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COVID-19
Use of Renin-Angiotensin-Aldosterone System Inhibitors and Severe COVID-19 Outcomes in Patients with Hypertension: A Nationwide Cohort Study
Jae Hyun Bae, Sun Kyu Choi, Nam Hoon Kim, Juneyoung Lee, Sin Gon Kim
Diabetes Metab J. 2021;45(3):430-438.   Published online February 22, 2021
DOI: https://doi.org/10.4093/dmj.2020.0279
  • 8,209 View
  • 298 Download
  • 3 Crossref
Graphical AbstractGraphical Abstract AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Angiotensin-converting enzyme 2 facilitates the entry of severe acute respiratory syndrome coronavirus 2 into the human body. We investigated the association of renin-angiotensin-aldosterone system (RAAS) inhibitor use with severe coronavirus disease 2019 (COVID-19) outcomes in hypertensive patients.
Methods
We identified hypertensive patients with confirmed COVID-19 from the Korean Health Insurance Review and Assessment Service from inception to May 15, 2020. The primary outcome was the composite of intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO), and death from COVID-19. The individual components were evaluated as secondary outcomes.
Results
Of 1,374 hypertensive patients with COVID-19, 1,076 (78.3%) and 298 (21.7%) were users and never-users of RAAS inhibitors, respectively. The RAAS inhibitor users were not associated with the risk of the primary outcome (adjusted odds ratio [aOR], 0.72; 95% confidence interval [CI], 0.46 to 1.10). The risk of ICU admission was significantly lower in the users than the never-users (aOR, 0.44; 95% CI, 0.24 to 0.84). The RAAS inhibitors were beneficial only in ICU admissions that did not require IMV (aOR, 0.28; 95% CI, 0.14 to 0.58). The risk of death from COVID-19 was comparable between the groups (aOR, 1.09; 95% CI, 0.64 to 1.85). We could not evaluate the risks of CRRT and ECMO owing to the small number of events.
Conclusion
RAAS inhibitor use was not associated with the composite of severe outcomes in the hypertensive patients with COVID-19 but significantly lowered the risk of ICU admission, particularly in patients who did not require IMV.

Citations

Citations to this article as recorded by  
  • Systematic review and meta-analysis of the clinical outcomes of ACEI/ARB in East-Asian patients with COVID-19
    Nancy Xurui Huang, Qi Yuan, Fang Fang, Bryan P. Yan, John E. Sanderson, Masaki Mogi
    PLOS ONE.2023; 18(1): e0280280.     CrossRef
  • Renin‐Angiotensin Aldosterone System Inhibitors and COVID‐19: A Systematic Review and Meta‐Analysis Revealing Critical Bias Across a Body of Observational Research
    Jordan Loader, Frances C. Taylor, Erik Lampa, Johan Sundström
    Journal of the American Heart Association.2022;[Epub]     CrossRef
  • Renin-angiotensin-aldosterone system blockers in Bulgarian COVID-19 patients with or without chronic kidney disease
    Rumen Filev, Lionel Rostaing, Mila Lyubomirova, Boris Bogov, Krassimir Kalinov, Dobrin Svinarov
    Medicine.2022; 101(48): e31988.     CrossRef
Clinical Diabetes & Therapeutics
Asian Subpopulations May Exhibit Greater Cardiovascular Benefit from Long-Acting Glucagon-Like Peptide 1 Receptor Agonists: A Meta-Analysis of Cardiovascular Outcome Trials
Yu Mi Kang, Yun Kyung Cho, Jiwoo Lee, Seung Eun Lee, Woo Je Lee, Joong-Yeol Park, Ye-Jee Kim, Chang Hee Jung, Michael A. Nauck
Diabetes Metab J. 2019;43(4):410-421.   Published online December 27, 2018
DOI: https://doi.org/10.4093/dmj.2018.0070
  • 6,535 View
  • 137 Download
  • 19 Web of Science
  • 19 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   
Background

Based on reported results of three large cardiovascular outcome trials (CVOTs) of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), we aimed to investigate the overall effect of GLP-1 RAs on major adverse cardiovascular events (MACEs) and to identify subpopulations exhibiting the greatest cardiovascular (CV) benefit.

Methods

Three CVOTs reporting effects of long-acting GLP-1 RAs were included: LEADER (liraglutide), SUSTAIN-6 (semaglutide), and EXSCEL (exenatide once weekly). In all studies, the primary endpoint was three-point MACE, comprising CV death, non-fatal myocardial infarction, and non-fatal stroke. Overall effect estimates were calculated as hazard ratios and 95% confidence intervals (CIs) using the random-effects model; subgroup analyses reported in the original studies were similarly analyzed.

