Diabetes & Metabolism Journal

Original Article

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Repeated Glucose Deprivation/Reperfusion Induced PC-12 Cell Death through the Involvement of FOXO Transcription Factor: Na Han, You Jeong Kim, Su Min Park, Seung Man Kim, Ji Suk Lee, Hye Sook Jung, Eun Ju Lee, Tae Kyoon Kim, Tae Nyun Kim, Min Jeong Kwon, Soon Hee Lee, Mi-kyung Kim, Byoung Doo Rhee, Jeong Hyun Park; Diabetes Metab J. 2016;40(5):396-405. Published online September 1, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.5.396

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Background

Cognitive impairment and brain damage in diabetes is suggested to be associated with hypoglycemia. The mechanisms of hypoglycemia-induced neural death and apoptosis are not clear and reperfusion injury may be involved. Recent studies show that glucose deprivation/reperfusion induced more neuronal cell death than glucose deprivation itself. The forkhead box O (FOXO) transcription factors are implicated in the regulation of cell apoptosis and survival, but their role in neuronal cells remains unclear. We examined the role of FOXO transcription factors and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt and apoptosis-related signaling pathways in PC-12 cells exposed to repeated glucose deprivation/reperfusion.

Methods

PC-12 cells were exposed to control (Dulbecco's Modified Eagle Medium [DMEM] containing 25 mM glucose) or glucose deprivation/reperfusion (DMEM with 0 mM glucose for 6 hours and then DMEM with 25 mM glucose for 18 hours) for 5 days. MTT assay and Western blot analysis were performed for cell viability, apoptosis, and the expression of survival signaling pathways. FOXO3/4',6-diamidino-2-phenylindole staining was done to ascertain the involvement of FOXO transcription factors in glucose deprivation/reperfusion conditions.

Results

Compared to PC-12 cells not exposed to hypoglycemia, cells exposed to glucose deprivation/reperfusion showed a reduction of cell viability, decreased expression of phosphorylated Akt and Bcl-2, and an increase of cleaved caspase-3 expression. Of note, FOXO3 protein was localized in the nuclei of glucose deprivation/reperfusion cells but not in the control cells.

Conclusion

Repeated glucose deprivation/reperfusion caused the neuronal cell death. Activated FOXO3 via the PI3K/Akt pathway in repeated glucose deprivation/reperfusion was involved in genes related to apoptosis.

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Predictive factors for the development of diabetes in cancer patients treated with phosphatidylinositol 3-kinase inhibitors
Gyuri Kim, Myungeun Yoo, Min Hee Hong, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Hye Ryun Kim, Yong-ho Lee, Byoung Chul Cho
Cancer Chemotherapy and Pharmacology.2019; 84(2): 405. CrossRef

Brief Report

Glycated Hemoglobin Value for Fasting Plasma Glucose of 126 mg/dL in Korean: The 2011 Korea National Health and Nutrition Examination Survey: Jung Min Kim, Jae Won Hong, Jong Chul Won, Jung Hyun Noh, Kyung Soo Ko, Byoung Doo Rhee, Dong-Jun Kim; Diabetes Metab J. 2014;38(6):480-483. Published online December 15, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.6.480

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We aimed to estimate the cutoff value of glycated hemoglobin (HbA1c, A1c) for fasting plasma glucose (FPG) of 126 mg/dL in the Korean adult population, using the 2011 Korea National Health and Nutrition Examination Survey. A total of 5,421 participants without a history of diabetes and over 19 years of age were included in the analysis. A point-wise area under the receiver operating characteristic curve was used to estimate the optimal A1c cutoff value. A1c threshold of 6.1% produced the highest sum of sensitivity (85.2%) and specificity (90.5%) for FPG of 126 mg/dL (area under the curve, 0.941, P<0.001). A1c of 6.5% produced a sensitivity of 67.7% and specificity of 98.0% for FPG of 126 mg/dL. Considering A1c as one of three criteria for the diagnosis of diabetes and the specificity of an A1c cutoff of 6.5%, the current diagnostic criteria of A1c≥6.5% might be acceptable in the Korean adult population.

