Diabetes & Metabolism Journal

Original Articles

Basic Research
Hypoxia Increases β-Cell Death by Activating Pancreatic Stellate Cells within the Islet: Jong Jin Kim, Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song; Diabetes Metab J. 2020;44(6):919-927. Published online May 11, 2020; DOI: https://doi.org/10.4093/dmj.2019.0181

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Background

Hypoxia can occur in pancreatic islets in type 2 diabetes mellitus. Pancreatic stellate cells (PSCs) are activated during hypoxia. Here we aimed to investigate whether PSCs within the islet are also activated in hypoxia, causing β-cell injury.

Methods

Islet and primary PSCs were isolated from Sprague Dawley rats, and cultured in normoxia (21% O₂) or hypoxia (1% O₂). The expression of α-smooth muscle actin (α-SMA), as measured by immunostaining and Western blotting, was used as a marker of PSC activation. Conditioned media (hypoxia-CM) were obtained from PSCs cultured in hypoxia.

Results

Islets and PSCs cultured in hypoxia exhibited higher expressions of α-SMA than did those cultured in normoxia. Hypoxia increased the production of reactive oxygen species. The addition of N-acetyl-L-cysteine, an antioxidant, attenuated the hypoxia-induced PSC activation in islets and PSCs. Islets cultured in hypoxia-CM showed a decrease in cell viability and an increase in apoptosis.

Conclusion

PSCs within the islet are activated in hypoxia through oxidative stress and promote islet cell death, suggesting that hypoxia-induced PSC activation may contribute to β-cell loss in type 2 diabetes mellitus.

Citations

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Effects of hypoxia in the diabetic corneal stroma microenvironment
Purnima Sharma, Jian-Xing Ma, Dimitrios Karamichos
Experimental Eye Research.2024; 240: 109790. CrossRef
High‐resolution magic angle spinning nuclear magnetic resonance of donor pancreatic tissue may predict islet viability prior to isolation
Carolyn M. Slupsky, Brian D. Sykes, Jonathan R. T. Lakey
NMR in Biomedicine.2024;[Epub] CrossRef
Nanomedicine regulating PSC-mediated intercellular crosstalk: Mechanisms and therapeutic strategies
Hui Wang, Liang Qi, Han Han, Xuena Li, Mengmeng Han, Lei Xing, Ling Li, Hulin Jiang
Acta Pharmaceutica Sinica B.2024;[Epub] CrossRef
Visualizing hypoxic modulation of beta cell secretions via a sensor augmented oxygen gradient
Kai Duan, Mengyang Zhou, Yong Wang, Jose Oberholzer, Joe F. Lo
Microsystems & Nanoengineering.2023;[Epub] CrossRef
Pancreatic stellate cells promote pancreatic β-cell death through exosomal microRNA transfer in hypoxia
Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song
Molecular and Cellular Endocrinology.2023; 572: 111947. CrossRef
Pancreatic stellate cells in pancreatic cancer: as potential targets for future therapy
Zhengfeng Wang, Ru He, Shi Dong, Wence Zhou
Frontiers in Oncology.2023;[Epub] CrossRef
Recent advances in the development of bioartificial pancreas using 3D bioprinting for the treatment of type 1 diabetes: a review
Anushikha Ghosh, Arka Sanyal, Abhik Mallick
Exploration of Medicine.2023; : 886. CrossRef
Pancreas and islet morphology in cystic fibrosis: clues to the etiology of cystic fibrosis-related diabetes
Sarah S. Malik, Diksha Padmanabhan, Rebecca L. Hull-Meichle
Frontiers in Endocrinology.2023;[Epub] CrossRef
Diabetic mellitus, vascular calcification and hypoxia: A complex and neglected tripartite relationship
Xue-Jiao Sun, Nai-Feng Liu
Cellular Signalling.2022; 91: 110219. CrossRef
HIF-1 and NRF2; Key Molecules for Malignant Phenotypes of Pancreatic Cancer
Shin Hamada, Ryotaro Matsumoto, Atsushi Masamune
Cancers.2022; 14(2): 411. CrossRef
Pancreatic Stellate Cells and Metabolic Alteration: Physiology and Pathophysiology
Shin Hamada, Ryotaro Matsumoto, Atsushi Masamune
Frontiers in Physiology.2022;[Epub] CrossRef
Exosomal miR-140–3p and miR-143–3p from TGF-β1-treated pancreatic stellate cells target BCL2 mRNA to increase β-cell apoptosis
Xiangyun Zhu, Dechen Liu, Guoqing Li, Mengmeng Zhi, Ji Sun, Liang Qi, Jingbo Li, Stephen J. Pandol, Ling Li
Molecular and Cellular Endocrinology.2022; 551: 111653. CrossRef
Mitochondria oxidative stress mediated nicotine-promoted activation of pancreatic stellate cells by regulating mitochondrial dynamics
Yue Yuan, Zhiren Li, Miaomiao Li, Tong Jin, Xiaoyun Zhang, Xinjuan Liu, Jianyu Hao
Toxicology in Vitro.2022; 84: 105436. CrossRef
Antioxidant Mitoquinone Alleviates Chronic Pancreatitis via Anti-Fibrotic and Antioxidant Effects
Miaomiao Li, Yue Yuan, Xue Han, Xinjuan Liu, Weizhen Zhang, Jianyu Hao
Journal of Inflammation Research.2022; Volume 15: 4409. CrossRef
Diabetic Ferroptosis and Pancreatic Cancer: Foe or Friend?
Le Li, Xing-jia Yu, Lei Gao, Long Cheng, Bei Sun, Gang Wang
Antioxidants & Redox Signaling.2022; 37(16-18): 1206. CrossRef
Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia
Matias Estaras, Manuel R. Gonzalez-Portillo, Miguel Fernandez-Bermejo, Jose M. Mateos, Daniel Vara, Gerardo Blanco-Fernandez, Diego Lopez-Guerra, Vicente Roncero, Gines M. Salido, Antonio González
International Journal of Molecular Sciences.2021; 22(11): 5555. CrossRef
Integrated pancreatic microcirculatory profiles of streptozotocin‐induced and insulin‐administrated type 1 diabetes mellitus
Yuan Li, Bingwei Li, Bing Wang, Mingming Liu, Xiaoyan Zhang, Ailing Li, Jian Zhang, Honggang Zhang, Ruijuan Xiu
Microcirculation.2021;[Epub] CrossRef
Pancreatic stellate cells - rising stars in pancreatic pathologies
P Hrabák, M Kalousová, T Krechler, T Zima
Physiological Research.2021; (S4): S597. CrossRef

