Diabetes & Metabolism Journal

Original Articles

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

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Background

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

Methods

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

Results

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

Conclusion

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

Citations

Citations to this article as recorded by

Impact of diabetes distress on glycemic control and diabetic complications in type 2 diabetes mellitus
Hye-Sun Park, Yongin Cho, Da Hea Seo, Seong Hee Ahn, Seongbin Hong, Young Ju Suh, Suk Chon, Jeong-Taek Woo, Sei Hyun Baik, Kwan Woo Lee, So Hun Kim
Scientific Reports.2024;[Epub] CrossRef
The Association between the Severity of Distal Sensorimotor Polyneuropathy and Increased Carotid Atherosclerosis in Individuals with Type 2 Diabetes
Dong-Yi Hsieh, Yun-Ru Lai, Chih-Cheng Huang, Chi-Ping Ting, Wen-Chan Chiu, Yung-Nien Chen, Chia-Yi Lien, Ben-Chung Cheng, Ting-Yin Lin, Hui Ching Chiang, Cheng-Hsien Lu
Diagnostics.2024; 14(17): 1922. CrossRef
Risk factors for rapid kidney function decline in diabetes patients
Jixin Xing, Linxi Huang, Weifu Ren, Xiaobin Mei
Renal Failure.2024;[Epub] CrossRef
Correlation analysis of carotid plaque in young patients with newly diagnosed type 2 diabetes and platelet-to-lymphocyte ratio and neutrophil–lymphocyte ratio
Huijun Wen, Hai Yu
Vascular.2023; 31(1): 90. CrossRef
Diabetic vascular diseases: molecular mechanisms and therapeutic strategies
Yiwen Li, Yanfei Liu, Shiwei Liu, Mengqi Gao, Wenting Wang, Keji Chen, Luqi Huang, Yue Liu
Signal Transduction and Targeted Therapy.2023;[Epub] CrossRef
Carotid intima-media thickness and atherosclerotic plaques are associated with renal function decline: a 14-year longitudinal population-based study
Miriam Goepfert, Till Ittermann, Marcus Dörr, Nele Friedrich, Henry Völzke, Thomas Dabers, Stephan B Felix, Ulf Schminke, Sylvia Stracke, Sabrina von Rheinbaben
Nephrology Dialysis Transplantation.2023; 38(11): 2598. CrossRef
Blood pressure and vascular determinants of glomerular filtration rate decline in diabetic kidney disease
Luca Truscello, Dina Nobre, Vehashini Sabaratnam, Olivier Bonny, Grégoire Wuerzner, Michel Burnier, Fadi Fakhouri, Menno Pruijm, Anne Zanchi
Frontiers in Cardiovascular Medicine.2023;[Epub] CrossRef
Explainable Artificial Intelligence Paves the Way in Precision Diagnostics and Biomarker Discovery for the Subclass of Diabetic Retinopathy in Type 2 Diabetics
Fatma Hilal Yagin, Seyma Yasar, Yasin Gormez, Burak Yagin, Abdulvahap Pinar, Abedalrhman Alkhateeb, Luca Paolo Ardigò
Metabolites.2023; 13(12): 1204. CrossRef
Evaluation of Subclinical Vascular Disease in Diabetic Kidney Disease: A Tool for Personalization of Management of a High-Risk Population
Christodoula Kourtidou, Vasileios Rafailidis, Garyfallia Varouktsi, Efthimios Kanakis, Vassilios Liakopoulos, Timoleon-Achilleas Vyzantiadis, Maria Stangou, Smaragdi Marinaki, Konstantinos Tziomalos
Journal of Personalized Medicine.2022; 12(7): 1139. CrossRef
Prevalence and Predictors of Renal Disease in a National Representative Sample of the Romanian Adult Population: Data from the SEPHAR IV Survey
Călin Pop, Oana Florentina Gheorghe Fronea, Ioana Antonia Branea, Lucian Mihai Itu, Roxana Darabont, Irinel Parepa, Theodora Benedek, Maria Dorobantu
Diagnostics.2022; 12(12): 3199. CrossRef
Clinical features of and risk factors for normoalbuminuric diabetic kidney disease in hospitalized patients with type 2 diabetes mellitus: a retrospective cross-sectional study
Qi Dai, Nan Chen, Ling Zeng, Xin-Jie Lin, Feng-Xiu Jiang, Xiong-Jie Zhuang, Ze-Yuan Lu
BMC Endocrine Disorders.2021;[Epub] CrossRef
The Predictive Value of Carotid Ultrasonography With Cardiovascular Risk Factors—A “SPIDER” Promoting Atherosclerosis
Hongwei Li, Xiaolin Xu, Baoming Luo, Yuling Zhang
Frontiers in Cardiovascular Medicine.2021;[Epub] CrossRef
Update on pathogenesis and diagnosis flow of normoalbuminuric diabetes with renal insufficiency
Le Deng, Wenjie Li, Gaosi Xu
European Journal of Medical Research.2021;[Epub] CrossRef
Association of serum fibroblast growth factor 21 with kidney function in a population-based Chinese cohort
Rui Zhang, Yufeng Li, Xianghai Zhou, Fang Zhang, Meng Li, Simin Zhang, Xiuying Zhang, Xin Wen, Linong Ji
Medicine.2021; 100(50): e28238. CrossRef
Letter: Presence of Carotid Plaque Is Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes Mellitus and Normal Renal Function (Diabetes Metab J 2019;43:840–53)
Min-Ji Kim, Jae-Han Jeon
Diabetes & Metabolism Journal.2020; 44(1): 201. CrossRef
Response: Presence of Carotid Plaque Is Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes Mellitus and Normal Renal Function (Diabetes Metab J 2019;43:840–53)
Da Hea Seo, So Hun Kim, Moonsuk Nam
Diabetes & Metabolism Journal.2020; 44(1): 205. CrossRef
Serum Levels of Adipocyte Fatty Acid-Binding Protein Are Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes Mellitus and Preserved Renal Function
Da Hea Seo, Moonsuk Nam, Mihye Jung, Young Ju Suh, Seong Hee Ahn, Seongbin Hong, So Hun Kim
Diabetes & Metabolism Journal.2020; 44(6): 875. CrossRef
Proteinuria Is Associated with Carotid Artery Atherosclerosis in Non-Albuminuric Type 2 Diabetes: A Cross-Sectional Study
Jaehyun Bae, Yong-ho Lee, Eun Seok Kang, Bong-Soo Cha, Byung-Wan Lee
Journal of Clinical Medicine.2020; 9(1): 136. CrossRef