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Morning Spot Urine Glucose-to-Creatinine Ratios Predict Overnight Urinary Glucose Excretion in Patients With Type 2 Diabetes
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Glycosylated Hemoglobin Threshold for Predicting Diabetes and Prediabetes from the Fifth Korea National Health and Nutrition Examination Survey
Sangmo Hong, Jun Goo Kang, Chul Sik Kim, Seong Jin Lee, Cheol-Young Park, Chang Beom Lee, Sung-Hee Ihm
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Comparison of the clinical characteristics of diabetes mellitus diagnosed using fasting plasma glucose and haemoglobin A1c: The 2011 Korea National Health and Nutrition Examination Survey
Sangmo Hong, Jun Goo Kang, Chul Sik Kim, Seong Jin Lee, Chang Beom Lee, Sung-Hee Ihm
Diabetes Research and Clinical Practice.2016; 113: 23. CrossRef
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G Danaei, S Fahimi, Y Lu, B Zhou, K Hajifathalian, M Di Cesare, WC Lo, B Reis-Santos, MJ Cowan, JE Shaw, J Bentham, JK Lin, H Bixby, D Magliano, P Bovet, JJ Miranda, YH Khang, GA Stevens, LM Riley, MK Ali, M Ezzati, ZA Abdeen, KA Kadir, M Abu-Rmeileh, B A
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Original Articles

Factors Associated for Mild Cognitive Impairment in Older Korean Adults with Type 2 Diabetes Mellitus: Yun Jeong Lee, Hye Mi Kang, Na Kyung Kim, Ju Yeon Yang, Jung Hyun Noh, Kyung Soo Ko, Byoung Doo Rhee, Dong-Jun Kim; Diabetes Metab J. 2014;38(2):150-157. Published online April 18, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.2.150

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Background

The aim of this study was to identify factors associated with mild cognitive impairment (MCI) in older Korean adults with type 2 diabetes mellitus.

Methods

A total of 226 older (age ≥65 years) adults without a history of cerebrovascular disease or dementia participated in this study. Cognitive function was assessed with the Montreal Cognitive Assessment-Korean version (MoCA-K). A MoCA-K score <23 was defined as MCI.

Results

The prevalence of MCI was 32.7%. In a logistic regression analysis, age (≥74 years old vs. 65-68 years old; odds ratio [OR], 3.69; 95% confidence interval [CI], 1.55 to 8.82; P=0.003), educational background (college graduation vs. no school or elementary school graduation; OR, 0.16; 95% CI, 0.05 to 0.46; P=0.001), and systolic blood pressure (≥135 mm Hg vs. ≤120 mm Hg; OR, 3.25; 95% CI, 1.29 to 8.17; P=0.012) were associated with MCI.

Conclusion

More concentrated efforts focused on early detection and appropriate management of MCI may be required in older Korean adults with type 2 diabetes mellitus.

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The Effects of Glyburide on Apoptosis and Endoplasmic Reticulum Stress in INS-1 Cells in a Glucolipotoxic Condition: Min Jeong Kwon, Hye Suk Chung, Chang Shin Yoon, Jung Hae Ko, Hae Jung Jun, Tae Kyun Kim, Soon Hee Lee, Kyung Soo Ko, Byoung Doo Rhee, Mi Kyung Kim, Jeong Hyun Park; Diabetes Metab J. 2011;35(5):480-488. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.480

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Background

β-cell death due to endoplasmic reticulum (ER) stress has been regarded as an important pathogenic component of type 2 diabetes. The possibility has been suggested that sulfonylurea, currently being used as one of the main oral hypoglycemic agents of type 2 diabetes, increases ER stress, which could lead to sulfonylurea failure. The authors of the present study examined ER stress of β-cells in a glucolipotoxic condition using glyburide (GB) in an environment mimicking type 2 diabetes.

Methods

Apoptosis was induced by adding various concentrations of GB (0.001 to 200 µM) to a glucolipotoxic condition using 33 mM glucose, and the effects of varied concentrations of palmitate were evaluated via annexin V staining. The markers of ER stress and pro-apoptotic markers were assessed by Western blotting and semi-quantitative reverse transcription-polymerase chain reaction. Additionally, the anti-apoptotic markers were evaluated.

Results

Addition of any concentration of GB in 150 µM palmitate and 33 mM glucose did not increase apoptosis. The expression of phosphorylated eukaryotic initiation factor (eIF-2α) was increased and cleaved caspase 3 was decreased by adding GB to a glucolipotoxic condition. However, other ER stress-associated markers such as Bip-1, X-box binding protein-1, ATF-4 and C/EBP-homologous protein transcription factor and anti-apoptotic markers phosphor-p85 phosphatidylinositol 3-kinase and phosphorylation of Akt did not change significantly.

