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

¹ Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
² Department of Internal Medicine, and Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea
³ Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Kwangju, Republic of Korea
⁴ Departments of Medicine and Pharmacology, University of Kansas Medical Center, Kansas
⁵ Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
⁶ Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Republic of Korea

Address correspondence and reprint requests to In-Kyu Lee, MD, PhD, Department of Internal Medicine, Kyungpook National University Hospital, 50 Samduk-2ga, Jung-gu, Daegu, 700-721, Republic of Korea. E-mail: leei{at}knu.ac.kr

Abbreviations: FBS, fetal bovine serum; GSIS, glucose-stimulated insulin secretion; KRBB, Krebs-Ringer bicarbonate buffer; PDX, pancreatic duodenal homeobox factor; SHP, small heterodimer partner; siRNA, small interfering RNA

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

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