Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner

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

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Prolonged elevations of glucose concentration have deleterious effects on β-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 β-cell dysfunction induced by glucotoxicity.

Original languageEnglish
Pages (from-to)431-437
Number of pages7
JournalDiabetes
Volume56
Issue number2
DOIs
StatePublished - Feb 2007

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