Conclusion

GB did not show further deleterious effects on the degree of apoptosis or ER stress of INS-1 cells in a glucolipotoxic condition. Increased phosphorylation of eIF-2α may attenuate ER stress for adaptation to increased ER protein load.

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The Duration of Sulfonylurea Treatment Is Associated withβ-Cell Dysfunction in Patients with Type 2 Diabetes Mellitus
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The Effect of Glucose Fluctuation on Apoptosis and Function of INS-1 Pancreatic Beta Cells: Mi Kyung Kim, Hye Sook Jung, Chang Shin Yoon, Jung Hae Ko, Hae Jung Jun, Tae Kyun Kim, Min Jeong Kwon, Soon Hee Lee, Kyung Soo Ko, Byoung Doo Rhee, Jeong Hyun Park; Korean Diabetes J. 2010;34(1):47-54. Published online February 28, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.1.47

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Background

Blood glucose level continuously fluctuates within a certain range in the human body. In diabetes patients, the extent of such fluctuation is large, despite the strict control of blood glucose. Blood glucose fluctuation has been shown to mediate more adverse effects on vascular endothelial cells and diabetes complications than chronic hyperglycemia, which has been explained as due to oxidative stress. As few previous studies have reported the effects of chronic and intermittent hyperglycemia on the apoptosis and function of pancreatic beta cells, this study reported herein was performed to investigate such effects on these cells.

Methods

For chronic hyperglycemia, INS-1 cells were cultured for 5 days with changes of RPMI 1640 medium containing 33 mM glucose every 12 hours. For intermittent hyperglycemia, the medium containing 11 mM glucose was exchanged with the medium containing 33 mM glucose every 12 hours. Apoptosis was assessed by TUNEL assay Hoechst staining and cleaved caspase 3. Insulin secretory capacity was assessed, and the expression of Mn-SOD and Bcl-2 was measured by Western blotting.

Results

In comparison to the control group, INS-1 cells exposed to chronic hyperglycemia and intermittent hyperglycemia showed an increase in apoptosis. The apoptosis of INS-1 cells exposed to intermittent hyperglycemia increased significantly more than the apoptosis of INS-1 cells exposed to chronic hyperglycemia. In comparison to the control group, the insulin secretory capacity in the two hyperglycemic states was decreased, and more with intermittent hyperglycemia than with chronic hyperglycemia. The expression of Mn-SOD and Bcl-2 increased more with chronic hyperglycemia than with intermittent hyperglycemia.

Conclusion

Intermittent hyperglycemia induced a higher degree of apoptosis and decreased the insulin secretory capacity more in pancreatic beta cells than chronic hyperglycemia. This activity may be mediated by the anti-oxidative enzyme Mn-SOD and the anti-apoptotic signal Bcl-2.