Results

Overall, statistically significant risk reductions in MACE and CV death were observed. Subgroup analysis indicated a significant racial difference with respect to CV benefit (P for interaction <0.001), and more substantial risk reductions were observed in subjects of African origin (relative risk [RR], 0.78; 95% CI, 0.60 to 0.99) and in Asians (RR, 0.35; 95% CI, 0.09 to 1.32). However, post hoc analysis (Bonferroni method) revealed that only Asians exhibited a significantly greater CV benefit from treatment, compared with white subjects (P<0.0001).

Conclusion

Long-acting GLP-1 RAs reduced risks of MACE and CV deaths in high-risk patients with type 2 diabetes mellitus. Our findings of a particularly effective reduction in CV events with GLP-1 RA in Asian populations merits further exploration and dedicated trials in specific populations.

Citations

Citations to this article as recorded by  
  • Sex, racial, ethnic, and geographical disparities in major adverse cardiovascular outcome of glucagon-like peptide-1 receptor agonists among patients with and without diabetes mellitus: A meta-analysis of placebo-controlled randomized controlled trials,
    Frederick Berro Rivera, Nathan Ross B. Bantayan, John Paul Aparece, Linnaeus Louisse A. Cruz, John Vincent Magallong, Polyn Luz Pine, Anne Mira Nicca Idian-Javier, Grace Nooriza O. Lumbang, Edgar V. Lerma, Kyla M. Lara-Breitinger, Martha Gulati, Krishnasw
    Journal of Clinical Lipidology.2024;[Epub]     CrossRef
  • A randomized, double‐blind trial assessing the efficacy and safety of two doses of dulaglutide in Japanese participants with type 2 diabetes (AWARD‐JPN)
    Tomoaki Morioka, Masakazu Takeuchi, Akichika Ozeki, Masanori Emoto
    Diabetes, Obesity and Metabolism.2024;[Epub]     CrossRef
  • Coronary Artery Disease in South Asian Patients: Cardiovascular Risk Factors, Pathogenesis and Treatments
    Vincenzo Sucato, Giuseppe Coppola, Girolamo Manno, Giuseppe Vadalà, Giuseppina Novo, Egle Corrado, Alfredo Ruggero Galassi
    Current Problems in Cardiology.2023; 48(8): 101228.     CrossRef
  • Retrospective Analysis of the Effectiveness of Oral Semaglutide in Type 2 Diabetes Mellitus and Its Effect on Cardiometabolic Parameters in Japanese Clinical Settings
    Hodaka Yamada, Masashi Yoshida, Shunsuke Funazaki, Jun Morimoto, Shiori Tonezawa, Asuka Takahashi, Shuichi Nagashima, Kimura Masahiko, Otsuka Kiyoshi, Kazuo Hara
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  • Efficacy of treatment with glucagon-like peptide receptor agonists-1 in Asian patients with type 2 diabetes mellitus
    L. Yu. Khamnueva, L. S. Andreeva
    Problems of Endocrinology.2023; 69(2): 38.     CrossRef
  • Role of diabetes in stroke: Recent advances in pathophysiology and clinical management
    Sian A. Bradley, Kevin J. Spring, Roy G. Beran, Dimitrios Chatzis, Murray C. Killingsworth, Sonu M. M. Bhaskar
    Diabetes/Metabolism Research and Reviews.2022;[Epub]     CrossRef
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    Harold Edward Bays, Jennifer Ng, Jeffrey Sicat, Michelle Look
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    Calvin Ke, K. M. Venkat Narayan, Juliana C. N. Chan, Prabhat Jha, Baiju R. Shah
    Nature Reviews Endocrinology.2022; 18(7): 413.     CrossRef
  • Effect of race on cardiometabolic responses to once-weekly exenatide: insights from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)
    Timothy M. E. Davis, Anna Giczewska, Yuliya Lokhnygina, Robert J. Mentz, Naveed Sattar, Rury R. Holman
    Cardiovascular Diabetology.2022;[Epub]     CrossRef
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    Xiaoling Cai, Linong Ji
    Diabetes Therapy.2021; 12(7): 1861.     CrossRef
  • Current trends in epidemiology of cardiovascular disease and cardiovascular risk management in type 2 diabetes
    Jae-Seung Yun, Seung-Hyun Ko
    Metabolism.2021; 123: 154838.     CrossRef
  • Sex and ethnic differences in the cardiovascular complications of type 2 diabetes
    Jian L. Yeo, Emer M. Brady, Gerry P. McCann, Gaurav S. Gulsin
    Therapeutic Advances in Endocrinology and Metabolism.2021; 12: 204201882110342.     CrossRef
  • Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis
    Yuan Zhu, Jiao Xu, Dong Zhang, Xingyu Mu, Yi Shi, Shangtao Chen, Zengxiang Wu, Shuangqing Li
    Frontiers in Endocrinology.2021;[Epub]     CrossRef
  • Efficacy and safety of dulaglutide in type 2 diabetes patients in endocrinology clinics of Islamabad, Pakistan
    Matiullah Kamin, SajjadAli Khan, UmarYousaf Raja, Osama Ishtiaq, Asmara Malik, Tejhmal Rehman, MuhammadUmar Wahab
    Indian Journal of Endocrinology and Metabolism.2021; 25(5): 456.     CrossRef
  • Type 2 Diabetes and Atherosclerotic Cardiovascular Disease in South Asians: a Unique Population with a Growing Challenge
    Afreen I. Shariff, Nitya Kumar, William S. Yancy, Leonor Corsino
    Current Diabetes Reports.2020;[Epub]     CrossRef
  • Antihypertensive and Renal Mechanisms of SGLT2 (Sodium-Glucose Linked Transporter 2) Inhibitors
    Christopher S. Wilcox
    Hypertension.2020; 75(4): 894.     CrossRef
  • Subpopulation Differences in the Cardiovascular Efficacy of Long-Acting Glucagon-Like Peptide 1 Receptor Agonists in Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis
    Liyun He, Na Yang, Lingling Xu, Fan Ping, Wei Li, Yuxiu Li, Huabing Zhang
    Diabetes Therapy.2020; 11(9): 2121.     CrossRef
  • 2020 Consensus of Taiwan Society of Cardiology on the pharmacological management of patients with type 2 diabetes and cardiovascular diseases
    Chern-En Chiang, Kwo-Chang Ueng, Ting-Hsing Chao, Tsung-Hsien Lin, Yih-Jer Wu, Kang-Ling Wang, Shih-Hsien Sung, Hung-I Yeh, Yi-Heng Li, Ping-Yen Liu, Kuan-Cheng Chang, Kou-Gi Shyu, Jin-Long Huang, Cheng-Dao Tsai, Huei-Fong Hung, Ming-En Liu, Tze-Fan Chao,
    Journal of the Chinese Medical Association.2020; 83(7): 587.     CrossRef
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    Kyung-Soo Kim, Byung-Wan Lee
    Clinical and Molecular Hepatology.2020; 26(4): 430.     CrossRef
Reviews
Clinical Diabetes & Therapeutics
Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association
Hyun Jin Kim, Seok O Park, Seung-Hyun Ko, Sang Youl Rhee, Kyu-Yeon Hur, Nan-Hee Kim, Min Kyong Moon, Byung-Wan Lee, Jin Hwa Kim, Kyung Mook Choi
Diabetes Metab J. 2017;41(6):423-429.   Published online December 19, 2017
DOI: https://doi.org/10.4093/dmj.2017.41.6.423
  • 5,925 View
  • 72 Download
  • 5 Web of Science
  • 6 Crossref
AbstractAbstract PDFPubReader   