Complications
The Association between Pancreatic Steatosis and Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients: Jee Sun Jeong, Mee Kyung Kim, Kyung Do Han, Oak Kee Hong, Ki-Hyun Baek, Ki-Ho Song, Dong Jin Chung, Jung-Min Lee, Hyuk-Sang Kwon; Diabetes Metab J. 2018;42(5):425-432. Published online August 9, 2018; DOI: https://doi.org/10.4093/dmj.2017.0107

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Abstract PDF PubReader

Background

Whether pancreatic steatosis has a local or systemic effect, like ectopic fat of other major organs, remains unknown. Data on the influence of pancreatic steatosis on microvascular complication are rare. Therefore, we investigated the relationship between pancreatic steatosis and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

Methods

The attenuation of three pancreatic regions (head, body, and tail) and the spleen (S) in 186 patients with T2DM was measured using non-enhanced computed tomography imaging. We used three parameters for the assessment of pancreatic steatosis (‘P’ mean: mean attenuation of three pancreatic regions; P–S: difference between ‘P’ mean and ‘S’; P/S: the ‘P’ mean to ‘S’ ratio). The presence of DR was assessed by an expert ophthalmologist using dilated fundoscopy.

Results

The average P mean was 29.02 Hounsfield units (HU), P–S was −18.20 HU, and P/S was 0.61. The three pancreatic steatosis parameters were significantly associated with the prevalence of DR in non-obese T2DM patients. In the non-obese group, the odds ratios of P mean, P–S, and P/S for the prevalence of DR, after adjustment for age, sex, and glycosylated hemoglobin level, were 2.449 (P=0.07), 2.639 (P=0.04), and 2.043 (P=0.02), respectively.

Conclusion

In this study, pancreatic steatosis was significantly associated with DR in non-obese patients with T2DM. Further studies are necessary to clarify the causal relationship between pancreatic steatosis and the development of DR.

Citations

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Intra‐pancreatic fat is associated with continuous glucose monitoring metrics
Yutong Liu, Wandia Kimita, Xiatiguli Shamaitijiang, Loren Skudder‐Hill, Ivana R. Sequeira‐Bisson, Maxim S. Petrov
Diabetes, Obesity and Metabolism.2024; 26(6): 2359. CrossRef
Association between Intrapancreatic Fat Deposition and Lower High-Density Lipoprotein Cholesterol in Individuals with Newly Diagnosed T2DM
Jianliang Wang, Qingyun Cai, Xiaojuan Wu, Jiaxuan Wang, Xiaona Chang, Xiaoyu Ding, Jia Liu, Guang Wang, Muhittin Yurekli
International Journal of Endocrinology.2023; 2023: 1. CrossRef
The comparison of pancreatic and hepatic steatosis in healthy liver donor candidates
Bedriye Koyuncu Sokmen, Tolga Sahin, Alihan Oral, Erdem Kocak, Nagihan Inan
Scientific Reports.2021;[Epub] CrossRef
Computed Tomography-Estimated Pancreatic Steatosis is Associated with Carotid Plaque in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study from China
Pengtao Sun, Chunzhi Fan, Rengui Wang, Tongwei Chu, Xiaoli Sun, Dongxue Zhang, Xuechao Du
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2021; Volume 14: 1329. CrossRef

Complications
Clinical Course and Risk Factors of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus in Korea: Jae-Seung Yun, Tae-Seok Lim, Seon-Ah Cha, Yu-Bae Ahn, Ki-Ho Song, Jin A Choi, Jinwoo Kwon, Donghyun Jee, Yang Kyung Cho, Yong-Moon Park, Seung-Hyun Ko; Diabetes Metab J. 2016;40(6):482-493. Published online October 5, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.6.482

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Abstract PDF Supplementary Material PubReader

Background

We investigated clinical course and risk factors for diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).