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Sixu Xin, Xin Zhao, Jiaxiang Ding, Xiaomei Zhang
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Plant polyphenols mechanisms of action on insulin resistance and against the loss of pancreatic beta cells
Camelia Papuc, Gheorghe V. Goran, Corina N. Predescu, Liliana Tudoreanu, Georgeta Ștefan
Critical Reviews in Food Science and Nutrition.2022; 62(2): 325. CrossRef
Correlation between HbA1c and Triglyceride Level with Coronary Stenosis Degree in Type 2 Diabetes Mellitus with Coronary Heart Disease
Laily Adninta, Indranila Samsuria, Edward Kurnia Setiawan Limijadi
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Age‐specific associations of glycated haemoglobin variability with cardiovascular disease and mortality in patients with type 2 diabetes mellitus: A 10‐ year cohort study
Eric Yuk Fai Wan, Esther Yee Tak Yu, Weng Yee Chin, Florence Ting Yan Ng, Shu Ming Cheryl Chia, Ian Chi Kei Wong, Esther Wai Yin Chan, Cindy Lo Kuen Lam
Diabetes, Obesity and Metabolism.2020; 22(8): 1316. CrossRef
Molecular Mechanisms of Glucose Fluctuations on Diabetic Complications
Zhen-Ye Zhang, Ling-Feng Miao, Ling-Ling Qian, Ning Wang, Miao-Miao Qi, Yu-Min Zhang, Shi-Peng Dang, Ying Wu, Ru-Xing Wang
Frontiers in Endocrinology.2019;[Epub] CrossRef
Resolution on the results of the first working meeting of the scientific advisory board «Actual problems of glycemic variability as a new criterion of glycemic control and safety of diabetes therapy»
Mikhail B. Antsiferov, Gagik R. Galstyan, Alexey V. Zilov, Alexander Y. Mayorov, Tatyana N. Markova, Nikolay A. Demidov, Olga M. Koteshkova, Dmitry N. Laptev, Alisa V. Vitebskaya
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Eric Yuk Fai Wan, Colman Siu Cheung Fung, Daniel Yee Tak Fong, Cindy Lo Kuen Lam
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Ginsenoside Rg3 prevents INS-1 cell death from intermittent high glucose stress
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Ke Chen, ping jin, Hong-hui He, Yan-hong Xie, Xiao-yun Xie, Zhao-hui Mo
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Lithospermic acid B protects beta-cells from cytokine-induced apoptosis by alleviating apoptotic pathways and activating anti-apoptotic pathways of Nrf2–HO-1 and Sirt1
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Risk Factors Associated with Left Ventricular Diastolic Dysfunction in Type 2 Diabetic Patients without Hypertension: Jung Hyun Noh, Joon Hyung Doh, Sung Yun Lee, Tae Nyun Kim, Hyuk Lee, Hwa Young Song, Jeong Hyun Park, Kyung Soo Ko, Byoung Doo Rhee, Dong Jun Kim; Korean Diabetes J. 2010;34(1):40-46. Published online February 28, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.1.40

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Background

Hypertension and age are recognized as important risk factors for left ventricular (LV) diastolic dysfunction. Some studies have shown that diabetes itself may also be an independent risk factor for LV diastolic dysfunction, although this is controversial. The aim of this study was to determine the factors associated with LV diastolic dysfunction in patients with type 2 diabetes in the absence of hypertension or ischemic heart disease (IHD).

Methods

Participants in this study consisted of 65 type 2 diabetes patients (M : F = 45 : 20; mean age 51 [26 to 76] years; mean body mass index [BMI] 25.0 ± 2.5 kg/m²) without hypertension, heart disease, or renal disease. Individuals with ischemic electrocardiographic changes were excluded. LV diastolic function was evaluated by Doppler echocardiographic studies.

Results

Fifteen patients (23.1%) showed LV diastolic dysfunction on Doppler echocardiographic studies. Patients with LV diastolic dysfunction were older than those without diastolic dysfunction (60.0 ± 2.5 vs. 50.5 ± 1.9 years; P < 0.01). After adjusting for age and sex, BMI was higher (26.6 ± 0.7 vs. 24.6 ± 0.3 kg/m²; P < 0.01) and diabetes duration was longer (9.65 ± 1.48 vs. 4.71 ± 0.78 years; P < 0.01) in patients with LV diastolic dysfunction than in those without diastolic dysfunction. There were no differences in sex, smoking, blood pressure, lipid profiles, hemoglobin A₁C, fasting glucose, fasting insulin, or diabetic microvascular complications between the LV diastolic dysfunction group and the normal diastolic function group. After adjusting for age, sex, and BMI, diabetes duration was found to be independently associated with LV diastolic dysfunction (odds ratio 1.38; confidence interval 1.12 to 1.72; P = 0.003).

Conclusion

These results suggest that diabetes duration may be a risk factor for LV diastolic dysfunction in type 2 diabetic patients without hypertension or IHD.

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Mark M. P. van den Dorpel, Ilkka Heinonen, Sanne M. Snelder, Hendrik J. Vos, Oana Sorop, Ron T. van Domburg, Daphne Merkus, Dirk J. Duncker, Bas M. van Dalen
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Risk Factors Associated with Left Ventricular Diastolic Dysfunction in Type 2 Diabetic Patients without Hypertension (Korean Diabetes J 2010;34:40-6)
Dong-Lim Kim
Korean Diabetes Journal.2010; 34(2): 135. CrossRef

Serum Adiponectin, TNF-alpha, IL-6 and Insulin Resistance in Women with Polycystic Ovary Syndrome.: Young A Kim, Jung Hyun Noh, Dong Jun Kim, Tae Hyun Um, Chong Rae Cho, Na young Jang, Soo Kyung Kwon, Soon Hee Lee, Jeong Hyun Park, Kyung Soo Ko, Byoung Doo Rhee, Kyung Ho Lim; Korean Diabetes J. 2006;30(2):104-111. Published online March 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.2.104