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The cardiovascular safety of GLP-1RAs has been assessed in several randomized clinical trials and systematic reviews. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RA may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA.

Citations

Citations to this article as recorded by  
  • Anti-inflammatory effect of glucagon-like Peptide-1 receptor agonist on the neurosensory retina in an acute optic nerve injury rat model
    Yeon Woong Chung, Ji Young Lee, Hyun Hee Ju, Jin A. Choi
    European Journal of Pharmacology.2022; 933: 175269.     CrossRef
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    Yang Liu, Zhaoxiang Yu, Yunlong Yang, Zhihan Lv
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    Doo Soo Jeon
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    Ju-Ming Lu
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    Diabetes Therapy.2019; 10(1): 5.     CrossRef
  • Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus: A Position Statement of the Korean Diabetes Association
    Hyun Jin Kim
    The Journal of Korean Diabetes.2018; 19(1): 35.     CrossRef
Islet Studies and Transplantation
An Update on the Effect of Incretin-Based Therapies on β-Cell Function and Mass
Suk Chon, Jean-François Gautier
Diabetes Metab J. 2016;40(2):99-114.   Published online April 25, 2016
DOI: https://doi.org/10.4093/dmj.2016.40.2.99
  • 5,101 View
  • 112 Download
  • 43 Web of Science
  • 42 Crossref
AbstractAbstract PDFPubReader   

Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a complex and progressive pathogenesis. The two primary mechanisms of T2DM pathogenesis are pancreatic β-cell dysfunction and insulin resistance. Pancreatic β-cell dysfunction is recognized to be a prerequisite for the development of T2DM. Therapeutic modalities that improve β-cell function are considered critical to T2DM management; however, blood glucose control remains a challenge for many patients due to suboptimal treatment efficacy and the progressive nature of T2DM. Incretin-based therapies are now the most frequently prescribed antidiabetic drugs in Korea. Incretin-based therapies are a favorable class of drugs due to their ability to reduce blood glucose by targeting the incretin hormone system and, most notably, their potential to improve pancreatic β-cell function. This review outlines the current understanding of the incretin hormone system in T2DM and summarizes recent updates on the effect of incretin-based therapies on β-cell function and β-cell mass in animals and humans.

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    Tatiana Yu. Demidova
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Obesity and Metabolic Syndrome
Perspective of Small-Molecule AdipoR Agonist for Type 2 Diabetes and Short Life in Obesity
Miki Okada-Iwabu, Masato Iwabu, Kohjiro Ueki, Toshimasa Yamauchi, Takashi Kadowaki
Diabetes Metab J. 2015;39(5):363-372.   Published online October 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.5.363
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AbstractAbstract PDFPubReader   

Obesity associated with unhealthy diet and lack of exercise is shown to contribute to the onset and/or aggravation of the metabolic syndrome and diabetes, thus placing affected individuals at increased risk of cardiovascular disease and cancer. Plasma adiponectin levels are decreased in obesity, which causes insulin resistance and diabetes. Therefore, we identified adiponectin receptors (AdipoRs) as the therapeutic target. It was suggested that, similarly to caloric restriction and exercise, activation of the AdipoRs may have the potential not only to improve lifestyle-related diseases but to contribute to prolonged the shortened lifespan on a high caloric unhealthy diet. To this end, we have identified "AdipoRon" as an adiponectin receptor agonist. Indeed, AdipoRon ameliorated diabetes associated with obesity as well as to increase exercise endurance, thus prolonging shortened lifespan of obese mice fed on a high fat diet. Additionally, we have recently determined the crystal structures of the human AdipoRs. The seven-transmembrane helices of AdipoRs are structurally distinct from those of G-protein coupled receptors. It is expected that these findings will contribute not only to the elucidation of the AdipoR-related signal transduction but to the development and optimization of AdipoR-targeted therapeutics for obesity-related diseases such as diabetes.

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The Role of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Understanding How Data Can Inform Clinical Practice in Korea
Seungjoon Oh, Suk Chon, Kyu Jeong Ahn, In-Kyung Jeong, Byung-Joon Kim, Jun Goo Kang
Diabetes Metab J. 2015;39(3):177-187.   Published online June 15, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.3.177
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AbstractAbstract PDFPubReader   

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce glycosylated hemoglobin (HbA1c, 0.5% to 1.0%), and are associated with moderate weight loss and a relatively low risk of hypoglycemia. There are differences between Asian and non-Asian populations. We reviewed available data on GLP-1RAs, focusing on Korean patients, to better understand their risk/benefit profile and help inform local clinical practice. Control of postprandial hyperglycemia is important in Asians in whom the prevalence of post-challenge hyperglycemia is higher (vs. non-Asians). The weight lowering effects of GLP-1RAs are becoming more salient as the prevalence of overweight and obesity among Korean patients increases. The higher rate of gastrointestinal adverse events amongst Asian patients in clinical trials may be caused by higher drug exposure due to the lower body mass index of the participants (vs. non-Asian studies). Data on the durability of weight loss, clinically important health outcomes, safety and optimal dosing in Korean patients are lacking. Use of GLP-1RAs is appropriate in several patient groups, including patients whose HbA1c is uncontrolled, especially if this is due to postprandial glucose excursions and patients who are overweight or obese due to dietary problems (e.g., appetite control). The potential for gastrointestinal adverse events should be explained to patients at treatment initiation to facilitate the promotion of better compliance.