Methods

A total of 759 patients with T2DM without DR were included from January 2001 to December 2004. Retinopathy evaluation was performed at least annually by ophthalmologists. The severity of the DR was classified into five categories according to the International Clinical Diabetic Retinopathy Severity Scales.

Results

Of the 759 patients, 523 patients (68.9%) completed the follow-up evaluation. During the follow-up period, 235 patients (44.9%) developed DR, and 32 patients (13.6%) progressed to severe nonproliferative DR (NPDR) or proliferative DR (PDR). The mean duration of diabetes at the first diagnosis of mild NPDR, moderate NPDR, and severe NPDR or PDR were 14.8, 16.7, and 17.3 years, respectively. After adjusting multiple confounding factors, the significant risk factors for the incidence of DR risk in patients with T2DM were old age, longer duration of diabetes, higher mean glycosylated hemoglobin (HbA1c), and albuminuria. Even in the patients who had been diagnosed with diabetes for longer than 10 years at baseline, a decrease in HbA1c led to a significant reduction in the risk of developing DR (hazard ratio, 0.73 per 1% HbA1c decrement; 95% confidence interval, 0.58 to 0.91; P=0.005).

Conclusion

This prospective cohort study demonstrates that glycemic control, diabetes duration, age, and albuminuria are important risk factors for the development of DR. More aggressive retinal screening for T2DM patients diagnosed with DR should be required in order to not miss rapid progression of DR.

Citations

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Diabetes & Metabolic Syndrome: Clinical Research & Reviews.2024; 18(5): 103044. CrossRef
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Ali Dehghani, Hamid Korozhdehi, Saeid Hossein Khalilzadeh, Hossein Fallahzadeh, Vahid Rahmanian
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Symon Chikumba, Yuqian Hu, Jing Luo
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Effect of anticoagulant/antiplatelet therapy on the development and progression of diabetic retinopathy
Chi-Juei Jeng, Yi-Ting Hsieh, Cheng-Li Lin, I-Jong Wang
BMC Ophthalmology.2022;[Epub] CrossRef
A deep learning model for screening type 2 diabetes from retinal photographs
Jae-Seung Yun, Jaesik Kim, Sang-Hyuk Jung, Seon-Ah Cha, Seung-Hyun Ko, Yu-Bae Ahn, Hong-Hee Won, Kyung-Ah Sohn, Dokyoon Kim
Nutrition, Metabolism and Cardiovascular Diseases.2022; 32(5): 1218. CrossRef
Risk factor analysis and clinical decision tree model construction for diabetic retinopathy in Western China
Yuan-Yuan Zhou, Tai-Cheng Zhou, Nan Chen, Guo-Zhong Zhou, Hong-Jian Zhou, Xing-Dong Li, Jin-Rui Wang, Chao-Fang Bai, Rong Long, Yu-Xin Xiong, Ying Yang
World Journal of Diabetes.2022; 13(11): 986. CrossRef
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Zahra Heidari, Zahra Sharafi
Iranian South Medical Journal.2022; 25(1): 30. CrossRef
The Related Risk Factors of Diabetic Retinopathy in Elderly Patients with Type 2 Diabetes Mellitus: A Hospital-Based Cohort Study in Taiwan
Tsai-Tung Chiu, Tien-Lung Tsai, Mei-Yin Su, Tsan Yang, Peng-Lin Tseng, Yau-Jiunn Lee, Chao-Hsien Lee
International Journal of Environmental Research and Public Health.2021; 18(1): 307. CrossRef
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Dandan Song, Chengqian Li, Zhongchao Wang, Yuhang Zhao, Baoming Shen, Wenjuan Zhao
Journal of Diabetes Investigation.2021; 12(8): 1471. CrossRef
PREVALENCE OF ADVANCED DIABETIC EYE DISEASE AND ITS ASSOCIATED RISK FACTORS IN TYPE 2 DIABETES MELLITUS
Likathung Ngullie, Bratatee Roy, Sayantan Ghosh, Sneha Jain, Lakshmi Kanta Mondal
INTERNATIONAL JOURNAL OF SCIENTIFIC RESEARCH.2021; : 25. CrossRef
Progression of Diabetic Retinopathy and Declining Renal Function in Patients with Type 2 Diabetes
AJin Cho, Hayne Cho Park, Young-Ki Lee, Young Joo Shin, So Hyun Bae, Hakyoung Kim
Journal of Diabetes Research.2020; 2020: 1. CrossRef
First nation-wide study of diabetic retinopathy in Poland in the years 2013–2017
Milena Kozioł, Michał S. Nowak, Monika Udziela, Paweł Piątkiewicz, Iwona Grabska-Liberek, Jacek P. Szaflik
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Awareness of diabetic retinopathy among Saudis with diabetes type 2 in Riyadh city
YousefM Alluhaymid, FawzanY Alotaibi, AbdulmajeedB Alotaibi, AbdullahM Albasha, AbdulrahmanS Alnaim, EssaM Sabi, AhmedH Mujamammi
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Jun Sung Moon
Diabetes & Metabolism Journal.2019; 43(6): 911. CrossRef
Past and Current Status of Adult Type 2 Diabetes Mellitus Management in Korea: A National Health Insurance Service Database Analysis
Seung-Hyun Ko, Kyungdo Han, Yong-ho Lee, Junghyun Noh, Cheol-Young Park, Dae-Jung Kim, Chang Hee Jung, Ki-Up Lee, Kyung-Soo Ko
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RNA sequencing identified specific circulating miRNA biomarkers for early detection of diabetes retinopathy
Zhen Liang, Kai P. Gao, Yi X. Wang, Zi C. Liu, Li Tian, Xin Z. Yang, Jing Y. Ding, Wei T. Wu, Wen H. Yang, Yi L. Li, Ze B. Zhang, Ri H. Zhai
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Ping Zhu, Xiong-Fei Pan, Liting Sheng, Henggui Chen, An Pan
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Complications
Baseline-Corrected QT (QTc) Interval Is Associated with Prolongation of QTc during Severe Hypoglycemia in Patients with Type 2 Diabetes Mellitus: Seon-Ah Cha, Jae-Seung Yun, Tae-Seok Lim, Yoon-Goo Kang, Kang-Min Lee, Ki-Ho Song, Ki-Dong Yoo, Yong-Moon Park, Seung-Hyun Ko, Yu-Bae Ahn; Diabetes Metab J. 2016;40(6):463-472. Published online October 5, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.6.463

