robina Dendooven, Adrienne W. Paton, James C. Paton, Martin Schröder, James Arthur Olzmann
Molecular Biology of the Cell.2020; 31(23): 2597. CrossRef
PTB and TIAR binding to insulin mRNA 3′- and 5′UTRs; implications for insulin biosynthesis and messenger stability
Rikard G. Fred, Syrina Mehrabi, Christopher M. Adams, Nils Welsh
Heliyon.2016; 2(9): e00159. CrossRef
Asna1/TRC40 Controls β-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport
Stefan Norlin, Vishal S. Parekh, Peter Naredi, Helena Edlund
Diabetes.2016; 65(1): 110. CrossRef
Role of the Unfolded Protein Response inβCell Compensation and Failure during Diabetes
Nabil Rabhi, Elisabet Salas, Philippe Froguel, Jean-Sébastien Annicotte
Journal of Diabetes Research.2014; 2014: 1. CrossRef
Endoplasmic Reticulum Stress and Insulin Biosynthesis: A Review
Mi-Kyung Kim, Hye-Soon Kim, In-Kyu Lee, Keun-Gyu Park
Experimental Diabetes Research.2012; 2012: 1. CrossRef

Association of the Polymorphisms in the PSMA6 (rs1048990) and PSMB5 (rs2230087) Genes with Type 2 Diabetes in Korean Subjects.: Hee Kyoung Kim, Su Won Kim, Yun Jeong Doh, Sae Rom Kim, Mi Kyung Kim, Keun Gyu Park, Hye Soon Kim, Kyong Soo Park, Min Yoo, Jung Guk Kim, Bo Wan Kim, In Kyu Lee; Korean Diabetes J. 2008;32(3):204-214. Published online June 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.3.204

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Abstract PDF

BACKGROUND
The 26S ubiquitin-proteasome system (UPS) is a principal proteolytic pathway of intracellular molecules regulating apoptosis, cell cycle, cell proliferation or differentiation, inflammation and etc. The recent study suggests that the rs1048990 (C/G) polymorphism of the proteasome subunit alpha type 6 (PSMA6) gene is associated with the increase of the risk of myocardial infarction by the dysregulation of IkappaB degradation. We hypothesized that 26S UPS is important in the development of insulin resistance and type 2 diabetes (T2DM) by controlling the degradation of IkappaB and insulin receptor substances as a substrate. We therefore investigated whether the rs1048990 (C/G) polymorphism of PSMA6 gene and the rs2230087 (G/A) polymorphism of proteasome subunit beta type 5 gene (PSMB5), that is chymotrypsin-like protease determining the rate of proteolysis, are associated with susceptibility to T2DM in Korean subjects. METHODS: We examined the polymorphisms of these genes in 309 diabetic subjects and 170 non-diabetic controls. The polymorphisms of rs1048990 (C/G) and rs2230087 (G/A) were genotyped by real-time PCR. RESULTS: The frequency of the G allele of rs1048990 (C/G) and the A allele of rs2230087 (G/A) polymorphisms was significantly higher in diabetic patients (28% and 13%) compared to that in controls (13% and 1%; P = 0.000 and P = 0.000, respectively). Logistic regression analysis of the rs1048990 (C/G) polymorphism showed that the odds ratio (OR) (adjusted for age, smoking, waist circumference, fasting plasma glucose, systolic blood pressure, HDL-C, triglyceride, and total cholesterol) was 3.93 (95% confidence interval [CI], 2.35-6.59; P = 0.000) for the G allele and 5.09 (95% CI, 2.71-9.57; P = 0.000) for CG and GG genotype when compared with the CC genotype. Logistic regression analysis of the rs2230087 (G/A) polymorphism showed that the adjusted OR was 5.70 (95% CI, 1.63-19.98; P = 0.007) for the A allele and 6.08 (95% CI, 1.66-22.29; P = 0.006) for GA and AA genotype when compared with the GG genotype. In multiple logistic regression analysis with T2DM as the independent Variable rs1048990 (C/G) and rs2230087 (G/A) polymorphisms were the predictor for T2DM. CONCLUSION: We suggest that the G allele of rs1048990 (C/G) polymorphism and the A allele of rs2230087 (G/A) polymorphism may be genetic risk factor to type 2 diabetes mellitus in Korean subjects.