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  • Tolerability and Effectiveness of Switching to Dulaglutide in Patients With Type 2 Diabetes Inadequately Controlled With Insulin Therapy
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    Seung-Hyun Ko, Kyu-Yeon Hur, Sang Youl Rhee, Nan-Hee Kim, Min Kyong Moon, Seok-O Park, Byung-Wan Lee, Hyun Jin Kim, Kyung Mook Choi, Jin Hwa Kim
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Refocusing Peroxisome Proliferator Activated Receptor-α: A New Insight for Therapeutic Roles in Diabetes
Hannah Seok, Bong Soo Cha
Diabetes Metab J. 2013;37(5):326-332.   Published online October 17, 2013
DOI: https://doi.org/10.4093/dmj.2013.37.5.326
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AbstractAbstract PDFPubReader   

Although glucose-lowering treatment shows some risk lowering effects in cardiovascular diseases, risks of macrovascular and microvascular complications have still remained, and development of new therapeutic strategies is needed. Recent data have shown that peroxisome proliferator activated receptor-α (PPAR-α) plays a pivotal role in the regulation of lipid homeostasis, fatty acid oxidation, cellular differentiation, and immune response such as inflammation or vascularization related to diabetic complication. This review will re-examine the metabolic role of PPAR-α, summarize data from clinical studies on the effect of PPAR-α agonist in diabetes, and will discuss the possible therapeutic role of PPAR-α activation.

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Original Articles
Role of Glucocorticoid Receptor on Insulin Secretion and Synthesis in INS-1 Cells.
Ju Yeon Yang, Myong Su Kang, Tak Ho Song, In Kook Jeong, Pyong Ju Seo, Hee Jin Kim
Korean Diabetes J. 2006;30(6):428-434.   Published online November 1, 2006
DOI: https://doi.org/10.4093/jkda.2006.30.6.428
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AbstractAbstract PDF
BACKGROUND
Glucocorticoids play important roles in the regulation of glucose homeostasis. It is well known that glucocorticoids reduce hepatic and peripheral tissue sensitivity to insulin, but the roles of glucocorticoids on insulin secretion and synthesis in pancreatic beta cells are still unclear. We have investigated the direct effects of glucocorticoids on insulin secretion and synthesis in rat insulinoma (INS-1) cells. METHODS: Insulin content and 11.2 mM glucose-stimulated insulin secretion (GSIS) were measured in INS-1 cells after culture with or without 1 micrometer dexamethasone (DEX). Preproinsulin mRNA levels were analyzed by real-time RT-PCR and normalized to the internal control. Effect of RU486 on DEX-induced inhibition of GSIS and preproinsulin mRNA synthesis was evaluated. RESULTS: Insulin content of INS-1 cells cultured in RPMI containing 11.2 mM glucose in the presence of DEX was not different from that of control cells. After 1-h preincubation in 2.8 mM glucose, basal insulin secretion from cells treated with DEX did not differ from that of controls, but GSIS was significantly reduced in the cells treated with DEX in comparison to control cells. The expression of preproinsulin mRNA relative to beta-actin mRNA was also lower in the cells treated with DEX. Glucocorticoid receptor antagonist improved DEX-induced inhibition of GSIS and preproinsulin mRNA synthesis. CONCLUSION: DEX inhibited GSIS and preproinsulin mRNA synthesis in INS-1 cells. Glucocorticoid receptor antagonist ameliorated the reduced GSIS and preproinsulin mRNA synthesis induced by DEX.
Effects of PPAR-alpha and-gamma Agonists on Fatty Acid Metabolism of Muscle Cells in Hyperlipidemic and Hyperglycemic Conditions.
Yong jik Lee, Zheng Shan Zhao, Soo Kyung Kim, Hae Jin Kim, Wan Sub Shim, Chul Woo Ahn, Hyun Chul Lee, Bong Soo Cha
Korean Diabetes J. 2006;30(5):324-335.   Published online September 1, 2006
DOI: https://doi.org/10.4093/jkda.2006.30.5.324
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AbstractAbstract PDF
BACKGROUND
Studies for the regulation of fatty acid metabolism are deficient relatively in skeletal muscle and heart. The investigations in pathological conditions for malonyl-CoA decarboxylase (MCD) and for the relation of MCD and PPAR-alpha.-gamma agonists are insufficient in particular. METHODS: In the current study, fully differentiated H9c2 muscle cells were exposed to pathological conditions such as hyperlipidemic (0.1 mM Palmitate) and hyperglycemic (16.5 mM Glucose) condition with 5 uM PPAR-gamma agonist (rosiglitazone) and 10 uM PPAR-alpha agonist (WY14,643) and then experiments such as MCD activity assay, MCD real-time RT-PCR, MCD reporter gene assay, MCD Western blotting, PPAR-alpha Western blotting, and palmitate oxidation test were carried out. RESULTS: Only PPAR-alpha agonist increased MCD activity. In the result of real-time RT-PCR, both PPAR-alpha and PPAR-gamma agonists elevated MCD mRNA expression in hyperlipidemic condition. MCD protein expression was decreased in hyperlipidemic condition, however, increased in rosiglitazone, or WY14,643 treated conditions. Rosiglitazone, and WY14,643 treated groups showed incresed MCD protein expression in hyperglycemic condition. Hyperlipidemic control group and PPAR-alpha.-gamma agonists treated groups presented about 3.8 times more increased palmitate oxidation level than normolipidemic control group in hyperlipidemic condition. PPAR-alpha agonist treated group showed 49% more increased palmitate oxidation rate than hyperlipidemic control group in primary cultured rat skeletal muscle cells. The amount of palmitate oxidation from differentiated H9c2 muscle cells that had overexpressed PPAR-alpha structural genes was more increased than control group. CONCLUSION: This study suggests that PPAR-alpha agonist ameliorates the defects induced by hyperlipidemic condition through the regulation of MCD. In summary, a closely reciprocal relation among PPAR-alpha agonist, MCD, and fatty acid oxidation existed distinctly in hyperlipidemic condition, but not in hyperglycemic condition.

