Diabetes & Metabolism Journal

Original Articles

Basic research
Reducing Oxidative Stress and Inflammation by Pyruvate Dehydrogenase Kinase 4 Inhibition Is Important in Prevention of Renal Ischemia-Reperfusion Injury in Diabetic Mice: Ah Reum Khang, Dong Hun Kim, Min-Ji Kim, Chang Joo Oh, Jae-Han Jeon, Sung Hee Choi, In-Kyu Lee; Received June 22, 2023 Accepted July 13, 2023 Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0196 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Reactive oxygen species (ROS) and inflammation are reported to have a fundamental role in the pathogenesis of ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury. The present study investigated the role of pyruvate dehydrogenase kinase 4 (PDK4) in ROS production and inflammation following IR injury.
Methods
We used a streptozotocin-induced diabetic C57BL6/J mouse model, which was subjected to IR by clamping both renal pedicles. Cellular apoptosis and inflammatory markers were evaluated in NRK-52E cells and mouse primary tubular cells after hypoxia and reoxygenation using a hypoxia work station.
Results
Following IR injury in diabetic mice, the expression of PDK4, rather than the other PDK isoforms, was induced with a marked increase in pyruvate dehydrogenase E1α (PDHE1α) phosphorylation. This was accompanied by a pronounced ROS activation, as well as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1) production. Notably, sodium dichloroacetate (DCA) attenuated renal IR injury-induced apoptosis which can be attributed to reducing PDK4 expression and PDHE1α phosphorylation levels. DCA or shPdk4 treatment reduced oxidative stress and decreased TNF-α, IL-6, IL-1β, and MCP-1 production after IR or hypoxia-reoxygenation injury.
Conclusion
PDK4 inhibition alleviated renal injury with decreased ROS production and inflammation, supporting a critical role for PDK4 in IR mediated damage. This result indicates another potential target for reno-protection during IR injury; accordingly, the role of PDK4 inhibition needs to be comprehensively elucidated in terms of mitochondrial function during renal IR injury.

Exercise Treadmill Test in Detecting Asymptomatic Coronary Artery Disease in Type 2 Diabetes Mellitus: Mee Kyoung Kim, Ki Hyun Baek, Ki Ho Song, Hyuk Sang Kwon, Jung Min Lee, Moo Il Kang, Kun Ho Yoon, Bong Yun Cha, Ho Young Son, Kwang Woo Lee; Diabetes Metab J. 2011;35(1):34-40. Published online February 28, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.1.34

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Background

The present study was designed to develop criteria for screening patients with type 2 diabetes mellitus (T2DM) for asymptomatic coronary artery disease (CAD).

Methods

A total of 213 patients with T2DM without typical angina or chest pain were studied between 2002 and 2007. We also evaluated 53 patients with T2DM who had reported chest discomfort using an exercise treadmill test (ETT).

Results

Thirty-one of the 213 asymptomatic patients had positive ETT results. We performed coronary angiography on 23 of the 31 patients with a positive ETT and found that 11 of them had significant coronary stenosis. The main differences between the patients with significant stenosis and those with a negative ETT were age (63.1±9.4 vs. 53.7±10.1 years, P=0.008) and duration of diabetes (16.0±7.5 vs. 5.5±5.7 years, P<0.001). The positive predictive value (PPV) of the ETT was calculated to be 47.8%. The PPV of the ETT increased to 87.5% in elderly patients (≥60 years) with a long duration of diabetes (≥10 years). The latter value is similar to that of patients with T2DM who presented with chest discomfort or exertional dyspnea. The PPV of the ETT in symptomatic patients was 76.9%.

Conclusion

In the interest of cost-effectiveness, screening for asymptomatic CAD could be limited to elderly patients with a duration of diabetes ≥10 years.

