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Diabetes Metab J : Diabetes & Metabolism Journal



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Original Article
The Effect of Tribbles-Related Protein 3 on ER Stress-Suppressed Insulin Gene Expression in INS-1 Cells
Young Yun Jang, Nam Keong Kim, Mi Kyung Kim, Ho Young Lee, Sang Jin Kim, Hye Soon Kim, Hye-Young Seo, In Kyu Lee, Keun Gyu Park
Korean Diabetes J. 2010;34(5):312-319.   Published online October 31, 2010
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AbstractAbstract PDFPubReader   

The highly developed endoplasmic reticulum (ER) structure in pancreatic beta cells is heavily involved in insulin biosynthesis. Thus, any perturbation in ER function inevitably impacts insulin biosynthesis. Recent studies showed that the expression of tribbles-related protein 3 (TRB3), a mammalian homolog of Drosophilia tribbles, in various cell types is induced by ER stress. Here, we examined whether ER stress induces TRB3 expression in INS-1 cells and found that TRB3 mediates ER stress-induced suppression of insulin gene expression.


The effects of tunicamycin and thapsigargin on insulin and TRB3 expression in INS-1 cells were measured by Northern and Western blot analysis, respectively. The effects of adenovirus-mediated overexpression of TRB3 on insulin, PDX-1 and MafA gene expression in INS-1 cells were measured by Northern blot analysis. The effect of TRB3 on insulin promoter was measured by transient transfection study with constructs of human insulin promoter.


The treatment of INS-1 cells with tunicamycin and thapsigargin decreased insulin mRNA expression, but increased TRB3 protein expression. Adenovirus-mediated overexpression of TRB3 decreased insulin gene expression in a dose-dependent manner. A transient transfection study showed that TRB3 inhibited insulin promoter activity, suggesting that TRB3 inhibited insulin gene expression at transcriptional level. Adenovirus-mediated overexpression of TRB3 also decreased PDX-1 mRNA expression, but did not influence MafA mRNA expression.


This study showed that ER stress induced TRB3 expression, but decreased both insulin and PDX-1 gene expression in INS-1 cells. Our data suggest that TRB3 plays an important role in ER stress-induced beta cell dysfunction.


Citations to this article as recorded by  
  • Endoplasmic reticulum stress causes insulin resistance by inhibiting delivery of newly synthesized insulin receptors to the cell surface
    Max Brown, Samantha Dainty, Natalie Strudwick, Adina D. Mihai, Jamie N. Watson, Robina Dendooven, Adrienne W. Paton, James C. Paton, Martin Schröder, James Arthur Olzmann
    Molecular Biology of the Cell.2020; 31(23): 2597.     CrossRef
  • PTB and TIAR binding to insulin mRNA 3′- and 5′UTRs; implications for insulin biosynthesis and messenger stability
    Rikard G. Fred, Syrina Mehrabi, Christopher M. Adams, Nils Welsh
    Heliyon.2016; 2(9): e00159.     CrossRef
  • Asna1/TRC40 Controls β-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport
    Stefan Norlin, Vishal S. Parekh, Peter Naredi, Helena Edlund
    Diabetes.2016; 65(1): 110.     CrossRef
  • Role of the Unfolded Protein Response inβCell Compensation and Failure during Diabetes
    Nabil Rabhi, Elisabet Salas, Philippe Froguel, Jean-Sébastien Annicotte
    Journal of Diabetes Research.2014; 2014: 1.     CrossRef
  • Endoplasmic Reticulum Stress and Insulin Biosynthesis: A Review
    Mi-Kyung Kim, Hye-Soon Kim, In-Kyu Lee, Keun-Gyu Park
    Experimental Diabetes Research.2012; 2012: 1.     CrossRef
Case Report
A Case of Cured Diabetes Mellitus after Occult Malignant Pheochromocytoma Removal.
Ho Chan Cho, Hye Soon Kim, Yoon Jung Kim, Yu Jin Hah, Nam Keong Kim, Mi Kyung Kim, Keun Gyu Park, Yong Hoon Kim, Sun Young Kwon
Korean Diabetes J. 2007;31(6):520-524.   Published online November 1, 2007
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  • 1 Crossref
AbstractAbstract PDF
Pheochromocytoma is characterized by a combination of various clinical manifestations that include the classic triad of severe headache, palpitations and diaphoresis. In addition, hyperglycemia can be caused by overproduction of catecholamines, which are secreted by a catecholamine-secreting neoplasm of adrenal or extra-adrenal chromaffin tissue. We encountered a case of diabetes with an occult malignant adrenal pheochromocytoma, who did not have any classic manifestations. A 37-year-old male was admitted because of polydipsia, polyuria, and weight loss. Fasting blood glucose level was 497 mg/dL, hemoglobin A1c level was 15%, and diabetic retinopathy and peripheral polyneuropathy were also accompanied. Incidentally, right adrenal mass was detected by ultrasonography of abdomen. Urinary excretion of total metanephrine and epinephrine were elevated. Adrenal CT showed a 7.1 cm sized right adrenal cystic mass with enhancing solid portion and hemorrhagic content. The scan with 123I-MIBG revealed the cystic mass with increased rim uptake in the region of right adrenal gland. After removal of the tumor, the increased levels of catecholamine were normalized. Moreover, blood glucose level was normalized without administration of insulin or oral hypoglycemic agents. The pathologic examination showed that the neoplasm was a malignant adrenal pheochromocytoma. We report this case that diabetes was cured after removal of malignant tumor with literature review at first in Korea.


