RGD Reference Report - Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner. - Rat Genome Database
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Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner.

Authors: Park, KG  Lee, KM  Seo, HY  Suh, JH  Kim, HS  Wang, L  Won, KC  Lee, HW  Park, JY  Lee, KU  Kim, JG  Kim, BW  Choi, HS  Lee, IK 
Citation: Park KG, etal., Diabetes. 2007 Feb;56(2):431-7.
RGD ID: 2311606
Pubmed: (View Article at PubMed) PMID:17259388
DOI: Full-text: DOI:10.2337/db06-0753

Prolonged elevations of glucose concentration have deleterious effects on beta-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that inhibits nuclear receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose-induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1-and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of beta-cell dysfunction induced by glucotoxicity.

Annotation

Disease Annotations    
diabetes mellitus  (IEP,ISO)

Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Nr0b2  (nuclear receptor subfamily 0, group B, member 2)

Genes (Mus musculus)
Nr0b2  (nuclear receptor subfamily 0, group B, member 2)

Genes (Homo sapiens)
NR0B2  (nuclear receptor subfamily 0 group B member 2)


Additional Information