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Abstract PDF PubReader

Background

We investigated an association between baseline heart rate-corrected QT (QTc) interval before severe hypoglycemia (SH) and prolongation of QTc interval during SH in patients with type 2 diabetes mellitus (T2DM).

Methods

Between January 2004 and June 2014, 208 patients with T2DM, who visited the emergency department because of SH and underwent standard 12-lead electrocardiography within the 6-month period before SH were consecutively enrolled. The QTc interval was analyzed during the incidence of SH, and 6 months before and after SH. QTc intervals of 450 ms or longer in men and 460 ms or longer in women were considered abnormally prolonged.

Results

The mean age and diabetes duration were 68.1±12.1 and 14.1±10.1 years, respectively. The mean QTc intervals at baseline and SH episodes were 433±33 and 460±33 ms, respectively (P<0.001). One hundred and fourteen patients (54.8%) had a prolonged QTc interval during SH. There was a significant decrease in the prolonged QTc interval within 6 months after SH (QTc interval prolongation during SH vs. after recovery, 54.8% vs. 33.8%, P<0.001). The prolonged QTc interval was significantly associated with baseline QTc interval prolongation (odds ratio, 2.92; 95% confidence interval, 1.22 to 6.96; P=0.016) after adjusting for multiple confounders.

Conclusion

A prolonged QTc interval at baseline was significantly associated with prolongation of the QTc interval during SH in patients with T2DM, suggesting the necessity of QTc interval monitoring and attention to those with a prolonged QTc interval to prevent SH.

Citations

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Prevalence of QT prolongation and its risk factors in patients with type 2 diabetes
Khaled Aburisheh, Mohammad F. AlKheraiji, Saleh I. Alwalan, Arthur C. Isnani, Mohamed Rafiullah, Muhammad Mujammami, Assim A. Alfadda
BMC Endocrine Disorders.2023;[Epub] CrossRef
U-shaped association between the triglyceride–glucose index and atrial fibrillation incidence in a general population without known cardiovascular disease
Xiao Liu, Ayiguli Abudukeremu, Yuan Jiang, Zhengyu Cao, Maoxiong Wu, Jianyong Ma, Runlu Sun, Wanbing He, Zhiteng Chen, Yangxin Chen, Peng Yu, Wengen Zhu, Yuling Zhang, Jingfeng Wang
Cardiovascular Diabetology.2023;[Epub] CrossRef
Celebrities in the heart, strangers in the pancreatic beta cell: Voltage‐gated potassium channels Kv7.1 and Kv11.1 bridge long QT syndrome with hyperinsulinaemia as well as type 2 diabetes
Anniek F. Lubberding, Christian R. Juhl, Emil Z. Skovhøj, Jørgen K. Kanters, Thomas Mandrup‐Poulsen, Signe S. Torekov
Acta Physiologica.2022;[Epub] CrossRef
Severe hypoglycemia as a risk factor for cardiovascular outcomes in patients with type 2 diabetes: is it preventable?
Seung-Hyun Ko
Cardiovascular Prevention and Pharmacotherapy.2022; 4(3): 106. CrossRef
Heart rate-corrected QT interval prolongation is associated with decreased heart rate variability in patients with type 2 diabetes
Seon-Ah Cha
Medicine.2022; 101(45): e31511. CrossRef
Severe hypoglycemia as a preventable risk factor for cardiovascular disease in patients with type 2 diabetes mellitus
Soo-Yeon Choi, Seung-Hyun Ko
The Korean Journal of Internal Medicine.2021; 36(2): 263. CrossRef
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Marile Santamarina, Curt J. Carlson
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Ting Cao, Xiong Zhang, Dan Yang, Yue-Qian Wang, Zheng-Dong Qiao, Jian-Ming Huang, Peng Zhang
Biochemical and Biophysical Research Communications.2018; 495(1): 693. CrossRef
Severe hypoglycemia is a risk factor for atrial fibrillation in type 2 diabetes mellitus: Nationwide population-based cohort study
Seung-Hyun Ko, Yong-Moon Park, Jae-Seung Yun, Seon-Ah Cha, Eue-Keun Choi, Kyungdo Han, Eugene Han, Yong-ho Lee, Yu-Bae Ahn
Journal of Diabetes and its Complications.2018; 32(2): 157. CrossRef
Incidence of prolonged QTc and severe hypoglycemia in type 1 diabetes: the EURODIAB Prospective Complications Study
Cristina Amione, Sara Giunti, Paolo Fornengo, Sabita S. Soedamah-Muthu, Nish Chaturvedi, J. H. Fuller, Federica Barutta, Gabriella Gruden, Graziella Bruno
Acta Diabetologica.2017; 54(9): 871. CrossRef