Citations to this article as recorded by  
  • Pheochromocytoma with Markedly Abnormal Liver Function Tests and Severe Leukocytosis
    Chai Ryoung Eun, Jae Hee Ahn, Ji A Seo, Nan Hee Kim
    Endocrinology and Metabolism.2014; 29(1): 83.     CrossRef
Original Article
Ascochlorin Derivative, AS-6, Inhibits TNF-alpha-Induced fractalkine, MCP-1 and VCAM-1 Expression in Rat Aortic Smooth Muscle Cells.
Young Yun Jang, Sang Yoon Kim, Nam Keong Kim, Mi Kyung Kim, Hee Kyoung Kim, Hye Soon Kim, Chang Wook Nam, Seong Yeol Ryu, Sung Il Nam, Keun Gyu Park
Korean Diabetes J. 2005;29(5):401-408.   Published online September 1, 2005
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AbstractAbstract PDF
BACKGOUND: Inflammation is one of the key mechanisms in the development and progression of atherosclerosis. Accumulating evidence suggests that peroxisome proliferators- activated receptorgamma(PPARgamma) plays an important role in the prevention of arterial inflammation and the formation of atherogenesis. This study was designed to evaluate whether the new synthetic PPARgamma, ascochlorin-6(AS-6) has anti-inflammatory and anti-atherogenic effects in primary cultured rat vascular smooth muscle cells(VSMCs). METHODS: Rat VSMCs were isolated and cultured. Northern and Western blot analyses were performed to evaluate the effects of AS-6 on the expressions of tumor necrosis factor (TNF)-alpha-stimulated fractalkine, monocyte chemoattractant protein(MCP)-1 and vascular cell adhesion molecule (VCAM)-1 in VSMCs. A gel shift assay was performed to examine the mechanism by which AS-6 inhibits the expressions of fractalkine, MCP-1 and VCAM-1. RESULTS: TNF-alpha markedly induced the expressions of fractalkine, MCP-1 and VCAM-1 in primary cultured VSMCs. AS-6 inhibited the expressions of TNF-alpha-stimulated fractalkine, MCP-1 and VCAM-1 in primary cultured VSMCs. The result of the gel shift assay suggested the inhibitory effects of AS-6 on the expressions of TNF-alpha-stimulated fractalkine, MCP-1 and VCAM-1 were mediated through a nuclear factor kappaB associated pathway. CONCLUSION: The present study shows that AS-6 has anti-inflammatory effects on VSMCs, suggesting the possibility for the use of AS-6 for prevention of the development and progression of atherosclerosis.

Diabetes Metab J : Diabetes & Metabolism Journal
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