Citations

Citations to this article as recorded by

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Muhammad Khalil, Muhammad Shafique Arshad, Asma Zafar Khawaja, Iffat Aqeel, . Hidayatullah, Mahboob Ur Rehman, Sumeet Kumar, Shoaib Ahmed
Pakistan Journal of Health Sciences.2023; : 126. CrossRef
Anatomical and Neuromuscular Factors Associated to Non-Contact Anterior Cruciate Ligament Injury
Marc Dauty, Vincent Crenn, Bastien Louguet, Jérôme Grondin, Pierre Menu, Alban Fouasson-Chailloux
Journal of Clinical Medicine.2022; 11(5): 1402. CrossRef
Prevalence of asymptomatic silent myocardial ischemia among type 2 diabetes mellitus patients in Bangalore - A hospital-based cross-sectional study
NagappaH Handargal, ShristiJ Shetty
Journal of the Practice of Cardiovascular Sciences.2021; 7(3): 207. CrossRef
Influence of sex on the incidence of potential coronary artery disease and long-term outcomes in asymptomatic patients with diabetes mellitus
Chisato Sato, Kohei Wakabayashi, Naoko Ikeda, Yuki Honda, Ken Sato, Toshiaki Suzuki, Keita Shibata, Kaoru Tanno
IJC Heart & Vasculature.2020; 27: 100504. CrossRef
Gauging the Positive Predictive Value of Exercise Tolerance Test Using Angiographic Evaluation: A Cross-Sectional Analysis From a Developing Country
Ismail Khan, Maria Hasan, Javeria Hasan, Ali Imran Dhillon, Moosa Khan, Mehwish Kaneez
Cureus.2020;[Epub] CrossRef
EVALUATION OF SILENT MYOCARDIAL ISCHEMIA IN ASYMPTOMATIC TYPE 2 DIABETES MELLITUS PATIENTS BY TREAD MILL TEST IN TERTIARY CARE CENTER IN SOUTH INDIA
Malepati Sai Sarath Reddy, Uma Mylandlahalli Anandkumar, Srinivasa Rao
Journal of Evolution of Medical and Dental Sciences.2019; 8(10): 740. CrossRef
Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes
Stefan Kopf, Jan B. Groener, Zoltan Kender, Thomas Fleming, Maik Brune, Christin Riedinger, Nadine Volk, Esther Herpel, Dominik Pesta, Julia Szendrödi, Mark O. Wielpütz, Hans-Ulrich Kauczor, Hugo A. Katus, Michael Kreuter, Peter P. Nawroth
Respiration.2018; 96(1): 29. CrossRef
Comparison of the presence of fragmented QRS complexes in the inferior versus the anterior leads for predicting coronary artery disease severity
Mehmet Eyuboglu, Ugur Kucuk, Omer Senarslan, Bahri Akdeniz
Revista Portuguesa de Cardiologia.2017; 36(2): 89. CrossRef
Comparison of the presence of fragmented QRS complexes in the inferior versus the anterior leads for predicting coronary artery disease severity
Mehmet Eyuboglu, Ugur Kucuk, Omer Senarslan, Bahri Akdeniz
Revista Portuguesa de Cardiologia (English Edition).2017; 36(2): 89. CrossRef
High serum YKL-40 level positively correlates with coronary artery disease
Yan Jin, Jia-Ning Cao, Chun-Xia Wang, Qiu-Ting Feng, Xin-He Ye, Xin Xu, Cheng-Jian Yang
Biomarkers in Medicine.2017; 11(2): 133. CrossRef
Fragmented QRS Is Associated with Improved Predictive Value of Exercise Treadmill Testing in Patients with Intermediate Pretest Likelihood of Significant Coronary Artery Disease
Eyyup Tusun, Abdulselam Ilter, Feyzullah Besli, Emre Erkus, Ibrahim Halil Altiparmak, Mehmet Bozbay
Annals of Noninvasive Electrocardiology.2016; 21(2): 196. CrossRef
Use of imaging and clinical data to screen for cardiovascular disease in asymptomatic diabetics
Carlos Henrique Reis Esselin Rassi, Timothy W. Churchill, Carlos A. Fernandes Tavares, Mateus Guimaraes Fahel, Fabricia P. O. Rassi, Augusto H. Uchida, Bernardo L. Wajchenberg, Antonio C. Lerario, Edward Hulten, Khurram Nasir, Márcio S. Bittencourt, Carlo
Cardiovascular Diabetology.2016;[Epub] CrossRef
Obese sedentary patients with dyspnoea on exertion who are at low risk for coronary artery disease by clinical criteria have a very low prevalence of coronary artery disease
J. T. Bruckel, G. Larsen, M. R. Benson
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Potential association between coronary artery disease and the inflammatory biomarker YKL-40 in asymptomatic patients with type 2 diabetes mellitus
Hyun Min Kim, Byung-Wan Lee, Young-Mi Song, Won Jin Kim, Hyuk-Jae Chang, Dong-Hoon Choi, Hee Tae Yu, EunSeok Kang, Bong Soo Cha, Hyun Chul Lee
Cardiovascular Diabetology.2012;[Epub] CrossRef
Exercise Treadmill Test for Evaluation of Cardiovascular Disease in Diabetic Patients
Ju Youn Kim, Mee Kyoung Kim, Woo-Baek Chung
The Journal of Korean Diabetes.2012; 13(4): 182. CrossRef

Frequency of Silent Myocardial Ischemia Detected by Thallium-201 SPECT in Patients with Type 2 Diabetes.: Dong Woo Kim, Eun Hee Jung, Eun Hee Koh, Min Seon Kim, Joong Yeol Park, Seung Whan Lee, Seong Wook Park, Jin Sook Ryu, Ki Up Lee; Korean Diabetes J. 2009;33(3):225-231. Published online June 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.3.225

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Abstract PDF: BACKGROUND
Silent myocardial ischemia (SMI) is more common in diabetic patients than among the general population. It is not yet established whether a routine screening test for SMI is necessary, and which screening test would be most useful. The purpose of this study was to estimate the prevalence of SMI detected by Thallium-201 perfusion single photon emission computed tomography (SPECT) in type 2 diabetic patients. METHODS: A total of 173 asymptomatic type 2 diabetic patients were included in the study. Thallium-201 perfusion SPECT was performed to screen for SMI. RESULTS: Among the 173 patients, abnormal perfusion patterns were found in 11 patients. Coronary angiography was carried out for these patients, and significant coronary artery stenosis was found in ten of them (positive predictive value; 90.9%). There was a significant association between SMI and overt albuminuria (OR = 7.33, 95% CI, 1.825-29.437). CONCLUSION: Thallium-201 perfusion SPECT is not sensitive enough to identify SMI, but is accurate in detecting decreased myocardial perfusion. This may be a useful screening tool for detecting SMI in type 2 diabetic patients with impaired renal function.

