Diabetes & Metabolism Journal

Original Articles

Basic Research
Glucagon-Like Peptide Receptor Agonist Inhibits Angiotensin II-Induced Proliferation and Migration in Vascular Smooth Muscle Cells and Ameliorates Phosphate-Induced Vascular Smooth Muscle Cells Calcification: Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Diabetes Metab J. 2024;48(1):83-96. Published online January 3, 2024; DOI: https://doi.org/10.4093/dmj.2022.0363

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Background
Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system.
Methods
To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide.
Results
Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors AT1 and AT2, proliferation marker of proliferation Ki-67 (Mki-67), proliferating cell nuclear antigen (Pcna), and cyclin D1 (Ccnd1), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of Pcna, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs.
Conclusion
These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1Rdependent and independent pathways and inhibit Pi-induced vascular calcification.

Citations

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Cardiometabolic Crossroads: Obesity, Sleep-Disordered Breathing, and Epicardial Adipose Tissue in Heart Failure with Preserved Ejection Fraction – A Mini-Review
Fulvio Cacciapuoti, Ciro Mauro, Valentina Capone, Angelo Sasso, Luca Gaetano Tarquinio, Federico Cacciapuoti
Heart and Mind.2025; 9(2): 147. CrossRef
ALOX15 Aggravates Metabolic Dysfunction-Associated Steatotic Liver Disease in Mice with Type 2 Diabetes via Activating the PPARγ/CD36 Axis
Wenhui Yan, Xin Cui, Tingli Guo, Na Liu, Zhuanzhuan Wang, Yuzhuo Sun, Yuanrui Shang, Jieyun Liu, Yuanyuan Zhu, Yangyang Zhang, Lina Chen
Antioxidants & Redox Signaling.2025;[Epub] CrossRef
Targeting the S100A9/P38 MAPK/HSPB1 axis as a novel approach for aortic dissection therapy
Likang Ma, Linfeng Xie, Qingsong Wu, Lei Jin, Jiakang Li, Lele Tang, Li Zhang, Liangwan Chen, Zhihuang Qiu
International Immunopharmacology.2025; 149: 114225. CrossRef
Involvement of miRNA-204 carried by the exosomes of macrophages in the AT2 receptor-mediated improvement of vascular calcification
Hui-Yu Bai, Xiao-Rui Lv, Hai-Bo Gu, Hui Li, Bao-Shuai Shan
Cellular and Molecular Life Sciences.2025;[Epub] CrossRef
Incretin Hormone Secretion in Women with Polycystic Ovary Syndrome: Roles of Obesity, Insulin Sensitivity and Treatment with Metformin and GLP-1s
Andrea Etrusco, Mislav Mikuš, Antonio D’Amato, Fabio Barra, Petar Planinić, Trpimir Goluža, Giovanni Buzzaccarini, Jelena Marušić, Mara Tešanović, Antonio Simone Laganà
Biomedicines.2024; 12(3): 653. CrossRef
BRCC36 regulates β-catenin ubiquitination to alleviate vascular calcification in chronic kidney disease
Yalan Li, Xiaoyue Chen, Yiqing Xiong, Xueqiang Xu, Caidie Xie, Min Min, Dongmei Liang, Cheng Chen, Huijuan Mao
Journal of Translational Medicine.2024;[Epub] CrossRef
Perioperative Glucagon-Like Peptide-1 Agonist Use and Rates of Pseudarthrosis After Single-Level Lumbar Fusion: A Large Retrospective Cohort Study
Vedant Agrawal, Saketh Amasa, Mert Karabacak, Konstantinos Margetis
Neurosurgery.2024;[Epub] CrossRef

Basic Research
Pharmacologic Activation of Angiotensin-Converting Enzyme II Alleviates Diabetic Cardiomyopathy in db/db Mice by Reducing Reactive Oxidative Stress: Donghyun Kim, Wooju Jeong, Yumin Kim, Jibeom Lee, Sung Woo Cho, Chang-Myung Oh, Raekil Park; Diabetes Metab J. 2023;47(4):487-499. Published online April 25, 2023; DOI: https://doi.org/10.4093/dmj.2022.0125