Citations

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Ubiquitin-proteasome system in diabetic retinopathy
Zane Svikle, Beate Peterfelde, Nikolajs Sjakste, Kristine Baumane, Rasa Verkauskiene, Chi-Juei Jeng, Jelizaveta Sokolovska
PeerJ.2022; 10: e13715. CrossRef
1,4‐Dihydropyridine derivatives without Ca2+‐antagonist activity up‐regulate Psma6 mRNA expression in kidneys of intact and diabetic rats
Kristīne Ošiņa, Evita Rostoka, Jelizaveta Sokolovska, Natalia Paramonova, Egils Bisenieks, Gunars Duburs, Nikolajs Sjakste, Tatjana Sjakste
Cell Biochemistry and Function.2016; 34(1): 3. CrossRef
Genetic variations in the PSMA3, PSMA6 and PSMC6 genes are associated with type 1 diabetes in Latvians and with expression level of number of UPS-related and T1DM-susceptible genes in HapMap individuals
Tatjana Sjakste, Natalia Paramonova, Kristine Osina, Kristine Dokane, Jelizaveta Sokolovska, Nikolajs Sjakste
Molecular Genetics and Genomics.2016; 291(2): 891. CrossRef

The Effect of Chronic High Glucose Concentration on Endoplasmic Reticulum Stress in INS-1 Cells.: Mi Kyung Kim, Hye Young Seo, Tae Sung Yun, Nam Kyung Kim, Yu Jin Hah, Yun Jung Kim, Ho Chan Cho, Young Yun Jang, Hye Soon Kim, Seong Yeol Ryu, In Kyu Lee, Keun Gyu Park; Korean Diabetes J. 2008;32(2):112-120. Published online April 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.2.112

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Abstract PDF: BACKGROUND
The highly developed endoplasmic reticulum (ER) structure is one of the characteristic features of pancreatic beta-cells. Recent study showed that ER stress causes beta-cell dysfunction. However, little is known about the effects of high glucose concentration on induction of ER stress in pancreatic beta-cells. Therefore, this study was designed to evaluate whether exposure of high glucose concentration in rat insulinoma cell line, INS-1 cell induces ER stress and whether ER stress decreases insulin gene expression. METHODS: The effect of 30 mM glucose on insulin expression and secretion in INS-1 cells was evaluated by Northern blot analysis and glucose-stimulated insulin secretion (GSIS). Cell viability was evaluated by XTT assay. The effect of 30 mM glucose on phosphorylation of eIF2alpha and CHOP expression, which are markers of ER stress were evaluated by Western blot analysis. RT-PCR analysis was performed to determine whether high glucose concentration induces XBP-1 splicing. To investigate whether ER stress decreases insulin gene expression, the effect of tunicamycin on insulin mRNA expression was evaluated by Northern blot analysis. RESULTS: The prolonged exposure of INS-1 cells with the 30 mM glucose concentration decreased insulin mRNA expression in a time dependent manner and impaired GSIS while did not influence on cell viability. 30 mM glucose increased phosphorylation of eIF2alpha, XBP-1 splicing and CHOP expression in INS-1 cells. Tunicamycin-treated INS-1 increased XBP-1 splicing and decreased insulin mRNA expression in a dose dependent manner. CONCLUSION: This study showed that prolonged exposure of INS-1 with high glucose concentration induces ER stress and ER stress decreases insulin gene expression. Further studies about underlying molecular mechanism by which ER stress induces beta-cell dysfunction are needed.