Complications
Risk Factors for the Development and Progression of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Advanced Diabetic Retinopathy: Kyung-Jin Yun, Hye Ji Kim, Mee Kyoung Kim, Hyuk-Sang Kwon, Ki-Hyun Baek, Young Jung Roh, Ki-Ho Song; Diabetes Metab J. 2016;40(6):473-481. Published online September 20, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.6.473

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Background

Some patients with type 2 diabetes mellitus (T2DM) do not develop diabetic kidney disease (DKD) despite the presence of advanced diabetic retinopathy (DR). We aimed to investigate the presence of DKD and its risk factors in patients with T2DM and advanced DR.

Methods

We conducted a cross-sectional study in 317 patients with T2DM and advanced DR. The phenotypes of DKD were divided into three groups according to the urine albumin/creatinine ratio (uACR, mg/g) and estimated glomerular filtration rate (eGFR, mL/min/1.73 m²): no DKD (uACR <30 and eGFR ≥60), non-severe DKD (uACR ≥30 or eGFR <60), and severe DKD (uACR ≥30 and eGFR <60). Mean systolic and diastolic blood pressure, mean glycosylated hemoglobin (HbA1c) level, and HbA1c variability (standard deviation [SD] of serial HbA1c values or HbA1c-SD) were calculated for the preceding 2 years.

Results

The prevalence of no DKD, non-severe DKD, and severe DKD was 37.2% (n=118), 37.0% (n=117), and 25.8% (n=82), respectively. HbA1c-SD and the triglyceride/high density lipoprotein cholesterol (TG/HDL-C) ratio correlated positively with uACR and negatively with eGFR. Multiple linear regression analyses showed that the HbA1c-SD and TG/HDL-C ratio were significantly related with eGFR. Multiple logistic regression analyses after adjusting for several risk factors showed that HbA1c-SD and the TG/HDL-C ratio were significant risk factors for severe DKD.

Conclusion

The prevalence of DKD was about 60% in patients with T2DM and advanced DR. HbA1c variability and TG/HDL-C ratio may affect the development and progression of DKD in these patients.

Citations

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Complications
Severe Hypoglycemia and Cardiovascular or All-Cause Mortality in Patients with Type 2 Diabetes: Seon-Ah Cha, Jae-Seung Yun, Tae-Seok Lim, Seawon Hwang, Eun-Jung Yim, Ki-Ho Song, Ki-Dong Yoo, Yong-Moon Park, Yu-Bae Ahn, Seung-Hyun Ko; Diabetes Metab J. 2016;40(3):202-210. Published online April 5, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.3.202

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Background

We investigated the association between severe hypoglycemia (SH) and the risk of cardiovascular (CV) or all-cause mortality in patients with type 2 diabetes.

Methods

The study included 1,260 patients aged 25 to 75 years with type 2 diabetes from the Vincent Type 2 Diabetes Resgistry (VDR), who consecutively enrolled (n=1,260) from January 2000 to December 2010 and were followed up until May 2015 with a median follow-up time of 10.4 years. Primary outcomes were death from any cause or CV death. We investigated the association between the CV or all-cause mortality and various covariates using Cox proportional hazards regression analysis.