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Background
Diabetes mellitus is one of the most common chronic diseases worldwide, and cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. Diabetic cardiomyopathy (DCM) is a phenomenon characterized by a deterioration in cardiac function and structure, independent of vascular complications. Among many possible causes, the renin-angiotensin-aldosterone system and angiotensin II have been proposed as major drivers of DCM development. In the current study, we aimed to investigate the effects of pharmacological activation of angiotensin-converting enzyme 2 (ACE2) on DCM.
Methods
The ACE2 activator diminazene aceturate (DIZE) was administered intraperitoneally to male db/db mice (8 weeks old) for 8 weeks. Transthoracic echocardiography was used to assess cardiac mass and function in mice. Cardiac structure and fibrotic changes were examined using histology and immunohistochemistry. Gene and protein expression levels were examined using quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Additionally, RNA sequencing was performed to investigate the underlying mechanisms of the effects of DIZE and identify novel potential therapeutic targets for DCM.
Results
Echocardiography revealed that in DCM, the administration of DIZE significantly improved cardiac function as well as reduced cardiac hypertrophy and fibrosis. Transcriptome analysis revealed that DIZE treatment suppresses oxidative stress and several pathways related to cardiac hypertrophy.
Conclusion
DIZE prevented the diabetes mellitus-mediated structural and functional deterioration of mouse hearts. Our findings suggest that the pharmacological activation of ACE2 could be a novel treatment strategy for DCM.

Citations

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Empagliflozin in diabetic cardiomyopathy: elucidating mechanisms, therapeutic potentials, and future directions
Aiswarya Jaiswal, Poonam Yadav, Pushkar Singh Rawat, Maninder Kaur, Srivalliputturu Sarath Babu, Amit Khurana, Jasvinder Singh Bhatti, Umashanker Navik
Molecular Biology Reports.2025;[Epub] CrossRef
Integrative Analyses of Biomarkers and Pathways in Oxidative Stress‐Related Genes for Gestational Diabetes Mellitus
Yunyan Chen, Fuchu Qian, Yingying Chen
American Journal of Reproductive Immunology.2025;[Epub] CrossRef
Novel insights into the central protective role of ACE2 in diabetic cardiomyopathy: from underlying signaling pathways to therapeutic perspectives
Xinyi Li, Shunlin Qu
Molecular and Cellular Biochemistry.2025;[Epub] CrossRef
Mechanisms of diabetic cardiomyopathy: Focus on inflammation
Myriam Bellemare, Liane Bourcier, Josep Iglesies‐Grau, Jacinthe Boulet, Eileen O'Meara, Nadia Bouabdallaoui
Diabetes, Obesity and Metabolism.2025; 27(5): 2326. CrossRef
Update on clinical and experimental management of diabetic cardiomyopathy: addressing current and future therapy
Peter Galis, Linda Bartosova, Veronika Farkasova, Monika Bartekova, Kristina Ferenczyova, Tomas Rajtik
Frontiers in Endocrinology.2024;[Epub] CrossRef
Vascular remodelling in cardiovascular diseases: hypertension, oxidation, and inflammation
Justyna Totoń-Żurańska, Tomasz P. Mikolajczyk, Blessy Saju, Tomasz J. Guzik
Clinical Science.2024; 138(13): 817. CrossRef

COVID-19
Effects of a DPP-4 Inhibitor and RAS Blockade on Clinical Outcomes of Patients with Diabetes and COVID-19: Sang Youl Rhee, Jeongwoo Lee, Hyewon Nam, Dae-Sung Kyoung, Dong Wook Shin, Dae Jung Kim; Diabetes Metab J. 2021;45(2):251-259. Published online March 5, 2021; DOI: https://doi.org/10.4093/dmj.2020.0206

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Background
Dipeptidyl peptidase-4 inhibitor (DPP-4i) and renin-angiotensin system (RAS) blockade are reported to affect the clinical course of coronavirus disease 2019 (COVID-19) in patients with diabetes mellitus (DM).
Methods
As of May 2020, analysis was conducted on all subjects who could confirm their history of claims related to COVID-19 in the National Health Insurance Review and Assessment Service (HIRA) database in Korea. Using this dataset, we compared the short-term prognosis of COVID-19 infection according to the use of DPP-4i and RAS blockade. Additionally, we validated the results using the National Health Insurance Service (NHIS) of Korea dataset.
Results
Totally, data of 67,850 subjects were accessible in the HIRA dataset. Of these, 5,080 were confirmed COVID-19. Among these, 832 subjects with DM were selected for analysis in this study. Among the subjects, 263 (31.6%) and 327 (39.3%) were DPP4i and RAS blockade users, respectively. Thirty-four subjects (4.09%) received intensive care or died. The adjusted odds ratio for severe treatment among DPP-4i users was 0.362 (95% confidence interval [CI], 0.135 to 0.971), and that for RAS blockade users was 0.599 (95% CI, 0.251 to 1.431). These findings were consistent with the analysis based on the NHIS data using 704 final subjects. The adjusted odds ratio for severe treatment among DPP-4i users was 0.303 (95% CI, 0.135 to 0.682), and that for RAS blockade users was 0.811 (95% CI, 0.391 to 1.682).
Conclusion
This study suggests that DPP-4i is significantly associated with a better clinical outcome of patients with COVID-19.