Others
Rg3 Improves Mitochondrial Function and the Expression of Key Genes Involved in Mitochondrial Biogenesis in C2C12 Myotubes: Min Joo Kim, Young Do Koo, Min Kim, Soo Lim, Young Joo Park, Sung Soo Chung, Hak C. Jang, Kyong Soo Park; Diabetes Metab J. 2016;40(5):406-413. Published online August 12, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.5.406

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Background

Panax ginseng has glucose-lowering effects, some of which are associated with the improvement in insulin resistance in skeletal muscle. Because mitochondria play a pivotal role in the insulin resistance of skeletal muscle, we investigated the effects of the ginsenoside Rg3, one of the active components of P. ginseng, on mitochondrial function and biogenesis in C2C12 myotubes.

Methods

C2C12 myotubes were treated with Rg3 for 24 hours. Insulin signaling pathway proteins were examined by Western blot. Cellular adenosine triphosphate (ATP) levels and the oxygen consumption rate were measured. The protein or mRNA levels of mitochondrial complexes were evaluated by Western blot and quantitative reverse transcription polymerase chain reaction analysis.

Results

Rg3 treatment to C2C12 cells activated the insulin signaling pathway proteins, insulin receptor substrate-1 and Akt. Rg3 increased ATP production and the oxygen consumption rate, suggesting improved mitochondrial function. Rg3 increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor, which are transcription factors related to mitochondrial biogenesis. Subsequent increased expression of mitochondrial complex IV and V was also observed.