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Abstract PDF

BACKGROUND
To determine plasma adipokines such as adiponectin, IL-6 and TNF-alpha concentrations in women with and without polycystic ovary syndrome (PCOS) and to assess possible correlations of adipocytokines to the hormonal and metabolic parameters, including measures of insulin resistance (IR). METHODS: Forty-four selected women were classified as follows: 13 obese (body mass index [BMI] > or = 25 kg/m(2)) with PCOS; 15 non-obese (BMI < 25 kg/m(2)) with PCOS; 8 obese without PCOS, and 8 non-obese without PCOS. Blood samples were collected from all women with or without PCOS after an overnight fast. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone, 17-alpha-hydroxyprogesterone, dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG), insulin, glucose, adiponectin, TNF-alpha and IL-6 were measured. Measures of IR included HOMA-IR and QUICKI. RESULTS: In non-obese group, fasting insulin levels and HOMA-IR in PCOS were significantly higher compared to control. However, Adiponectin, TNF-alpha and IL-6 concentrations were found not to be different in obese women with PCOS as compared with obese women without PCOS and in non-obese women with PCOS as compared with non-obese women without PCOS. Adiponectin concentrations correlated inversely with BMI, waist circumference (WC), total fat mass, serum insulin, and HOMA-IR in PCOS group. However, multiple regression analysis showed that BMI was the only independent determinant of adiponectin concentration. CONCLUSION: Our results suggest that insulin sensitivity per se probably does not play any role in the control of adipokines levels such as adiponectin, TNF-alpha and IL-6 in PCOS women

Citations

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Adiponectin in Women with Polycystic Ovary Syndrome
Hyun-Young Shin, Duk-Chul Lee, Ji-Won Lee
Korean Journal of Family Medicine.2011; 32(4): 243. CrossRef

Reviews

Insulin Resistance and Metabolic Syndrome.: Kyung Soo Ko, Byoung Doo Rhee; Korean Diabetes J. 2005;29(6):501-506. Published online November 1, 2005

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Abstract PDF: No abstract available.

Epidemiological Characteristics of Diabetes Mellitus among Korean Population.: Byoung Doo Rhee; Korean Diabetes J. 2003;27(3):173-178. Published online June 1, 2003

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Abstract PDF: No abstract available.

Original Article

The Frequency of ICA and anti-GAD Antibody in Korean IDDM and NIDDM Patients.: Kyung Soo Ko, Sung Kwan Hong, Ki Up Lee, Nan Hee Kim, Dong Seop Choi, Sung Hee Ihm, Sung Woo Park, Chul Hee Kim, Dong Won Byun, Kyo Il Suh, Hak Chul Chang, Byoung Doo Rhee; Korean Diabetes J. 1998;22(3):312-319. Published online January 1, 2001

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Abstract PDF: BACKGROUND
It has been suggested that the clinical and immunological characteristics of diabetes mellitus in Koreans are different from those of Caucasians. This study was undertaken to investigate the prevalence of autoimmune markers in Korean adults with IDDM and recent-onset NIDDM. METHODS: Seventy-seven Korean adults with IDDM and 245 recently(within 2 years) diagnosed NIDDM were included in the study. Islet cell cytoplasmic antibody was measured by immunohistochemical method, and anti-glutamic acid decarboxylase (anti-GAD) antibody was measured by radioimmunoassay. RESULTS: 1) The prevalence of ICA, anti-GAD antibody positivity was 27% and 40% in IDDM patients, and 5% and 4% in recent-onset NIDDM patients, respectively. 2) The prevalence of ICA positivity in IDDM patients decreased from 42% within one year to 21% over one year after clinical onset of disease. On the other hand, the positivity of anti-GAD antibody did not change according to the duration of diabetes. 3) The prevalence of ICA tends to be lower in IDDW patients with low serum C-peptide concentrations. In contrast, the prevalence of anti-GAD antibody was not different according to sernm C-peptide levels. CONCLUSION: These results suggested that the prevalence of ICA and antii-GAD antibody was lower in Korean adult IDDM and recent-onset NIDDM patients than that in Caucasians.

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