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Decreased Circulating Dipeptidyl Peptidase-4 Enzyme Activity Is Prognostic for Severe Outcomes in Covid-19 Inpatients
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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

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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.

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Review

The Role of Oxidative Stress in the Pathogenesis of Diabetic Vascular Complications: Shuji Sasaki, Toyoshi Inoguchi; Diabetes Metab J. 2012;36(4):255-261. Published online August 20, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.4.255

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Oxidative stress has been paid increasing attention to as an important causative factor for diabetic vascular complications. Among possible various sources, accumulating evidence has indicated that NAD(P)H oxidase may be the most important source for reactive oxygen species production in diabetic vascular tissues. The mechanisms underlying activation and up-regulation of NAD(P)H oxidase has been supposed to be mediated by high glucose-induced protein kinase C (PKC) activation. In this review article, activation of local renin-angiotensin II system induced by chymase activation is also shown to amplify such a PKC-dependent activation of NAD(P)H oxidase. Additionally, human evidence showing the beneficial effect of antioxidants on diabetic vascular complications. Bilirubin has been recognized as a strong endogenous antioxidant. Here markedly lower prevalence of vascular complications is shown in diabetic patients with Gilbert syndrome, a congenital hyperbilirubinemia, as well as reduced markers of oxidative stress and inflammation. Lastly, statin, angiotensin II receptor blocker, chymase inhibitor, bilirubin and biliverdin, PKC β isoform inhibitor, and glucagon-like peptide-1 analog, are shown to serve as antioxidants and have some beneficial effect on diabetic vascular complications, via inhibiting PKC-NAD(P)H oxidase activation, supporting the notion that this mechanism may be an effective therapeutic target for preventing diabetic vascular complications.

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Original Articles

Angiotensin II Inhibits Insulin Binding to Endothelial Cells: Su-Jin Oh, Won-Chul Ha, Jee-In Lee, Tae-Seo Sohn, Ji-Hyun Kim, Jung-Min Lee, Sang-Ah Chang, Oak-Kee Hong, Hyun-Shik Son; Diabetes Metab J. 2011;35(3):243-247. Published online June 30, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.3.243

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Abstract PDF PubReader

Background

Insulin-mediated glucose uptake in insulin target tissues is correlated with interstitial insulin concentration, rather than plasma insulin concentration. Therefore, insulin delivery to the interstitium of target tissues is very important, and the endothelium may also play an important role in the development of insulin resistance.

Methods

After treating bovine aortic endothelial cells with angiotensin II (ATII), we observed the changes in insulin binding capacity and the amounts of insulin receptor (IR) on the cell membranes and in the cytosol.

Results

After treatment of 10^-7M ATII, insulin binding was decreased progressively, up to 60% at 60 minutes (P<0.05). ATII receptor blocker (eprosartan) dose dependently improved the insulin binding capacity which was reduced by ATII (P<0.05). At 200 µM, eprosartan fully restored insulin binding capacity, althogh it resulted in only a 20% to 30% restoration at the therapeutic concentration. ATII did not affect the total amount of IR, but it did reduce the amount of IR on the plasma membrane and increased that in the cytosol.

Conclusion

ATII decreased the insulin binding capacity of the tested cells. ATII did not affect the total amount of IR but did decrease the amount of IR on the plasma membrane. Our data indicate that ATII decreases insulin binding by translocating IR from the plasma membrane to the cytosol. The binding of insulin to IR is important for insulin-induced vasodilation and transendothelial insulin transport. Therefore, ATII may cause insulin resistance through this endothelium-based mechanism.

