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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
  • 5,204 View
  • 32 Download
  • 3 Web of Science
  • 2 Crossref
AbstractAbstract PDFPubReader   
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.

Citations

Citations to this article as recorded by  
  • Banxia Xiexin Decoction Prevents HT22 Cells from High Glucose-induced Neurotoxicity via JNK/SIRT1/Foxo3a Signaling Pathway
    Yinli Shi, Pei Sheng, Ming Guo, Kai Chen, Yun Zhao, Xu Wang, Mianhua Wu, Bo Li
    Current Computer-Aided Drug Design.2024; 20(6): 911.     CrossRef
  • 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
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Obesity and Metabolic Syndrome
Statins Increase Mitochondrial and Peroxisomal Fatty Acid Oxidation in the Liver and Prevent Non-Alcoholic Steatohepatitis in Mice
Han-Sol Park, Jung Eun Jang, Myoung Seok Ko, Sung Hoon Woo, Bum Joong Kim, Hyun Sik Kim, Hye Sun Park, In-Sun Park, Eun Hee Koh, Ki-Up Lee
Diabetes Metab J. 2016;40(5):376-385.   Published online April 5, 2016
DOI: https://doi.org/10.4093/dmj.2016.40.5.376
  • 7,127 View
  • 90 Download
  • 67 Web of Science
  • 128 Crossref
AbstractAbstract PDFPubReader   
Background

Non-alcoholic fatty liver disease is the most common form of chronic liver disease in industrialized countries. Recent studies have highlighted the association between peroxisomal dysfunction and hepatic steatosis. Peroxisomes are intracellular organelles that contribute to several crucial metabolic processes, such as facilitation of mitochondrial fatty acid oxidation (FAO) and removal of reactive oxygen species through catalase or plasmalogen synthesis. Statins are known to prevent hepatic steatosis and non-alcoholic steatohepatitis (NASH), but underlying mechanisms of this prevention are largely unknown.

Methods

Seven-week-old C57BL/6J mice were given normal chow or a methionine- and choline-deficient diet (MCDD) with or without various statins, fluvastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (15 mg/kg/day), for 6 weeks. Histological lesions were analyzed by grading and staging systems of NASH. We also measured mitochondrial and peroxisomal FAO in the liver.

Results

Statin treatment prevented the development of MCDD-induced NASH. Both steatosis and inflammation or fibrosis grades were significantly improved by statins compared with MCDD-fed mice. Gene expression levels of peroxisomal proliferator-activated receptor α (PPARα) were decreased by MCDD and recovered by statin treatment. MCDD-induced suppression of mitochondrial and peroxisomal FAO was restored by statins. Each statin's effect on increasing FAO and improving NASH was independent on its effect of decreasing cholesterol levels.

Conclusion

Statins prevented NASH and increased mitochondrial and peroxisomal FAO via induction of PPARα. The ability to increase hepatic FAO is likely the major determinant of NASH prevention by statins. Improvement of peroxisomal function by statins may contribute to the prevention of NASH.

Citations

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Others
Comparison of the Usefulness of the Updated Homeostasis Model Assessment (HOMA2) with the Original HOMA1 in the Prediction of Type 2 Diabetes Mellitus in Koreans
Young Seok Song, You-Cheol Hwang, Hong-Yup Ahn, Cheol-Young Park
Diabetes Metab J. 2016;40(4):318-325.   Published online May 27, 2016
DOI: https://doi.org/10.4093/dmj.2016.40.4.318
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AbstractAbstract PDFPubReader   
Background

The original homeostasis model assessment (HOMA1) and the updated HOMA model (HOMA2) have been used to evaluate insulin resistance (IR) and β-cell function, but little is known about the usefulness of HOMA2 for the prediction of diabetes in Koreans. The aim of this study was to demonstrate the usefulness of HOMA2 as a predictor of type 2 diabetes mellitus in Koreans without diabetes.

Methods

The study population consisted of 104,694 Koreans enrolled at a health checkup program and followed up from 2001 to 2012. Participants were divided into a normal glucose tolerance (NGT) group and a pre-diabetes group according to fasting glucose and glycosylated hemoglobin levels. Anthropometric and laboratory data were measured at the baseline checkup, and HOMA values were calculated at the baseline and follow-up checkups. The hazard ratios (HRs) of the HOMA1 and HOMA2 values and the prevalence of diabetes at follow-up were evaluated using a multivariable Cox proportional hazards model and Kaplan-Meier analysis.