Case Report

A Case of Cured Diabetes Mellitus after Occult Malignant Pheochromocytoma Removal.: Ho Chan Cho, Hye Soon Kim, Yoon Jung Kim, Yu Jin Hah, Nam Keong Kim, Mi Kyung Kim, Keun Gyu Park, Yong Hoon Kim, Sun Young Kwon; Korean Diabetes J. 2007;31(6):520-524. Published online November 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.6.520

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Abstract PDF

Pheochromocytoma is characterized by a combination of various clinical manifestations that include the classic triad of severe headache, palpitations and diaphoresis. In addition, hyperglycemia can be caused by overproduction of catecholamines, which are secreted by a catecholamine-secreting neoplasm of adrenal or extra-adrenal chromaffin tissue. We encountered a case of diabetes with an occult malignant adrenal pheochromocytoma, who did not have any classic manifestations. A 37-year-old male was admitted because of polydipsia, polyuria, and weight loss. Fasting blood glucose level was 497 mg/dL, hemoglobin A1c level was 15%, and diabetic retinopathy and peripheral polyneuropathy were also accompanied. Incidentally, right adrenal mass was detected by ultrasonography of abdomen. Urinary excretion of total metanephrine and epinephrine were elevated. Adrenal CT showed a 7.1 cm sized right adrenal cystic mass with enhancing solid portion and hemorrhagic content. The scan with 123I-MIBG revealed the cystic mass with increased rim uptake in the region of right adrenal gland. After removal of the tumor, the increased levels of catecholamine were normalized. Moreover, blood glucose level was normalized without administration of insulin or oral hypoglycemic agents. The pathologic examination showed that the neoplasm was a malignant adrenal pheochromocytoma. We report this case that diabetes was cured after removal of malignant tumor with literature review at first in Korea.

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Pheochromocytoma with Markedly Abnormal Liver Function Tests and Severe Leukocytosis
Chai Ryoung Eun, Jae Hee Ahn, Ji A Seo, Nan Hee Kim
Endocrinology and Metabolism.2014; 29(1): 83. CrossRef

Original Article

The Effect of Alpha-lipoic Acid on the Cell Cycle Arrest and Apoptosis in Rat Vascular Smooth Muscle Cells.: Hye Jin Kim, In Kyu Lee, Young Ho Kim, Soon Young Shin, Young Han Lee, Jung Guk Kim, Bo Wan Kim, Hye Soon Kim, Mi Kyoung Kim, Keun Gyu Park, Seong Yeol Ryu; Korean Diabetes J. 2007;31(3):200-207. Published online May 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.3.200

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Abstract PDF: BACKGROUND
The proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of atheroscelrosis and post-angioplasty restenosis. We previously showed that alpha-lipoic acid (ALA) inhibited neointimal hyperplasia and has potential anti-atherosclerosis effect in rat carotid artery balloon injured model. Here, we investigated whether alpha-lipoic acid inhibited proliferation of cells and induced apoptosis in rat vascular smooth muscle cells. METHODS: VSMCs were treated with ALA under each condition, harvested and protein was extracted. Same amount of protein was loaded into SDS-PAGE and western blot analysis was performed with various cell cycle regulation protein. To examine ALA induce apoptosis in VSMCs, FACS and DNA fragmentation assay were performed. Antioxidant effect of ALA was determined by DCF-DA staining. RESULTS: ALA induced VSMCs cell cycle arrest and induced p21, p27 and p53 proteins. Also ALA induced PTEN expression and AMPK phosphorylation. Increased AMPK phosphorylation reduced Erk-2 phosphorylation and finally arrested cell cycle promotion. The apoptotic effect was also shown by ALA treatment. Also we confirmed that ALA reduced ROS generation in VSMCs. CONCLUSION: The present data suggest that ALA has anti-proliferative effect and arrests cell proliferation. Therefore, ALA may provide new strategies for the prevention of neointimal hyperplasia after angioplasty.