Citations

Citations to this article as recorded by

Acute, local infusion of angiotensin II impairs microvascular and metabolic insulin sensitivity in skeletal muscle
Dino Premilovac, Emily Attrill, Stephen Rattigan, Stephen M Richards, Jeonga Kim, Michelle A Keske
Cardiovascular Research.2019; 115(3): 590. CrossRef
Angiotensin II type 2 receptor inhibits expression and function of insulin receptor in rat renal proximal tubule cells
Yang Yang, Caiyu Chen, Chunjiang Fu, Zaicheng Xu, Cong Lan, Yongchun Zeng, Zhi Chen, Pedro A. Jose, Ye Zhang, Chunyu Zeng
Journal of the American Society of Hypertension.2018; 12(2): 135. CrossRef
Endothelial function, its relation to arterial hypertension and the possibility of its modulation
Vladislav Biel, Jan Novák, Luděk Pluháček, Jiří Špác
Vnitřní lékařství.2018; 64(7-8): 762. CrossRef
Evidence to Consider Angiotensin II Receptor Blockers for the Treatment of Early Alzheimer’s Disease
Juan M. Saavedra
Cellular and Molecular Neurobiology.2016; 36(2): 259. CrossRef
Ameliorative effect of eprosartan on high-fat diet/streptozotocin-induced early diabetic nephropathy in rats
Mohamed A. Morsy, Gehan H. Heeba, Magda E. Mahmoud
European Journal of Pharmacology.2015; 750: 90. CrossRef
Metabolic actions of angiotensin II and insulin: A microvascular endothelial balancing act
Ranganath Muniyappa, Sahzene Yavuz
Molecular and Cellular Endocrinology.2013; 378(1-2): 59. CrossRef

The Effect of an Angiotensin Receptor Blocker on Arterial Stiffness in Type 2 Diabetes Mellitus Patients with Hypertension: Ji Hyun Kim, Su Jin Oh, Jung Min Lee, Eun Gyoung Hong, Jae Myung Yu, Kyung Ah Han, Kyung Wan Min, Hyun Shik Son, Sang Ah Chang; Diabetes Metab J. 2011;35(3):236-242. Published online June 30, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.3.236

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Background

Hypertension and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study analyzed the changes in central aortic waveforms and pulse wave velocity as well as related parameters after treatment with valsartan, an angiotensin II type 1 receptor blocker, in patients with type 2 diabetes and hypertension.

Methods

We used pulse wave analysis to measure central aortic waveform in a total of 98 subjects. In 47 of these patients, pulse wave velocity measurements were obtained before and after 12 weeks of treatment with valsartan.

Results

In the central aortic waveform analysis, the aortic pulse pressure and augmentation index were significantly decreased after valsartan treatment, as was the aortic pulse wave velocity. Factors contributing to the improvement in pulse wave velocity were the fasting blood glucose and haemoglobin A1c levels.

Conclusion

Short-term treatment with valsartan improves arterial stiffness in patients with type 2 diabetes and hypertension, and the glucose status at baseline was associated with this effect.

Citations

Citations to this article as recorded by

The Value of Serial Measurement of Arterial Stiffness in Cardiovascular Disease
Hack-Lyoung Kim
Reviews in Cardiovascular Medicine.2024;[Epub] CrossRef
Mechanisms underlying the blood pressure‐lowering effects of empagliflozin, losartan and their combination in people with type 2 diabetes: A secondary analysis of a randomized crossover trial
Rosalie A. Scholtes, Charlotte M. Mosterd, Anne C. Hesp, Mark M. Smits, Hiddo J. L. Heerspink, Daniël H. van Raalte
Diabetes, Obesity and Metabolism.2023; 25(1): 198. CrossRef
Distinct effects of losartan and atenolol on vascular stiffness in Marfan syndrome
Ami B Bhatt, J Stewart Buck, Jonah P Zuflacht, Jessica Milian, Samoneh Kadivar, Kimberlee Gauvreau, Michael N Singh, Mark A Creager
Vascular Medicine.2015; 20(4): 317. CrossRef
The impact of angiotensin receptor blockers on arterial stiffness: a meta-analysis
Feng Peng, Hongming Pan, Bin Wang, Jinxiu Lin, Wenquan Niu
Hypertension Research.2015; 38(9): 613. CrossRef
Arterial stiffness in atherosclerotic renovascular hypertension
Ljiljana Fodor, Vedran Premužić, Vanja Ivković, Dražen Perkov, Mario Laganović, Tajana Željković Vrkić, Živka Dika, Marijana Živko, Bojan Jelaković
Journal of Hypertension.2014; 32(11): 2238. CrossRef
Improvement of arterial wall characteristics by the low-dose fluvastatin and valsartan combination in type 1 diabetes mellitus patients
Vedran Savić, Barbara Eržen, Miodrag Janić, Mojca Lunder, Maja Boncelj, Karin Kanc, Andrej Janež, Mišo Šabovič
Diabetes and Vascular Disease Research.2013; 10(5): 420. CrossRef
The association between regional arterial stiffness and diabetic retinopathy in type 2 diabetes
Won Jun Kim, Cheol-Young Park, Se Eun Park, Eun Jung Rhee, Won Young Lee, Ki Won Oh, Sung Woo Park, Sun Woo Kim, SuJeong Song
Atherosclerosis.2012; 225(1): 237. CrossRef
Letter: The Effect of an Angiotensin Receptor Blocker on Arterial Stiffness in Type 2 Diabetes Mellitus Patients with Hypertension (Diabetes Metab J 2011;35:236-42)
Chul-Hee Kim
Diabetes & Metabolism Journal.2011; 35(4): 427. CrossRef