Conclusion

Our results suggest that Rg3 improves mitochondrial function and the expression of key genes involved in mitochondrial biogenesis, leading to an improvement in insulin resistance in skeletal muscle. Rg3 may have the potential to be developed as an anti-hyperglycemic agent.

Citations

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Comparison of Ginseng Leaf Extract and Its Acid-Treated Form, UG0712 Between Their Effects on Exercise Performance in Mice
Young Jin Lee, Su Hyun Yu, Gwang Yeong Seok, Su Yeon Kim, Mi Jeong Kim, Inhye Jeong, Wan Heo, Bo Su Lee, Seon Gil Do, Bok Kyung Han, Young Jun Kim
Food Supplements and Biomaterials for Health.2024;[Epub] CrossRef
Ginsenosides for the treatment of insulin resistance and diabetes: Therapeutic perspectives and mechanistic insights
Tae Hyun Kim
Journal of Ginseng Research.2024; 48(3): 276. CrossRef
Preparation and bioactivity of the rare ginsenosides Rg3 and Rh2: An updated review
Wenqi Xu, Wei Lyu, Cuicui Duan, Fumin Ma, Xiaolei Li, Dan Li
Fitoterapia.2023; 167: 105514. CrossRef
Ginsenoside Rc, an Active Component of Panax ginseng, Alleviates Oxidative Stress-Induced Muscle Atrophy via Improvement of Mitochondrial Biogenesis
Aeyung Kim, Sang-Min Park, No Soo Kim, Haeseung Lee
Antioxidants.2023; 12(8): 1576. CrossRef
Ginsenoside Rg3 protects glucocorticoid‑induced muscle atrophy in vitro through improving mitochondrial biogenesis and myotube growth
Ryuni Kim, Jee Kim, Sang-Jin Lee, Gyu-Un Bae
Molecular Medicine Reports.2022;[Epub] CrossRef
Beneficial Effects of Walnut Oligopeptides on Muscle Loss in Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice: Focusing on Mitochondrial Function
Rui Fan, Yuntao Hao, Qian Du, Jiawei Kang, Meihong Xu, Yong Li
Nutrients.2022; 14(10): 2051. CrossRef
Ginseng and ginsenosides: Therapeutic potential for sarcopenia
Weiwei Zha, Yuanhai Sun, Wenwen Gong, Linghuan Li, Wonnam Kim, Hanbing Li
Biomedicine & Pharmacotherapy.2022; 156: 113876. CrossRef
Bioactive Oligopeptides from Ginseng (Panax ginseng Meyer) Suppress Oxidative Stress-Induced Senescence in Fibroblasts via NAD+/SIRT1/PGC-1α Signaling Pathway
Na Zhu, Mei-Hong Xu, Yong Li
Nutrients.2022; 14(24): 5289. CrossRef
Review of ginsenosides targeting mitochondrial function to treat multiple disorders: Current status and perspectives
Qingxia Huang, Song Gao, Daqing Zhao, Xiangyan Li
Journal of Ginseng Research.2021; 45(3): 371. CrossRef
The Effects of Korean Red Ginseng on Biological Aging and Antioxidant Capacity in Postmenopausal Women: A Double-Blind Randomized Controlled Study
Tae-Ha Chung, Ji-Hye Kim, So-Young Seol, Yon-Ji Kim, Yong-Jae Lee
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A comprehensive review on the phytochemistry, pharmacokinetics, and antidiabetic effect of Ginseng