Randomized Controlled Trial

Randomized, Open Label, Multicenter Clinical Trial about the Effect of Cilazapril on Vascular Endothelial Function in Patients with Type 2 Diabetes Combined with Hypertension.: Sang Youl Rhee, Jeong Taek Woo, Sei Hyun Baik, Hyoung Woo Lee, In Kyu Lee, Hye Soon Kim, Moon Kyu Lee, Min Ho Shong, Chung Gu Cho, Byoung Hyun Park, Bong Soo Cha, Young Seol Kim; Korean Diabetes J. 2006;30(6):450-458. Published online November 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.6.450

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Abstract PDF

BACKGROUND
The angiotensin converting enzyme inhibitor (ACEi) improves the vascular endothelial cell function and has a better clinical outcome by decreasing the LDL cholesterol oxidation, hypercoagulability, oxidative stress and improving the level of endothelial nitric oxide synthesis in patients with type 2 diabetes and hypertension. However, the correlations between the ACEi and the serum markers for the vascular endothelial function in previous studies were not consistent. SUBJECTS AND METHODS: Between July 2003 and April 2005, 104 type 2 diabetes patients with hypertension, who had been admitted to 9 major university hospitals in Korea, were examined. The subjects were randomly allocated to the cilazapril (2.5~5 mg/day) and atenolol (50~100 mg/day) treatment group and given a combination of hydrochlorothiazide and amlodipine. The lipid profile and the markers for endothelial function, such as vWF, VCAM, E-selectin, tPA, fibrinogen, adiponectin, hsCRP, nitrotyrosine were evaluated and the differences in the variables were compared with those obtained 6 months later. RESULTS: A total 56 subjects completed the 6-months follow up period. Regarding the baseline characteristics, there were no significant differences in the variables observed in the two groups except for HbA1c (P = 0.037), vWF (P = 0.048), and hsCRP (P = 0.038). After 6 months, both groups showed a significant and identical decrease in the systolic and diastolic blood pressure compared with the baseline (P < 0.002). However, there were no significant differences in the endothelial markers between each group. On the other hand, there was some deterioration in the triglyceride (P = 0.009) and HbA1c (P = 0.017) levels in the atenolol treatment groups. CONCLUSIONS: There were no significant differences in the endothelial function markers observed between the cilazapril and atenolol groups. However, cilazapril had an identical effect on the blood pressure reduction compared with atenolol but had fewer adverse effects on the glucose and lipid metabolism.

Citations

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Potential Protective Role of Blood Pressure-Lowering Drugs on the Balance between Hemostasis and Fibrinolysis in Hypertensive Patients at Rest and During Exercise
Annabella Braschi
American Journal of Cardiovascular Drugs.2019; 19(2): 133. CrossRef

Original Articles

Alpha-Lipoic acid Inhibits TNF-alpha-Induced Fractalkine Expression in Rat aortic Smooth Muscle Cells.: Keun Gyu Park, Hye Soon Kim, Seong Yeol Ryu, Chang Wook Nam, Byung Kyu Chae, Eui Dal Jung, Jung Guk Kim, Bo Wan Kim, In Kyu Lee; Korean Diabetes J. 2005;29(5):409-417. Published online September 1, 2005

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Abstract PDF: BACKGOUND: The induction of vascular inflammation via the proinflammatory cytokine/ nuclear factor (NF)-kappaB pathway is one of the key mechanisms in the development and progression of atherosclerosis. Accumulating evidence suggests a recently identified chemokine, fractalkine, is involved in arterial inflammation and atherogenesis; however, few studies have examined the effects of pharmacological agents on this process. The purposes of this study were to determine if alpha-lipoic acid (ALA) inhibits the expression of tumor necrosis factor (TNF)-alpha-stimulated fractalkine in vascular smooth muscle cells(VSMCs). METHODS: Rat VSMCs were isolated and cultured. Northern and Western blot analyses were performed to evaluate the effects of ALA on the expression of TNF-alpha-stimulated fractalkine in VSMCs. A gel shift assay was performed to examine the mechanism by which ALA inhibits the expression of fractalkine. RESULTS: TNF-alpha markedly induced the expression of fractalkine in primary cultured VSMCs. ALA inhibited the expression of TNF-alpha-stimulated fractalkine in cultured VSMCs. The result of the gel shift assay suggested the inhibitory effects of AS-6 on the expression of TNF-alpha-stimulated fractalkine were mediated via the NF-kappaB pathway. CONCLUSION: This study has shown that ALA has anti-inflammatory effects on VSMCs, which are mediated by the inhibitoin, at least in part, of the NF-kappaB dependent inflammatory signal-stimulated expression of fractalkine. Our data suggest the possibility that antioxidants, such as ALA, inhibit the NF-kappaB pathway, which may be used to prevent the development and progression of atherosclerosis.