Effect of Valsartan on Blood Pressure and Urinary Albumin Excretion in Hypertensive Type 2 Diabetic Patients: An Open-Label, Multicenter Study.: Se Jun Park, Dae Jung Kim, Hae Jin Kim, Soo Yeon Park, Ji A Seo, Nan Hee Kim, Sung Hee Choi, Soo Lim, Hak Chul Jang, Seung Hyun Ko, Ki Ho Song, Yu Bae Ahn, Soo Kyoung Kim, Yong Wook Cho, Jun Goo Kang, Sung Hee Ihm, Cheol Young Park, Sung Woo Park, Dong Hyun Shin, Yong Hyun Kim, Kwan Woo Lee; Korean Diabetes J. 2008;32(6):513-521. Published online December 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.6.513

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Abstract PDF: BACKGROUND
Activation of renin-angiotensin system (RAS) has been an important mechanism of microvascular and macrovascular complications in diabetic patients. It has been reported that RAS blockades reduce the development and progression of diabetic nephropathy. The aim of this study was to evaluate whether valsartan, an angiotensin II receptor blocker (ARB), reduced blood pressure and urinary albumin excretion rate (UAER) in hypertensive type 2 diabetic patients. METHOD: Three hundred forty-seven hypertensive type 2 diabetic patients who had not taken angiotensin converting enzyme inhibitors or ARB for 6 months prior to this study were enrolled. We measured blood pressure and UAER before and after 24 weeks of valsartan treatment. RESULT: Baseline mean systolic and diastolic blood pressure was 143 +/- 15 and 87 +/- 11 mmHg, respectively and the median albumin excretion rate was 27 ug/mg. Reduction in systolic and diastolic blood pressure was 16 mmHg/10 mmHg and the median UAER was 19.3 ug/mg after 24 weeks (P < 0.01, respectively). When we divided the subjects into three groups according to the UAER (normoalbuminuria, microalbuminuria and macroalbuminuria), significant changes were reported in the microalbuminuria and the macroalbuminuria groups. Thirty-eight (42%) patients with microalbuminuria improved to normoalbuminuria and twelve (41%) patients with macroalbuminuria improved to microalbuminuria. We found an association between the improvement of blood pressure and UAER (R = 0.165, P = 0.015). CONCLUSION: We concluded that valsartan reduces urinary albumin excretion and blood pressure in hypertensive type 2 diabetic patients.

VEGF-Angiopoietin-Tie2 System in Diabetic Retinopathy.: Nan Hee Kim, Hee Young Kim, Ji A Seo, Kye Won Lee, Sin Gon Kim, Kyung Mook Choi, Sei Hyun Baik, Yoon Shin Park, Inho Jo, Dong Seop Choi; Korean Diabetes J. 2005;29(2):122-132. Published online March 1, 2005