Yage Liu, Hao Zhang, Xuan Dai, Ruyuan Zhu, Beibei Chen, Bingke Xia, Zimengwei Ye, Dandan Zhao, Sihua Gao, Alexander N. Orekhov, Dongwei Zhang, Lili Wang, Shuzhen Guo
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Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes
Federica Zatterale, Michele Longo, Jamal Naderi, Gregory Alexander Raciti, Antonella Desiderio, Claudia Miele, Francesco Beguinot
Frontiers in Physiology.2020;[Epub] CrossRef
Stereoisomer-specific ginsenoside 20(S)-Rg3 reverses replicative senescence of human diploid fibroblasts via Akt-mTOR-Sirtuin signaling
Kyeong-Eun Yang, Hyun-Jin Jang, In-Hu Hwang, Eun Mi Hong, Min-Goo Lee, Soon Lee, Ik-Soon Jang, Jong-Soon Choi
Journal of Ginseng Research.2020; 44(2): 341. CrossRef
Ginsenosides for the treatment of metabolic syndrome and cardiovascular diseases: Pharmacology and mechanisms
Wenxiang Fan, Yongliang Huang, Hui Zheng, Shuiqin Li, Zhuohong Li, Li Yuan, Xi Cheng, Chengshi He, Jianfeng Sun
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Ca2+-activated mitochondrial biogenesis and functions improve stem cell fate in Rg3-treated human mesenchymal stem cells
Taeui Hong, Moon Young Kim, Dat Da Ly, Su Jung Park, Young Woo Eom, Kyu-Sang Park, Soon Koo Baik
Stem Cell Research & Therapy.2020;[Epub] CrossRef
Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation
Chang-Yun Woo, Jung Eun Jang, Seung Eun Lee, Eun Hee Koh, Ki-Up Lee
Diabetes & Metabolism Journal.2019; 43(3): 247. CrossRef
Ginsenoside Rg3 upregulates myotube formation and mitochondrial function, thereby protecting myotube atrophy induced by tumor necrosis factor-alpha
Sang-Jin Lee, Ju Hyun Bae, Hani Lee, Hyunji Lee, Jongsun Park, Jong-Sun Kang, Gyu-Un Bae
Journal of Ethnopharmacology.2019; 242: 112054. CrossRef
Therapeutic Potential of Ginsenosides as an Adjuvant Treatment for Diabetes
Litao Bai, Jialiang Gao, Fan Wei, Jing Zhao, Danwei Wang, Junping Wei
Frontiers in Pharmacology.2018;[Epub] CrossRef
Ginseng and obesity
Zhipeng Li, Geun Eog Ji
Journal of Ginseng Research.2018; 42(1): 1. CrossRef
Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions
Padmanaban Mohanan, Sathiyamoorthy Subramaniyam, Ramya Mathiyalagan, Deok-Chun Yang
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Inactivation of glycogen synthase kinase-3β (GSK-3β) enhances skeletal muscle oxidative metabolism
W.F. Theeuwes, H.R. Gosker, R.C.J. Langen, K.J.P. Verhees, N.A.M. Pansters, A.M.W.J. Schols, A.H.V. Remels
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2017; 1863(12): 3075. CrossRef
Anti-Fatigue Effects of Small Molecule Oligopeptides Isolated from Panax ginseng C. A. Meyer in Mice
Lei Bao, Xiaxia Cai, Junbo Wang, Yuan Zhang, Bin Sun, Yong Li
Nutrients.2016; 8(12): 807. CrossRef