Ascochlorin Derivative, AS-6, Inhibits TNF-alpha-Induced fractalkine, MCP-1 and VCAM-1 Expression in Rat Aortic Smooth Muscle Cells.: Young Yun Jang, Sang Yoon Kim, Nam Keong Kim, Mi Kyung Kim, Hee Kyoung Kim, Hye Soon Kim, Chang Wook Nam, Seong Yeol Ryu, Sung Il Nam, Keun Gyu Park; Korean Diabetes J. 2005;29(5):401-408. Published online September 1, 2005

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Abstract PDF: BACKGOUND: Inflammation is one of the key mechanisms in the development and progression of atherosclerosis. Accumulating evidence suggests that peroxisome proliferators- activated receptorgamma(PPARgamma) plays an important role in the prevention of arterial inflammation and the formation of atherogenesis. This study was designed to evaluate whether the new synthetic PPARgamma, ascochlorin-6(AS-6) has anti-inflammatory and anti-atherogenic effects in primary cultured rat vascular smooth muscle cells(VSMCs). METHODS: Rat VSMCs were isolated and cultured. Northern and Western blot analyses were performed to evaluate the effects of AS-6 on the expressions of tumor necrosis factor (TNF)-alpha-stimulated fractalkine, monocyte chemoattractant protein(MCP)-1 and vascular cell adhesion molecule (VCAM)-1 in VSMCs. A gel shift assay was performed to examine the mechanism by which AS-6 inhibits the expressions of fractalkine, MCP-1 and VCAM-1. RESULTS: TNF-alpha markedly induced the expressions of fractalkine, MCP-1 and VCAM-1 in primary cultured VSMCs. AS-6 inhibited the expressions of TNF-alpha-stimulated fractalkine, MCP-1 and VCAM-1 in primary cultured VSMCs. The result of the gel shift assay suggested the inhibitory effects of AS-6 on the expressions of TNF-alpha-stimulated fractalkine, MCP-1 and VCAM-1 were mediated through a nuclear factor kappaB associated pathway. CONCLUSION: The present study shows that AS-6 has anti-inflammatory effects on VSMCs, suggesting the possibility for the use of AS-6 for prevention of the development and progression of atherosclerosis.

Insulin Gene Therapy Using HVJ-liposome and Epstein-Barr Virus Plasmid in Murine Streptozotocin Induced Diabetes.: Yong Deuk Kim, Keun Gyu Park, Seong Wook Han, Jong Doek Ahn, Hyo Jung Lee, Mi Jung Kim, Hye Soon Kim, Nam Hee Park, In Kyu Lee; Korean Diabetes J. 2003;27(5):405-413. Published online October 1, 2003

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Abstract PDF: BACKGROUND
Despite improvement in insulin preparation and delivery, the use of insulin therapy alone to maintain normal glucose concentration and prevent the development of diabetic complication is not easy. Therefore, there has been considerable interest in developing gene therapy to supply insulin. We investigated that the administration of hemagglutinating virus of Japan (HVJ)- liposome complex, containing human insulin construct into the portal vein to control the blood glucose level in murine streptozotocin (STZ)-induced diabetes. METHODS: Human insulin gene was delivered to STZ-induced diabetic rats through the portal vein using HVJ-liposome containing Epstein-Barr virus (EBV) replicon-based plasmid (pEB). Blood glucose and body weight were measured after insulin gene delivery. The animals were sacrificed 28 days later and the livers were collected for immuno-histochemical staining of insulin. In addition plasma insulin and C-peptide levels were measured. RESULTS: Significant decrease in blood glucose levels and an increase in insulin and C-peptide levels were observed in the insulin gene transfection group as compared to the control group. Immunohistochemical staining of insulin also showed significant differences between these two groups. CONCLUSION: This study demonstrated the possibility of insulin gene therapy through the portal vein using pEB and HVJ-liposome method to produce a sustained improvement of diabetic glucose metabolism.