Results

Among the 906 participants (71.9%) who completed follow-up, 85 patients (9.4%) had at least one episode of SH, and 86 patients (9.5%) died (9.1 per 1,000 patient-years). Patients who had died were older, had a longer duration of diabetes and hypertension, received more insulin, and had more diabetic microvascular complications at baseline, as compared with surviving patients. The experience of SH was significantly associated with an increased risk of all-cause mortality (hazard ratio [HR], 2.64; 95% confidence interval [CI], 1.39 to 5.02; P=0.003) and CV mortality (HR, 6.34; 95% CI, 2.02 to 19.87; P=0.002) after adjusting for sex, age, diabetic duration, hypertension, mean glycosylated hemoglobin levels, diabetic nephropathy, lipid profiles, and insulin use.

Conclusion

We found a strong association between SH and increased risk of all-cause and CV mortality in patients with type 2 diabetes.

Citations

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Complications
Cardiovascular Disease Predicts Severe Hypoglycemia in Patients with Type 2 Diabetes: Jae-Seung Yun, Seung-Hyun Ko, Sun-Hye Ko, Ki-Ho Song, Ki-Dong Yoo, Kun-Ho Yoon, Yong-Moon Park, Yu-Bae Ahn; Diabetes Metab J. 2015;39(6):498-506. Published online July 8, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.6.498

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Background

To investigate whether a history of prior cardiovascular disease (CVD) is associated with severe hypoglycemia (SH) in patients with type 2 diabetes.

Methods

We conducted a prospective cohort study from January 2001 to December 2012 with a median follow-up time of 9.5 years (5,814 person-years). Patients aged 25 to 75 years with type 2 diabetes and without chronic kidney disease were enrolled (n=894), and 624 patients completed follow-up. SH was defined as hypoglycemic episodes requiring hospitalization or medical care in an emergency department. We used the Cox proportional hazards regression analysis to test associations between SH episodes and potential explanatory variables.

Results

Among the 624 participants who completed follow-up, 60 patients (9.6%) had previous CVD. Compared to patients without CVD, patients with previous CVD were older, had a longer duration of diabetes and hypertension, received more insulin, and had more diabetic microvascular complications at baseline. During follow-up, 62 patients (9.9%) experienced at least one SH episode (incidence of 1.33 per 100 patient-years). The development of SH was associated with a history of CVD (hazard ratio, 1.99; 95% confidence interval, 1.07 to 3.72; P=0.031) after adjusting for sex, age, diabetic duration, hypertension, hemoglobin A1c levels, diabetic complications, cardiovascular autonomic neuropathy, and insulin use.

Conclusion

A history of CVD was an independent risk factor for the development of SH in patients with type 2 diabetes mellitus. For patients with CVD, modulation of glycemic targets and diabetic education for the prevention of hypoglycemia should be implemented.

Citations

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Concomitant Use of Sulfonylureas and β-Blockers and the Risk of Severe Hypoglycemia Among Patients With Type 2 Diabetes: A Population-Based Cohort Study
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Randomised controlled trial of pharmacist-led patient counselling in controlling hypoglycaemic attacks in older adults with type 2 diabetes mellitus (ROSE-ADAM): A study protocol of the SUGAR intervention
Huda Y. Almomani, Carlos Rodriguez Pascual, Sayer I. Al-Azzam, Keivan Ahmadi
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Management of hypoglycemia in older adults with type 2 diabetes
Jeffrey Freeman
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Use of stellate ganglion block for treatment of recurrent syncope followed by chest pain
Young-ung Kim, Yong-joon Shin, Young Woo Cho
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Coronary artery disease severity modifies associations between glycemic control and both mortality and myocardial infarction
Sridharan Raghavan, Wenhui G. Liu, P. Michael Ho, Mary E. Plomondon, Anna E. Barón, Liron Caplan, Karen E. Joynt Maddox, David Magid, David R. Saxon, Corrine I. Voils, Steven M. Bradley, Thomas M. Maddox
Journal of Diabetes and its Complications.2018; 32(5): 480. CrossRef
Depth and combined infection is important predictor of lower extremity amputations in hospitalized diabetic foot ulcer patients
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The Korean Journal of Internal Medicine.2018; 33(5): 952. CrossRef
Time- and frequency-domain measures of heart rate variability predict cardiovascular outcome in patients with type 2 diabetes
Seon-Ah Cha, Yong-Moon Park, Jae-Seung Yun, Seung-Hwan Lee, Yu-Bae Ahn, Sung-Rae Kim, Seung-Hyun Ko
Diabetes Research and Clinical Practice.2018; 143: 159. CrossRef
Risk Factors for Severe Hypoglycemia in Black and White Adults With Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study
Alexandra K. Lee, Clare J. Lee, Elbert S. Huang, A. Richey Sharrett, Josef Coresh, Elizabeth Selvin
Diabetes Care.2017; 40(12): 1661. CrossRef
Early inner retinal thinning and cardiovascular autonomic dysfunction in type 2 diabetes
Jin A. Choi, Hyo Won Kim, Jin-Woo Kwon, Yun-sub Shim, Dong Hyun Jee, Jae-Seung Yun, Yu-Bae Ahn, Chan Kee Park, Seung-Hyun Ko, Patrice E. Fort
PLOS ONE.2017; 12(3): e0174377. CrossRef
Cardiovascular Autonomic Dysfunction Predicts Diabetic Foot Ulcers in Patients With Type 2 Diabetes Without Diabetic Polyneuropathy
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Medicine.2016; 95(12): e3128. CrossRef
Clinical Course and Risk Factors of Diabetic Retinopathy in Patients with Type 2 Diabetes Mellitus in Korea
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Diabetes & Metabolism Journal.2016; 40(6): 482. CrossRef
Diabetic Cardiovascular Autonomic Neuropathy Predicts Recurrent Cardiovascular Diseases in Patients with Type 2 Diabetes
Seon-Ah Cha, Jae-Seung Yun, Tae-Seok Lim, Kyoungil Min, Ki-Ho Song, Ki-Dong Yoo, Yong-Moon Park, Yu-Bae Ahn, Seung-Hyun Ko, James M Wright
PLOS ONE.2016; 11(10): e0164807. CrossRef
Meta-analysis: Association between hypoglycaemia and serious adverse events in older patients
Katharina Mattishent, Yoon Kong Loke
Journal of Diabetes and its Complications.2016; 30(5): 811. CrossRef
Letter: Cardiovascular Disease Predicts Severe Hypoglycemia in Patients with Type 2 Diabetes (Diabetes Metab J 2015;39:498-506)
Mi-Kyung Kim
Diabetes & Metabolism Journal.2016; 40(1): 83. CrossRef
Response: Cardiovascular Disease Predicts Severe Hypoglycemia in Patients with Type 2 Diabetes (Diabetes Metab J 2015;39:498-506)
Jae-Seung Yun, Yu-Bae Ahn
Diabetes & Metabolism Journal.2016; 40(1): 85. CrossRef
Lipoprotein(a) predicts a new onset of chronic kidney disease in people with Type 2 diabetes mellitus
J.‐S. Yun, Y.‐B. Ahn, K.‐H. Song, K.‐D. Yoo, Y.‐M. Park, H.‐W. Kim, S.‐H. Ko
Diabetic Medicine.2016; 33(5): 639. CrossRef
Severe Hypoglycemia and Cardiovascular Disease in Type 2 Diabetes
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Diabetes & Metabolism Journal.2015; 39(6): 478. CrossRef