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Abstract PDF: BACKGROUND
Ischemia-induced neovascularization can cause the loss of vision in retinal disorders such as diabetic retinopathy. Recent studies have shown that the angiopoietin-Tie2 system is a major regulator of vascular integrity and it is involved in pathologic angiogenesis. However, its role in the pathophysiology of diabetic retinopathy is not yet known. We examined the regulation of the VEGF-angiopoietin-Tie2 system in both in vitro and in vivo studies to discover their possible role in diabetic retinopathy. METHODS: We investigated the effects of a well-known angiogenic stimulus, hypoxia(2% O2 concentration) and vascular endothelial growth factor(VEGF, 10 ng/mL) on the expression of the angiopoietin-Tie2 mRNA in bovine retinal pericytes(BRP) and bovine aortic endothelial cells(BAEC). We also examined the expressions of VEGF-angiopoietin-Tie2 mRNA in retinas of type 2 diabetic OLETF(Otsuka-Long-Evans-Tokushima-Fatty) rats at 30 and 50 weeks. We also investigated the effect of angiotensin II receptor type 1(AT1) antagonist on the VEGFangiopoietin-Tie2 expression. RESULTS: Hypoxia and VEGF treatment significantly increased angiopoietin-1(Ang1) mRNA expression in the BRPs. In contrast, the angiopoietin-2(Ang2) mRNA expression was unaltered in the BRPs treated with hypoxia and VEGF. Significant up-regulation of Tie2 mRNA expression was found and this lasted up to 12 h. However, using BAECs, we found that only the Ang2 expression responded to these two angiogenic stimuli. In OLETF rats, the Ang-Tie2 expression patterns were similar with those of the BAECs. Ang2 and VEGF mRNA were increased at 30 and 50 weeks for the OLETF rats, whereas the Ang1 expression was not changed. The up-regulation of Ang2 and VEGF was decreased with the losartan treatment, an AT1 receptor antagonist. Tie2 mRNA expression was increased only at 50 weeks and it did not show any decrement by the losartan treatment. CONCLUSION: Our data suggest that hypoxia and VEGF treatment differentially regulate the angiopoietin-Tie2 system in the two vascular cells. Ang2 and VEGF expressions were predominantly increased in type 2 diabetic rats, and the unopposed action of Ang2 with VEGF might be involved in the development of diabetic retinopathy. The renin-angiotensin system may be a potential mechanism for the up-regulated VEGF-Ang2 system

Case Report

A Case of Severe Prolonged Hypoglycemia Caused by Combined Ramipril and Amiloride Treatment in a Nondiabetic Woman.: Min Ho Cho, Dol Mi Kim, Chul Sik Kim, Joug Suk Park, Joo Young Nam, Jin Hyuck Chang, Jina Park, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; Korean Diabetes J. 2004;28(6):554-557. Published online December 1, 2004

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Abstract PDF: The relationship between angiotensin converting enzyme inhibition and hypoglycemia remains controversial. An 82-year-old, nondiabetic woman who had taken ramipril 5 mg with amiloride 5 mg for two months was admitted to the hospital because of her altered mentality. Her plasma glucose was 1.5 mmol/L and she regained her consciousness after normalization of the plasma glucose. The recurrent attacks of hypoglycemia ended when she stopped taking ramipril. Her hypoglycemia was thought to result from the combined deficiency of catecholamines and cortisol that was induced by a deficiency of angiotensin II. The glucagoninsensitivity was thought to result from a chronic elevation of bradykinin due to the ACE inhibitor, and the relative hyperinsulinemia was though to be cased by the amiloride.

Original Articles

Effect of Captopril on Insulin Sensitivity for Subjects with Insulin Resistance.: Hye Jung Lee, Hyuk Sang Kwon, Jin Hee Lee, Sung Koo Kang, Yoon Hee Choi, Sung Ha Hwang, Seung Hyun Ko, Jung Min Lee, Kun Ho Yoon, Bong Yun Cha, Won Chul Lee, Kwang Woo Lee, Ho Young Son; Korean Diabetes J. 2004;28(5):416-424. Published online October 1, 2004

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Abstract PDF: BACKGROUND
Angiotensin converting enzyme (ACE) inhibitors are becoming increasingly popular as the first-choice antihypertensive agents for diabetic patients. This could be partly related to their suggested beneficial effects on insulin sensitivity. This study was designed to compare the effect of captopril with that of control (nitrendipine) on insulin sensitivity for subjects with insulin resistance. METHODS: 24 subjects, aged less than 60 years, with their insulin resistance being defined as the area under the curve (AUCi) of insulin that was 2 standard deviations (SD) more than that of the control subjects during oral glucose tolerance test were recruited. A randomized, double-blind, crossover trial was conducted for an 8 weeks treatment period with captopril and the control (nitrendipine) that was given after an initial 6 weeks run-in period. Anthropometric measurement including weight, height, waist and hip circumference, blood pressure (systolic & diastolic), lipid profile blood chemistry, electrolytes levels & renal function testing, and frequently sampled intravenous glucose tolerance tests (FSIGT) for the insulin sensitivity index (SI) & acute insulin response to glucose (AIRg) were also done before and after treatment, respectively. RESULTS: 18 subjects (6 males, 12 females) completed the study. The mean age of the study subjects was 47.9+/-2.9 years (mean+/-SEM), and their BMI was 28.0+/-0.7 kg/m2 (mean+/-SEM).There was a significant decrease in weight (baseline; 71.5+/-9.2 kg vs. captopril; 70.7+/-9.0 kg and nitrendipine; 709+/-9.2 kg, p<0.05, respectively) and BMI (baseline; 28.0+/-3.0 kg/m2 vs. captopril; 27.7+/-2.8 kg/m2 and nitrendipine; 27.8+/-2.9 kg/m2, p<0.05, respectively) for both groups compared with the baseline, but there are no significant differences between the two groups. Triglyceride was significantly decreased after treatment with captopril compared to the baseline and nitrendipine (187.0+/-99.5 mg/dL vs. 224.5+/-134.2 mg/dL, respectively, p<0.05). The SI was significantly increased after captopril treatment compared with the baseline (1.4+/-1.0 vs. 2.5+/-0.8 min-1 per mU/ml, respectively, p<0.05), and the captopril group was significantly higher than that of nitrendipine (1.5+/-1.0 min-1 per mU/ml, p <0.05). Acute insulin response to glucose in both groups was also increased after treatment, but there was no statistically significance. CONCLUSION: Captopril therapy improved insulin sensitivity, and it decreased the concentration of fasting insulin in subjects with insulin resistance.