Results

After adjusting for several diabetes risk factors, all of the HOMA values except 1/HOMA1-β and 1/HOMA2-β in the NGT group were significant predictors of the progression to diabetes. In the NGT group, there was no significant difference in HOMA1-IR (HR, 1.09; 95% confidence interval [CI], 1.04 to 1.14) and HOMA2-IR (HR, 1.11; 95% CI, 1.04 to 1.19). However, in the pre-diabetes group, 1/HOMA2-β was a more powerful marker (HR, 1.29; 95% CI, 1.26 to 1.31) than HOMA1-IR (HR, 1.23; 95% CI, 1.19 to 1.28) or 1/HOMA1-β (HR, 1.14; 95% CI, 1.12 to 1.16). In the non-diabetic group (NGT+pre-diabetes), 1/HOMA2-β was also a stronger predictor of diabetes (HR, 1.27; 95% CI, 1.25 to 1.29) than HOMA1-IR (HR, 1.14; 95% CI, 1.12 to 1.15) or 1/HOMA1-β (HR, 1.13; 95% CI, 1.11 to 1.14).

Conclusion

HOMA2 is more predictive than HOMA1 for the progression to diabetes in pre-diabetes or non-diabetic Koreans.

Citations

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Complications
Renoprotective Effect of Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Streptozotocin-Induced Type 1 Diabetic Mice
Gwon-Soo Jung, Jae-Han Jeon, Mi Sun Choe, Sung-Woo Kim, In-Kyu Lee, Mi-Kyung Kim, Keun-Gyu Park
Diabetes Metab J. 2016;40(3):211-221.   Published online March 31, 2016
DOI: https://doi.org/10.4093/dmj.2016.40.3.211
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AbstractAbstract PDFPubReader   
Background

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the treatment of patients with type 2 diabetes and have proven protective effects on diabetic kidney disease (DKD). Whether DPP-4 inhibitors have renoprotective effects on insulin-deficient type 1 diabetes has not been comprehensively examined. The aim of this study was to determine whether gemigliptin, a new DPP-4 inhibitor, has renoprotective effects in streptozotocin (STZ)-induced type 1 diabetic mice.

Methods

Diabetes was induced by intraperitoneal administration of a single dose of STZ. Mice with diabetes were treated without or with gemigliptin (300 mg/kg) for 8 weeks. Morphological changes of the glomerular basement membrane (GBM) were observed by electron microscopy and periodic-acid Schiff staining. In addition, we measured blood glucose and urinary albumin excretion and evaluated fibrotic markers using immunohistochemical staining, quantitative reverse transcription polymerase chain reaction analysis, and Western blot analysis.

Results

Gemigliptin did not reduce the blood glucose levels of STZ-treated mice. In gemigliptin-treated mice with STZ, a significant reduction in urinary albumin excretion and GBM thickness was observed. Immunohistological examination revealed that gemigliptin attenuated renal fibrosis induced by STZ and decreased extracellular matrix protein levels, including those of type I collagen and fibronectin, and Smad3 phosphorylation. In cultured rat renal cells, gemigliptin inhibited transforming growth factor β-stimulated type I collagen and fibronectin mRNA and protein levels via down-regulation of Smad3 phosphorylation.

Conclusion

Our data demonstrate that gemigliptin has renoprotective effects on DKD, regardless of its glucose-lowering effect, suggesting that it could be used to prevent DKD, including in patients with type 1 diabetes.

Citations

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Clinical Care/Education
Hyperglycemia Is Associated with Impaired Muscle Quality in Older Men with Diabetes: The Korean Longitudinal Study on Health and Aging
Ji Won Yoon, Yong-Chan Ha, Kyoung Min Kim, Jae Hoon Moon, Sung Hee Choi, Soo Lim, Young Joo Park, Jae Young Lim, Ki Woong Kim, Kyong Soo Park, Hak Chul Jang
Diabetes Metab J. 2016;40(2):140-146.   Published online March 31, 2016
DOI: https://doi.org/10.4093/dmj.2016.40.2.140
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AbstractAbstract PDFPubReader   
Background

The study aimed to investigate the influence of hyperglycemia on muscle quality in older men with type 2 diabetes.