Changes in Adenosine Deaminase Activity in Patients with Type 2 Diabetes Mellitus and Effect of DPP-4 Inhibitor Treatment on ADA Activity: Jae-Geun Lee, Dong Gu Kang, Jung Re Yu, Youngree Kim, Jinsoek Kim, Gwanpyo Koh, Daeho Lee; Diabetes Metab J. 2011;35(2):149-158. Published online April 30, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.2.149

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Background

Dipeptidyl peptidase 4 (DPP-4, also known as CD26) binds with adenosine deaminase (ADA) to activate T lymphocytes. Here, we investigated whether ADA activity is specifically affected by treatment with DPP-4 inhibitor (DPP4I) compared with other anti-diabetic agents.

Methods

Fasting ADA activity, in addition to various metabolic and biochemical parameters, were measured in 262 type 2 diabetes mellitus (T2DM) patients taking various anti-diabetic agents and in 46 non-diabetic control subjects.

Results

ADA activity was increased in T2DM patients compared with that in non-diabetic control subjects (mean±standard error, 23.1±0.6 U/L vs. 18.6±0.8 U/L; P<0.05). ADA activity was correlated with fasting plasma glucose (r=0.258, P<0.05), HbA1c (r=0.208, P<0.05), aspartate aminotransferase (r=0.325, P<0.05), and alanine aminotransferase (r=0.248, P<0.05). Compared with the well-controlled T2DM patients (HbA1c<7%), the poorly controlled group (HbA1c>9%) showed significantly increased ADA activity (21.1±0.8 U/L vs. 25.4±1.6 U/L; P<0.05). The effect of DPP4I on ADA activity in T2DM patients did not differ from those of other oral anti-diabetic agents or insulin. T2DM patients on metformin monotherapy showed a lower ADA activity (20.9±1.0 U/L vs. 28.1±2.8 U/L; P<0.05) compared with that of those on sulfonylurea monotherapy.

Conclusion

Our results show that ADA activity is increased in T2DM patients compared to that in non-diabetic patients, is positively correlated with blood glucose level, and that DPP4I has no additional specific effect on ADA activity, except for a glycemic control- or HbA1c-dependent effect.

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Case Report

A Case of Hepatic Glycogenosis in a Patient with Uncontrolled Type 1 Diabetes Mellitus.: Seung Hwan Lee, Hyuk Sang Kwon, Jung Ah Shin, Won Chul Kim, Jeong Hoon Kim, Yoon Hee Choi, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2006;30(1):82-86. Published online January 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.1.82

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Abstract PDF

When a patient with diabetes presents with hepatomegaly and increased level of liver enzymes, glycogenosis or nonalcoholic steatohepatitis (NASH) should be considered. Glycogenosis is mainly developed in patients with type 1 diabetes, when blood glucose level is poorly controlled, when a high dosage of insulin is administered in ketoacidosis, or when glucose is given to control hypoglycemia caused by high dosage of insulin. On the other hand, the main causes of NASH, which are known to mainly affect type 2 diabetes patients, are obesity, dyslipidemia or insulin resistance. Glycogenosis differs from NASH, the former being a reversible change that improves with the control of blood glucose level and the minimum dosage requirement of insulin, and the latter being a progressive disease that may lead to fibrosis or cirrhosis of the liver. However, clinical differentiation of the two diseases is difficult and liver biopsy is helpful for making a definite diagnosis. We present a type 1 diabetes patient with poorly controlled blood glucose level, who have had a frequent history of diabetic ketoacidosis, showing hepatomegaly and a slight increase in liver enzyme level. The patient was diagnosed as diabetic glycogenosis, confirmed by liver biopsy. Strict control of the blood glucose level resulted in rapid improvement showing the reversible nature of the disease.

Citations

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Four cases of type 1 diabetes mellitus showing sharp serum transaminase increases and hepatomegaly due to glycogenic hepatopathy
Yuichi Ikarashi, Tomomi Kogiso, Etsuko Hashimoto, Kuniko Yamamoto, Kazuhisa Kodama, Makiko Taniai, Nobuyuki Torii, Hiroko Takaike, Yasuko Uchigata, Katsutoshi Tokushige
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Three cases of glycogenic hepatopathy mimicking acute and relapsing hepatitis in type I diabetes mellitus
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Hepatic glycogenosis in a patient with poorly controlled type 1 diabetes mellitus
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Korean Journal of Pediatrics.2009; 52(11): 1279. CrossRef

Original Articles

The Effect of Nitric Oxide on Insulin Binding and Insulin Receptor Recycling in Bovine Aortic Endothelial Cells.: Hyuk Sang Kwon, Oak Kee Hong, Hee Soo Kim, Jung Min Lee, Sung Rae Kim, Sung Dae Moon, Sang Ah Jang, Hyun Shik Son, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2003;27(3):213-227. Published online June 1, 2003