Influence of Visceral Adiposity on Cardiovascular Autonomic Neuropathy in Patients with Type 2 Diabetes Mellitus: Eun-Hee Jang, Na-Young Kim, Yong-Moon Park, Mee-Kyoung Kim, Ki Hyun Baek, Ki-Ho Song, Kwang Woo Lee, Hyuk-Sang Kwon; Diabetes Metab J. 2012;36(4):285-292. Published online August 20, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.4.285

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Background

The aim of this study was to investigate the influences of visceral adiposity on cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus.

Methods

Two hundred eleven patients with type 2 diabetes participated in this study. Anthropometric and metabolic parameters were measured, and the visceral fat area was assessed using computed tomography. CAN was diagnosed using a cardiovascular reflex test. We analyzed the correlation between the visceral fat area and each parameter in this test.

Results

The mean age, body mass index (BMI), and duration of diabetes of the study population were 60±14 years (mean±standard deviation), 25.1±4.2 kg/m², and 12.3±8.9 years, respectively. The visceral fat area showed positive correlations with age, BMI, waist circumference, and subcutaneous fat area. There was no statistically significant difference in the cardiovascular reflex test outcome between genders. Univariate linear regression analysis showed that an increased visceral fat area diminished good heart rate response to a Valsalva maneuver (R²=4.9%, P=0.013 in an unadjusted model), but only in women. This statistical association was preserved after adjusting for age and BMI (R²=9.8%, P=0.0072).

Conclusion

The results of this study suggest that visceral adiposity contributes to an autonomic imbalance to some degree, as demonstrated by the impaired cardiovascular reflex test among women with type 2 diabetes.

Citations

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Excessive generalized and visceral adiposity is associated with a higher prevalence of diabetic retinopathy in Caucasian patients with type 2 diabetes
Andrea Tumminia, Agostino Milluzzo, Nunzia Carrubba, Federica Vinciguerra, Roberto Baratta, Lucia Frittitta
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Niki Katsiki, Panagiotis Anagnostis, Kalliopi Kotsa, Dimitrios G. Goulis, Dimitri P. Mikhailidis
Current Pharmaceutical Design.2019; 25(18): 2051. CrossRef
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Kyung Ae Lee, Na Young Lee, Tae Sun Park, Heung Yong Jin
Diabetes & Metabolism Journal.2018; 42(2): 169. CrossRef
Gender differences in the perception of difficulty of self-management in patients with diabetes mellitus: a mixed-methods approach
Hideyo Tsutsui, Kyoko Nomura, Masataka Kusunoki, Tetsuya Ishiguro, Takayoshi Ohkubo, Yoshiharu Oshida
Diabetology International.2016; 7(3): 289. CrossRef
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Influence of the Duration of Diabetes on the Outcome of a Diabetes Self-Management Education Program: Seung-Hyun Ko, Sin-Ae Park, Jae-Hyoung Cho, Sun-Hye Ko, Kyung-Mi Shin, Seung-Hwan Lee, Ki-Ho Song, Yong-Moon Park, Yu-Bae Ahn; Diabetes Metab J. 2012;36(3):222-229. Published online June 14, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.3.222

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Background

Diabetes education and lifestyle modification are critical components in controlling blood glucose levels of people with type 2 diabetes. Until now, available data on the effectiveness of education with respect to the duration of diabetes are limited. We investigated whether adherence to lifestyle behavior modification prompted by diabetes education was influenced by the duration of diabetes.