Methods

This was a subsidiary study of the Korean Longitudinal Study of Health and Aging. Among 326 older men consenting to tests of body composition and muscle strength, 269 men were ultimately analyzed after the exclusion because of stroke (n=30) and uncertainty about the diagnosis of diabetes (n=27). Body composition was measured using dual-energy X-ray absorptiometry and computed tomography. Muscle strength for knee extension was measured using an isokinetic dynamometer. Muscle quality was assessed from the ratio of leg strength to the entire corresponding leg muscle mass.

Results

The muscle mass, strength, and quality in patients with type 2 diabetes did not differ significantly from controls. However, when patients with diabetes were subdivided according to their glycemic control status, patients with a glycosylated hemoglobin (HbA1c) level of ≥8.5% showed significantly decreased leg muscle quality by multivariate analysis (odds ratio, 4.510; P=0.045) after adjustment for age, body mass index, smoking amount, alcohol consumption, physical activity, and duration of diabetes. Physical performance status was also impaired in subjects with an HbA1c of ≥8.5%.

Conclusion

Poor glycemic control in these older patients with diabetes was associated with significant risk of decreased muscle quality and performance status. Glycemic control with an HbA1c of <8.5% might be needed to reduce the risk of adverse skeletal and functional outcomes in this population.

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    Journal of the American Medical Directors Association.2021; 22(4): 834.     CrossRef
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    Metabolites.2021; 11(4): 242.     CrossRef
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    Neil D. Reeves, Giorgio Orlando, Steven J. Brown
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  • Impact of frailty metabolic phenotypes on the management of older people with type 2 diabetes mellitus
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    Jeffrey Kingsley, Keiichi Torimoto, Tomoki Hashimoto, Satoru Eguchi
    Clinical Science.2021; 135(21): 2503.     CrossRef
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    Bo Kyung Koo, Seoil Moon, Min Kyong Moon
    BMC Geriatrics.2021;[Epub]     CrossRef
  • Associations between homocysteine, inflammatory cytokines and sarcopenia in Chinese older adults with type 2 diabetes
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  • The Association Between Diabetes Mellitus and Risk of Sarcopenia: Accumulated Evidences From Observational Studies
    Yu-Shun Qiao, Yin-He Chai, Hong-Jian Gong, Zhiyessova Zhuldyz, Coen D. A. Stehouwer, Jian-Bo Zhou, Rafael Simó
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  • The utility of the ultrasonographic assessment of the lower leg muscles to evaluate sarcopenia and muscle quality in older adults
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    JCSM Clinical Reports.2021; 6(2): 53.     CrossRef
  • Associations between grip strength and glycemic control in type 2 diabetes mellitus: an analysis of data from the 2014-2019 Korea National Health and Nutrition Examination Survey
    Harim Choe, Hoyong Sung, Geon Hui Kim, On Lee, Hyo Youl Moon, Yeon Soo Kim
    Epidemiology and Health.2021; 43: e2021080.     CrossRef
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    The Journals of Gerontology: Series A.2020; 75(6): 1191.     CrossRef
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    Peter Hanlon, Isabella Fauré, Neave Corcoran, Elaine Butterly, Jim Lewsey, David A McAllister, Frances S Mair
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  • Longitudinal association of type 2 diabetes and insulin therapy with muscle parameters in the KORA-Age study
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    A.H. Abdelhafiz, P.C. Davies, A.J. Sinclair
    Diabetes Research and Clinical Practice.2020; 161: 108065.     CrossRef
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    Redox Biology.2020; 35: 101513.     CrossRef
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    Turkish Journal of Diabetes and Obesity.2020; 4(3): 207.     CrossRef
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    Journal of Diabetes and its Complications.2019; 33(8): 598.     CrossRef
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    Tae Jung Oh, Yoojung Song, Jae Hoon Moon, Sung Hee Choi, Hak Chul Jang
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    Human Movement Science.2016; 49: 160.     CrossRef
  • Letter: Hyperglycemia Is Associated with Impaired Muscle Quality in Older Men with Diabetes: The Korean Longitudinal Study on Health and Aging (Diabetes Metab J 2016;40:140-6)
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  • Sarcopenia, Frailty, and Diabetes in Older Adults
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