Glucotoxicity in the INS-1 Rat Insulinoma Cell Line Is Mediated by the Orphan Nuclear Receptor Small Heterodimer Partner

Park, Keun-Gyu; Lee, Kyeong-Min; Seo, Hye‐Young; Suh, Ji-Ho; Kim, Hye-Soon; Wang, Li; Won, Kyu Chang; Lee, Hyoung-Woo; Park, Joong‐Yeol; Lee, Ki-Up; Kim, Jung‐Guk; Kim, Bo-Wan; Choi, Hueng-Sik; Lee, Inkyu

doi:10.2337/db06-0753

Cited by 54 publications

(47 citation statements)

References 39 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several mechanisms have been implicated in these effects of glucotoxicity, including ceramide formation [4], oxidative stress [5] and inflammation [6]. Alterations in the gene expression of pancreas-specific transcription factors, including pancreatic duodenal homeobox 1 (Pdx-1), beta cell E-box transcription factor (Beta2)/neuronal differentiation 1 (NeuroD; also known as NEUROD1) and v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (Mafa), contribute to the induction of beta cell dysfunction [7][8][9][10][11]. Our group has reported that the suppression of Beta2/NeuroD transcription by overexpression of the gene encoding peroxisome proliferator-activated receptor γ-coactivator-1α (Pgc-1α; also known as Ppargc1a) is an important initial step in beta cell glucotoxicity [12,13].…”

Section: Introductionmentioning

confidence: 99%

miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis The loss of beta cell function is a critical factor in the development of type 2 diabetes. Glucotoxicity plays a major role in the progressive deterioration of beta cell function and development of type 2 diabetes mellitus. Here we demonstrate that microRNA (miR)-30a-5p is a key player in early-stage glucotoxicity-induced beta cell dysfunction. Methods We performed northern blots, RT-PCR and western blots in glucotoxicity-exposed primary rat islets and INS-1 cells. We also measured glucose-stimulated insulin secretion and insulin content. In vivo approaches were used to evaluate the role of miR-30a-5p in beta cell dysfunction.Results miR-30a-5p expression was increased in beta cells after exposure to glucotoxic conditions, and exogenous miR-30a-5p overexpression also induced beta cell dysfunction in vitro. miR-30a-5p directly suppressed expression of Beta2/NeuroD (also known as Neurod1) by binding to a specific binding site in its 3′-untranslated region. After restoration of Beta2/NeuroD expression by knockdown miR-30a-5p or transfection of the Beta2/NeuroD gene, beta cell dysfunction, including decreased insulin content, gene expression and glucose-stimulated insulin secretion, recovered. Glucose tolerance and beta cell dysfunction improved on direct injection of Ad-si30a-5p into the pancreas of diabetic mice. Conclusions/interpretation Our data demonstrate that miR30a-5p-mediated direct suppression of Beta2/NeuroD gene expression is an important initiation step of glucotoxicityinduced beta cell dysfunction.

show abstract

Section: Introductionmentioning

confidence: 99%

miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Recently, SHP has been demonstrated to perform a significant function in the development of β cell dysfunction induced by glucotoxicity, when a sustained culture of INS-1 cells at high glucose concentrations resulted in an increase in the expression of SHP mRNA, followed by a reduction in insulin gene expression. Additionally, the proposed mechanisms for the downregulation of insulin gene expression by SHP suggested (i) the downregulation of PDX-1 and MafA gene expression and (ii) the inhibition of p300-mediated PDX-1 and BETA2-dependent transcriptional activity at the insulin promoter [100].…”