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Effect of Peroxisome Proliferator Activated Receptor-gamma Agonist, Angiotensin II Receptor Blocker and alpha-lipoic Acid on Renal VEGF Expression in Diabetic Nephropathy.
Jang Hyun Koh, Yeon Lee, Mi Jin Kim, Young Goo Shin, Eun Young Lee, Choon Hee Chung
Korean Diabetes J. 2004;28(5):367-376.   Published online October 1, 2004
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AbstractAbstract PDF
BACKGROUND
Diabetic nephropathy is one of the most serious complications in diabetes mellitus, and it is the leading cause of end stage renal disease. It has been reported that angiotensin converting enzyme inhibitor (ACEi) reduces the vascular endothelial growth factor (VEGF) expression, and so it plays an important role in reducing the renal damage. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist is known to reduce insulin resistance in type 2 diabetic patients. In the previous study, PPAR-gamma agonist was shown to lower VEGF expression in the retina, but it increased the plasma VEGF level. Alpha-lipoic acid (alpha-LA), which is an antioxidant, lowers the increased level of VEGF in retina as well. The precise role of PPAR-gamma agonist and alpha-LA on renal VEGF expression in diabetic nephropathy is still uncertain. We studied the effect of PPAR-gamma agonist, angiotensin II receptor blocker (ATIIRB) and alpha-LA on the renal VEGF expression in diabetic rats. METHODS: We used 60 Sprague-Dawley male rats, those were 8 weeks old and weighted about 300 g each as the study subjects. Among them, 48 rats were chosen and injected with streptozotocin (70 mg/kg) into peritoneal cavity to induce diabetes mellitus. The rast were than divided into 5 groups. Group I was a normal control group (n=12), group II was diabetic control group (n=12), group III was diabetic group that was given with PPAR-gamma agonist (n=12), group IV was the diabetic group that was given ATIIRB (n=12), and group V was the diabetic rats that were given alpha-LA (n=12). We measured their body weight, blood glucose levels, 24 hour urine protein and albumin levels at the baseline, the 8th and the 16th weeks of the experiment. On the 16th weeks of our experiment we extracted the kidneys to measure the glomerular volume, the optical density of the VEGF staining and VEGF mRNA expression. RESULTS: At the beginning of the study, the 5 groups all showed similar 24 hour urine albumin levels. At the 8th week, group II showed an increased urine albumin level of 143.4 +/- 117.2 mg/day; this was greater than that of group IV (60.7+/-30.6 mg/day) (p<0.05). The glomerular volume and optical densities of VEGF expression were significantly reduced in group III, IV and V compared to group II. For group IV and V, the renal VEGF mRNA expression was significantly lower than that of group II, but group III showed no significant difference. from group II. CONCLUSION: Angiotensin II receptor blocker delayed the progression of diabetic nephropathy. PPAR-gamma agonist and alpha-lipoic acid did not have any protective effect against the progression of diabetic nephropathy in spite of the decreased VEGF expression noted in this study.

Diabetes Metab J : Diabetes & Metabolism Journal