Effective Glycemic Control Achieved by the Transplantation of VEGF-Transfected Islets in STZ-induced Diabetic Mice.: Byung Wan Lee, Hee Young Chae, You Ran Ahn, Seung Hoon Oh, Ji Youn Kim, Yun Jae Chung, Sang Young Kim, Kyun Yung Cho, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; Korean Diabetes J. 2005;29(4):282-294. Published online July 1, 2005

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Abstract PDF: BACKGROUND
Hypoxic damage is one of the major causes of early islet graft failure, and VEGF is known to play a crucial role in revascularization. We tried to evaluate whether the VEGF transgene in an islet graft can increase islet revascularization and; therefore, increase the survival rate of transplanted islets in order to achieve effective glycemic control in diabetic mice models using a non-viral cationic lipid reagent for gene delivery into non- dividing islet cells. METHODS: Human VEGF165 cDNA was transfected into Balb/c mice islets using Effectene, and the vascular neogenesis and glucose levels examined in the recipient syngeneic Balb/c mice. A minimal number of VEGF-transfected islets(100 IEQ/animal) were transplanted into STZ-induced diabetic mice. The recipient mice were classified into three groups: islet transplantation(IT) without intervention(IT-alone group, n=8), IT with an islets transduced rhoJDK-control vector(IT-rhoJDK group, n=8), and IT with an islets transduced rhoJDK-VEGF vector(IT-rhoJDK-VEGF group, n=8). RESULTS: The transfection efficiency was highest with 4microgram/microliter cDNA and 25microliter Effectene(1: 6 weight ratio), with satisfactory cell viability under these conditions. The overproductions of VEGF mRNA and proteins from the conditioned cells were confirmed. A minimal number of the VEGF-transfected islets(100 IEQ/animal) were transplanted into STZ-induced diabetic mice. The control of hyperglycemia in the IT-alone(0/8) and IT-rhoJDK groups(0/8) failed. However, complete abrogation of hyperglycemia and viable islets, and an increased vascularization of the VEGF-transfected grafts were identified in the renal capsules of the IT-rhoJDK-VEGF group(8/8). CONCLUSION: These studies support the utility of VEGF-transfected islet delivery using a cationic lipid reagent to achieve euglycemia with minimal islets via neovascularization.

Changes of TBARS and GGTase in Ischemia / Reflowed Kidney of Alloxan-diabetic Rat.: Jong Hoon Chung, Hak Yeon Bae, Jong Hee Cha, Jae Yoon Park, Pyoung Sim Park, Kwang Sam Koh, Byoung Rai Lee; Korean Diabetes J. 1999;23(6):777-784. Published online January 1, 2001

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Abstract PDF: BACKGROUND
To investigate the influence of diabetes mellitus (DM) on ischemia/reflow injury, the contents of thiobarbituric acid reactive substance (TBARS: marker of peroxidative cell injury), and the activity of gamma-glutamyltransferase (GGTase: marker of brush border membrane injury) were measured in ischemia/reflowed kidney of diabetic rats. METHODS: Rats were divided into the 3 groups; control (C), diabetes for 2 weeks (DM2) and diabetes for 4 weeks (DM4), and DM was induced by alloxan (80 mg/kg ip). Left kidney was subjected to 30 min of ischemia and 15 min of blood reflow, and the right kidney was used as a control kidney. The activities of antioxidant enzymes and GGTase, and the contents of TBARS were determined in kidney homogenate. RESULT: Catalase activity in ischemia/reflowed kidney was decreased 20% (p<0.05) in C, 34% (p<0.01) in DM2 and 23% (p<0.01) in DM4, while the change of SOD and GSHPx activities were not observed in kidney of diabetic rats cornpared with group C. TBARS contents, when ischemia/reflow, increased by 23% in C, 19% (p<0.01) in DM2, 16% in DM4, while the activity of GGTase decreased by 40% i#n C, 54% in DM2, and 55% (p<0.01) in kidney of DM4. CONCLUSION: The TBARS contents in ischemia/ reflow kidney of diabetic group showed no change, while GGTase activity was decreased significantly when compared with control group. This study may suggested that in ischemia/reflow kidney, the peroxidative membrane lipid injury was not increased, but the brush border membrane injury was increased by DM.

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