Section: Glucose Metabolismmentioning

confidence: 99%

Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner

2008

Self Cite

View full text Add to dashboard Cite

Abstract. Nuclear receptors (NRs) are a unique superfamily of transcription factors (TFs) which are involved in and play a crucial role in almost all aspects of mammalian physiology. Small Heterodimer Partner (SHP; NR0B2), an exceptional member of this superfamily of NRs, have been identified as a key regulatory factor of the transcription of a variety of genes involved in diverse metabolic pathways, and are thereby an important factor in a variety of physiological functions. Since its discovery a decade ago, considerable progress has been made in the elucidation of the underlying mechanism by which SHP regulates various metabolic processes, and the results of previous studies support its importance in the maintenance of metabolic homeostasis. In this review, we have evaluated the current state of understanding of the molecular mechanisms and the resultant physiological interpretations governed by SHP. SMALL Heterodimer Partner is a unique member of the mammalian nuclear receptor superfamily, which is clearly distinct from the conventional nuclear receptors, both structurally and functionally. It is classified into the "orphan" subfamily, due to the absence of any known ligand for this receptor, and appears to function as a transcriptional co-regulator of numerous nuclear receptors and transcription factors. The dosage-sensitive sex reversal-adrenal hypoplasia congenital region gene on the X chromosome, gene-1 (DAX-1; NR0B1) is the closest relative to SHP. Both belong to the same subfamily, and both share considerable functional and structural similarities with SHP. SHP owes its place in the nuclear receptor family to the presence of a putative ligand binding domain (LBD), although it lacks the classical DNA binding domain (DBD) which is generally detected among other nuclear receptors. Intensive research conducted following its discovery last decade has resulted in a clearer understanding of the molecular basis for the inhibitory functions of SHP on a variety of metabolic processes, thereby providing us with ample evidence regarding its importance as a key regulator in a number of signaling pathways [1,2]. Hub-based topological analysis of the nuclear receptor network has demonstrated the extensive connections existing among these receptors as the result of their similarity in terms of interaction and tissue expression, as well as a considerable number of feedback loops that work in concert in this network, with SHP playing a principal role as the hub protein within this network [3]. In this review, we have attempted to survey the entirety of the information available thus far concerning the structural and functional aspects of the orphan nuclear receptor SHP, hoping to acquire a detailed understanding of the physiological significance of the activity of SHP.

show abstract

“…When glucotoxicity occurs, β-cell damage leads to defects in insulin production such that chronic glucose exposureinduced β-cell exhaustion becomes irreversible. Some of the explanations for glucoseinduced β-cell damage include depressed rates of insulin synthesis [450], increased small heterodimer partner (SHP) nuclear receptor mRNA [451], downregulation of glucokinase mRNA [425], reduced PDX-1 mRNA, protein and insulin promoter binding activity [312,450,452], compromised mitochondrial function and induction of apoptosis. Upregulation of the SHP receptor is thought to act as a competitive inhibitor to prevent p300-mediated PDX-1 and BETA2 complex formation [451].…”

Section: Glutotoxicity -Glycation and Reactive Oxygen Species (Ros) Pmentioning

confidence: 99%

“…Some of the explanations for glucoseinduced β-cell damage include depressed rates of insulin synthesis [450], increased small heterodimer partner (SHP) nuclear receptor mRNA [451], downregulation of glucokinase mRNA [425], reduced PDX-1 mRNA, protein and insulin promoter binding activity [312,450,452], compromised mitochondrial function and induction of apoptosis. Upregulation of the SHP receptor is thought to act as a competitive inhibitor to prevent p300-mediated PDX-1 and BETA2 complex formation [451]. Repeated exposure to elevated glucose also reduces activity of RIPE3b1 [453,454], while enhancing activity of insulin transcriptional repressor basic leucine zipper CCAAT/enhancer-binding protein β (C/EBPβ) [455,456].…”

Section: Glutotoxicity -Glycation and Reactive Oxygen Species (Ros) Pmentioning

confidence: 99%

Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes

Fu¹,

Gilbert²,

Liu³

2012

CDR

View full text Add to dashboard Cite

Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca 2+ ] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion. This article reviews current knowledge on how β-cells synthesize and secrete insulin. In addition, this review presents evidence that genetic and environmental factors can lead to hyperglycemia, dyslipidemia, inflammation, and autoimmunity, resulting in β-cell dysfunction, thereby triggering the pathogenesis of diabetes. Keywords β-cell; diabetes; glucose; hormones; insulin secretion; insulin synthesis INSULIN Insulin structureThe crystal structure of insulin is well documented as well as the structural features that confer receptor binding affinity and activity. This has been extensively reviewed and readers are encouraged to visit [1] and [2] for excellent discussions on insulin structure and structure-activity relationships. As discussed in this review, insulin receptor downstream signaling intersects with the signaling pathways of other growth factors, including IGF1 and Correspondence: Dongmin Liu, Ph.D, Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA 24061, Tel: 540-231-3402, Fax: 540-231-3916, doliu@vt.edu. CONFLICTS OF INTERESTThe authors declare that they have no conflict of interest. NIH Public Access Author ManuscriptCurr Diabetes Rev. Author manuscript; available in PMC 2014 February 25. Published in final edited form as:Curr Diabetes Rev. 2013 January 1; 9(1): 25-53. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript IGF2 [3]. This demonstrates the importance of identifying receptor ligand agonists as potential insulin-mimetic therapeutic agent...

show abstract

Glucotoxicity in the INS-1 Rat Insulinoma Cell Line Is Mediated by the Orphan Nuclear Receptor Small Heterodimer Partner

Cited by 54 publications

References 39 publications

miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models

miRNA-30a-5p-mediated silencing of Beta2/NeuroD expression is an important initial event of glucotoxicity-induced beta cell dysfunction in rodent models

Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner

Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes

Contact Info

Product

Resources

About