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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Abstract 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.

Effect of Angiotensin II Receptor Blockade on VEGF Expression in Diabetic Nephropathy.: Myoungsook Shim, Mijin Kim, Munkyu Kim, Hyunjin Chang, Younggoo Shin, Junam Kim, Jaeman Song, Hosuk Kang, Eunyoung Lee, Kihak Song, Choonhee Chung; Korean Diabetes J. 2003;27(2):106-114. Published online April 1, 2003

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Abstract PDF: BACKGROUND
Diabetic nephropathy is one of the most serious complications of diabetes, and is the leading cause of chronic renal failure. Vascular endothelial growth factor (VEGF) plays an important role in the pathophysiology of diabetic retinopathy, which can be blocked by ACE inhibitors, but its precise role in diabetic nephropathy is uncertain. METHODS: 32 eight week-old Sprague-Dawley male rats were prepared, of which 16 were chosen for injection with streptozotocin (60 mg/kg) into the peritoneal cavity, with the goal of inducing diabetes. One week later, the peripheral blood sugar, taken from the tail vein was checked. A glucose level exceeding 200 mg/dL was taken as evidence of diabetes. The rats were divided into 4 groups of 8. Group I served as a control. Group II was treated with angiotensin II receptor blockade (L-158,809, 5 mg/kg/day, in drinking water). Group III consisted of diabetic rats and group IV diabetic rats treated with the same angiotensin II receptor blockade (L-158,809). At the beginning of the experiment and on 8th and 12th weeks, 24-hour urine protein and body weight checks were performed. At the end of the study, I extracted kidney and the glomerular volumes and optical densities of the VEGF expression in the glomeruli compared. RESULTS: The basal characteristics were initially the same. However, on weeks 8 and 12 the amount of 24-hour urine protein had increased in groups III and IV (p<0.05). By week 12, it was noticeably greater in group III than in group IV (p<0.05). The glomerular volume was also greater in groups III and IV (p<0.05). Optical density of the VEGF in the glomeruli had increased more in group III than in groups I, II and IV (p<0.05). CONCLUSION: VEGF plays a precise role in diabetic nephropathy, and angiotensin II receptor blockade can reduce diabetic nephropathy by suppressing the expression of VEGF.

The Effect of Long-term Treatment of Ramipril on Glucose Tolerance and Pancreatic Islets in Type 2 Diabetes Animal Model (OLETF Rats).: Seung Hyun Ko, Kun Ho Yoon, Myung Mi Kim, Yu Bae Ahn, Ki Ho Song, Soon Jib Yoo, Hyun Shik Son, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2001;25(6):469-482. Published online December 1, 2001