Polymorphism of Melanocortin-4 Receptor and Obesity.: Hye Soon Kim, In Kyu Lee, Young Sung Suh; Korean Diabetes J. 2003;27(2):123-131. Published online April 1, 2003

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Abstract PDF: BACKGROUND
The application of genetics to obesity has made remarkable progress in recent years. The melanocortin-4 receptor (MC4R) regulates food intake, and possibly that of energy expenditure. The MC4R gene is the most prevalent obesity gene found to date in humans. The prevalence of single nucleotide substitution, replacing valine with isoleucine, at codon 103 was studied, and the role of the MC4R gene polymorphism on the body weight, fat distribution and lipid profile were determined. METHODS: Anthropometry and biochemical studies were performed on 226 subjects (82 male and 144 female subjects). The MC4R genotype was determined by a polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method. The body fat distributions were measured by computerized tomography. RESULTS: The frequencies of the homozygotes, Val103Val and Val103/Ile, were 88.9 and 11.1%, respectively. The frequencies of the heterozygotes were similar (11.8 vs. 10.6%) in the control and obese groups. However, the heterozygotes had lower waist-to-hip ratios (WHR) (p=0.033) and visceral fat masses (p=0.038) compared to the homozygotes. In the obese group, the heterozygotes had lower body mass indices (BMI) and visceral fat masses (p=0.043 and p=0.044, respectively). The heterozygote males had lower BMI and fasting plasma glucose levels (p=0.046 and p<0.001, respectively) than the homozygote males. The heterozygote females tended to have lower WHR (p=0.081) than the homozygote females. CONCLUSION: These results suggest that mutations in the MC4R gene are likely to be a cause of human obesity, and possibly of metabolic syndrome.

The Effect of alpha-lipoic Acid on Endothelial Dysfunction Induced by Intralipid Infusion in Healthy Volunteers.: Dong Wook Lee, Mi Jung Kim, Hye Soon Kim, Tae Sung Yun, Ho Chan Cho, Sang Jun Lee, Seung Ho Hur, Kyo Cheol Mun, Yong Won Cho, Jae Hoon Bae, In Kyu Lee; Korean Diabetes J. 2002;26(5):336-346. Published online October 1, 2002

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Abstract PDF: BACKGROUND
Endothelial dysfunciton has been proposed as an early manifestation of atherogenesis. Recently, emerging evidence suggests that hypertriglyceridemia and elevated free fatty acid are important risk factors in the development of atherosclerosis, probably through an increased oxidative stress. To clarify the hypothesis, we evaluated the effect of alpha-lipoic acid (ALA) on the endothelial dysfunction induced by intralipid infusion in healthy volunteers. METHODS: Hypertriglyceridemia and elevated free fatty acids was induced by infusion of intralipid. FMD (Flow-mediated dilation) of the brachial artery was investigated noninvasively by a high-resolution ultrasound technique in 13 young, healthy men without risk factors for coronary heart disease. RESULTS: Plasma triglyceride, free fatty acid and the superoxide anion were increased from 61.7+/-28.8 to 332.6+/-202.5 mg/dL, from 330.7+/-131.1 to 1267.0+/-486.2 microEq/L and from 6.6+/-2.2 to 8.7+/-1.5 X 10(-7)nmol/10(6)cells/30min (vs. basal p<0.001), respectively, following infusion of the intralipid. The FMD was decreased from 10.1+/-3.3 to 7.7+/-3.7% (vs. basal p<0.01) following infusion of the intralipid. After treatment with ALA, the increase in the FMD and the decrease in superoxide anion were significant. CONCLUSION: Acute hypertriglyceridemia, induced by intralipid infusion, is implicated in endothelial dysfunction. This endothelial dysfunction was reversed by treatment with ALA. These results suggest that chronic and repeated hypertriglyceridemia may play important roles in the development of atherosclerosis probably by increasing oxidative stress.

Editorial

The effect of advanced glycation and products on the proliferation of vascular smooth muscle cell.: Hye Soon Kim, In Kyu Lee; Korean Diabetes J. 2002;26(2):87-90. Published online April 1, 2002

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Abstract PDF: No abstract available.

Original Article

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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