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Abstract PDF: BACKGROUND
The coexistence of insulin resistance and endothelial dysfunction is commonly observed in a variety of metabolic and cardiovascular disorders, including athero-sclerosis and type 2 diabetes mellitus. Because nitric oxide (NO), or nitric oxide synthase (NOS), has been suggested as a significant contributing factor in the development of endothelial dysfunction and insulin resistance, reactive NO or NOS were investigated to see if they contribute to the insulin internalization pathway. METHODS: The production of NO (Nitrite), the expression of eNOS (endothelial NOS), insulin binding and the insulin receptor internalization and recycling, following 48 hours of incubation with bradykinin (BK), acetylcholine (Ach), NG-monomethyl- L-arginine (L-NMMA) and N-nitro-L-arginine methylester (L-NAME) in Bovine aortic endothelial cells (BAECs), were examined. RESULTS: The results were as follows: 1. In relation to the time course, the production of eNOS was increased, but was decreased after 8 hours of incubation. The production of eNOS in the L-NMMA and L-NAME treated groups was significantly decreased compared with that of the controls (p<0.05). 2. The specific insulin bindings to the receptors of the endothelial cells were maximized within 20 mins, and then decreased. At 20 mins, the binding rate of the L-NMMA treated group was significantly decreased compared to that of the controls. At a concentration of 0.4ng/ml of unlabelled insulin, the specific insulin binding of the L-NMMA treated group was significantly decreased compared to that of the controls (p<0.05). 3. The internalization of 125I-insulin into the endothelial cells, as assessed by the acid washing dissociation method, occurred rapidly. The internalized radioactivity of 125I-insulin, at 20 mins, was significantly increased in the BK and Ach groups compared with the controls (p<0.05). 4. The recycling of the internalized insulin receptors showed no significant differences between the study groups, but the recycling was slightly delayed compared with controls in the Ach group. CONCLUSION: In conclusion, the NO generating substances, BK and Ach, and the inhibitory substance, L-NMMA, may influence the binding and internalization of insulin-insulin receptors. Our results suggest that NO might contribute to the transcytosis of insulin in BAECs

Mechanism of Impaired Endothelium-dependent Vasodilation in Otsuka Long-Evans Tokushima Fatty (OLETF) Rats .: Kook Jin Chun, Seok Man Son, In Ju Kim, Chi Dae Kim, Seok Dong Yoo, Yong Ki Kim; Korean Diabetes J. 2002;26(1):47-57. Published online February 1, 2002

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Abstract PDF: BACKGROUND
Impaired vascular endothelium-dependent relaxation and augmented contractile responses have been reported in several long-term animals hyperglycemia models and human diabetic patients. Since oxidative stress has been implicated as a contributor to impaired vascular function, the mechanism of an impaired endothelium-dependent vasodilation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats was investigated. METHODS: This present study was undertaken to characterize both the vascular production and the enzymatic source of the superoxide anion in the type 2 diabetic rats. RESULTS: In the thoracic aortas of OLETF rats, endothelium-dependent relaxation was markedly attenuated compared to that of the control rats (LETO, Long-Evans Tokushima Otsuka) in association with a significant increase in superoxide production (2421.39+/-07.01 nmol/min/mg). There was no difference in eNOS expression between the OLETF rats and LETO rats. The increased production of superoxide anion was significantly attenuated by diphenyleneiodonium (DPI, 10 mol/L), NAD (P)H oxidase inhibitor. In line with these results, studies using various enzyme inhibitors such as DPI, allopurinol, rotenone and L-NMMA suggest that the main source of superoxide anions in the aorta is NAD (P)H oxidase. CONCLUSION: These results suggest that enhanced NAD(P)H oxidase activity and reduced nitric oxide (NO) availability through an interaction between NO and superoxide anion contribute to the impaired endothelium-dependent vasodilation in OLETF rats.

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