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Abstract PDF: BACKGROUND
In a Heart Outcomes Prevention Evaluation HOPE study, ramipril, a long- acting angiotensin-converting enzyme (ACE) inhibitor, significantly reduced the death rates the number of myocardial infarctions, strokes, heart failure as well as the risk of complications related to diabetes and of diabetes itself. However, it is known that ACE inhibitors improve glucose tolerance or insulin sensitivity or reduce the incidence of diabetes. METHODS: 24 week-old OLETF (Otsuka Long Evans Tokushima Fatty) rats weighing 400~450 g were used in this study. 4 groups of rats were examined in parallel for 40 weeks. The OLETF rats were randomized for treatment with an aqueous solution of ramipril ( 5mg/Kg) daily [OL (RMP), n=10)] and with saline [OL(CON), n=10)]. The LETO rats were also randomized in the same was as the OLETF rats (LT (RMP), n=10, LT (CON), n=10). The blood glucose level, body weight, systolic and diastolic blood pressure was assessed every month. At 3 and 6 months, the 24hrs urinary protein concentration was measured, and as insulin tolerance test and oral glucose tolerance test were conducted in all experimental groups. After 6 months, the body weight was matched for 2 months in each corresponding group. Subsequently, a 15% sucrose loading was done for 2 months. After the glucose tolerance test, the pancreas was excised and immunohistochemical staining was conducted for insulin to quantify the beta cell mass by a point-counting method. In addition, the islet morphology was evaluated in the pancreas. RESULTS: Ramipril treatment for a period of 6 months improved the 2hr blood glucose level, the area under the glucose curve in the oral glucose tolerance test, insulin sensitivity in addition to lowering significantly systolic and diastolic blood pressure and 24hrs urinary protein level significantly in OLETF rats. Of note, a lower weight gain was observed in both the ramipril-treated animals at 6 months. After weight matching, the AUCg and 2hr blood glucose level values were similar between the corresponding groups, but a 15% sucrose loading worsened the AUCg value. Histologically, the islets were less disorganized and the extent of fibrosis was lower in the ramipril- treated OLETF rats in the trichrome stain. CONCLUSION: Long-term treatment of ramipril, a long acting angiotensin-converting enzyme inhibitor may be useful for suppressing weight gain and proteinuria in addition to having aprotective effect on the islet to harmful stimuli such as hyperglycemia.

Relation of Angiotensin Converting Enzyme (ACE) Gene Polymorphism to Insulin Sensitivity and Carotid Atherosclerosis in Female Nondiabetic Offspring of NIDDM Patients.: Jee Young Oh, Yeon Ah Sung, Nan Ho Kyung, Yeon Jin Jang; Korean Diabetes J. 1999;23(6):831-842. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Angiotensin converting enzyme (ACE) gene polymorphism has been known to related to atherosclerotic heart disease such as acute myocardial infarction or left ventricular hypertrophy, diabetic nephropathy or retinopathy, as well as, insulin sensitivity. However, an exact relationship between ACE gene polymorphism and aforementioned diseases have not been fully established. It has been suggested that NIDDM and atherosclerosis may have common pathogenesis since some of NIDDM patients already have atherosclerotic changes at the time of the initial diagnosis. Futhermore, offspring of NIDDM patients are considered as a high risk group for both NIDDM and atherosclerosis, and these two disorders are known to be affected by some common genetic factors. Therefore, in the present study, we planned to investigate, by analyzing female offspring of NIDDM patients (offspring), the relationship of ACE gene polymorphism to insulin resistance and atherosclerosis. METHODS: Fifty-three female offspring of patients with NIDDM were participated in this study, and twenty age-BMI matched normal glucose tolerant subjects without a family history of diabetes were selected as the controls. Based on 75-g oral glucose tolerance test, subjects were divided into normal glucose tolerance (n=42) or impaired glucose tolerance (n=ll). We assessed the patterns of body fat distribution by anthropometric measurement, bioelectric impedence analysis and computed tomogram; insulin sensitivity by minimal model analysis using insulin modified frequently sampled intravenous glucose tolerance test; carotid intima-medial thickness by ultrasonography. We investigated the alleles of the ACE gene by PCR. RESULT: 1. ACE genotypes in offspring were distributed as follows; 39.6% for II, 32.0% for ID, 28.4% for DD 55.7% for I al#lele, 44.3% for D allele. This distribution was not significantly different from those in controls (35.0% for II, 55.0% for ID, 10.0% for DD, 62.5% for I allele, and 37.5% for D allele). 2. There was no significant difference in body mass index (BMI), systolic and diastolic blood pressure, and serum lipid concentrations among three genotypes. However, in the subjects with ID genotype, VSR was significantly increased compared to the subjects with DD genotype (p<0.05). In the subjects with ID genotype, percent body fat, visceral fat area, CIMT were increased, and SI and SG were decreased in comparison to II and DD subjects, although the differences between the two groups did not reached the statistical significance. 3. When the subjects were divided into quartiles of CIMT, the frequency of ID genotype of ACE showed the tendency of increment from the lowest to the highest quartile of CIMT. 4. Multiple regression analysis showed that ACE genotypes was significantly associated with visceral obesity, carotid intima-medial thickening and insulin sensitivity. CONCLUSION: ACE genotypes was not significantly associated with visceral obesity, carotid intima- medial thickening and insulin sensitivity. However, to explore the true associations of ACE gene polymorphism with insulin resistance and ather-osclerosis, we further suggest and recommend prospective studies.

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