Methods

Two hundred and twenty-five people with type 2 diabetes were recruited for an intensive, collaborative, group-based diabetes education program with annual reinforcement. We divided the patients into two groups based on the duration of their diabetes prior to the education program (≤1 year [≤1Y] vs. ≥3 years [≥3Y]). Dietary habits, physical activity, and the frequency of blood glucose self-monitoring were evaluated with a questionnaire prior to education and at the follow-up endpoint.

Results

The mean follow-up period was 32.2 months. The mean hemoglobin A1c (A1C) value was significantly lower in the ≤1Y group. Self-care behaviors, measured by scores for dietary habits (P=0.004) and physical activity (P<0.001), were higher at the endpoint in the ≤1Y group than in the ≥3Y group. Logistic regression analysis revealed that a longer diabetes duration before education was significantly associated with mean A1C levels greater than or equal to 7.0% (53 mmol/mol).

Conclusion

Diabetes duration influenced the effectiveness of diabetes education on lifestyle behavior modification and glycemic control. More-intense, regular, and sustained reinforcement with encouragement may be required for individuals with longstanding type 2 diabetes.

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Protective Effect of Heme Oxygenase-1 on High Glucose-Induced Pancreatic β-Cell Injury: Eun-Mi Lee, Young-Eun Lee, Esder Lee, Gyeong Ryul Ryu, Seung-Hyun Ko, Sung-Dae Moon, Ki-Ho Song, Yu-Bae Ahn; Diabetes Metab J. 2011;35(5):469-479. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.469

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Background

Glucose toxicity that is caused by chronic exposure to a high glucose concentration leads to islet dysfunction and induces apoptosis in pancreatic β-cells. Heme oxygenase-1 (HO-1) has been identified as an anti-apoptotic and cytoprotective gene. The purpose of this study is to investigate whether HO-1 up-regulation when using metalloprotophyrin (cobalt protoporphyrin, CoPP) could protect pancreatic β-cells from high glucose-induced apoptosis.

Methods

Reverse transcription-polymerase chain reaction was performed to analyze the CoPP-induced mRNA expression of HO-1. Cell viability of INS-1 cells cultured in the presence of CoPP was examined by acridine orange/propidium iodide staining. The generation of intracellular reactive oxygen species (ROS) was measured using flow cytometry. Glucose stimulated insulin secretion (GSIS) was determined following incubation with CoPP in different glucose concentrations.

Results

CoPP increased HO-1 mRNA expression in both a dose- and time-dependent manner. Overexpression of HO-1 inhibited caspase-3, and the number of dead cells in the presence of CoPP was significantly decreased when exposed to high glucose conditions (HG). CoPP also decreased the generation of intracellular ROS by 50% during 72 hours of culture with HG. However, decreased GSIS was not recovered even in the presence of CoPP.

Conclusion

Our data suggest that CoPP-induced HO-1 up-regulation results in protection from high glucose-induced apoptosis in INS-1 cells; however, glucose stimulated insulin secretion is not restored.

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Decreased Expression and Induced Nucleocytoplasmic Translocation of Pancreatic and Duodenal Homeobox 1 in INS-1 Cells Exposed to High Glucose and Palmitate: Gyeong Ryul Ryu, Jun Mo Yoo, Esder Lee, Seung-Hyun Ko, Yu-Bae Ahn, Ki-Ho Song; Diabetes Metab J. 2011;35(1):65-71. Published online February 28, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.1.65

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Background

Type 2 diabetes mellitus (T2DM) is often accompanied by increased levels of circulating fatty acid. Elevations in fatty acids and glucose for prolonged periods of time have been suggested to cause progressive dysfunction or apoptosis of pancreatic beta cells in T2DM. However, the precise mechanism of this adverse effect is not well understood.

Methods

INS-1 rat-derived insulin-secreting cells were exposed to 30 mM glucose and 0.25 mM palmitate for 48 hours.

Results

The production of reactive oxygen species increased significantly. Pancreatic and duodenal homeobox 1 (Pdx1) expression was down-regulated, as assessed by reverse transcription-polymerase chain reaction and Western blot analyses. The promoter activities of insulin and Pdx1 were also diminished. Of note, there was nucleocytoplasmic translocation of Pdx1, which was partially prevented by treatment with an antioxidant, N-acetyl-L-cysteine.

Conclusion

Our data suggest that prolonged exposure of beta cells to elevated levels of glucose and palmitate negatively affects Pdx1 expression via oxidative stress.

Citations

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