Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner.
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.
Park
Keun-Gyu
KG
Department of Internal Medicine, Kyungpook National University Hospital, 50 Samduk-2ga, Jung-gu, Daegu 700-721, Republic of Korea.
Lee
Kyeong-Min
KM
Seo
Hye-Young
HY
Suh
Ji-Ho
JH
Kim
Hye-Soon
HS
Wang
Li
L
Won
Kyu-Chang
KC
Lee
Hyoung-Woo
HW
Park
Joong-Yeol
JY
Lee
Ki-Up
KU
Kim
Jung-Guk
JG
Kim
Bo-Wan
BW
Choi
Hueng-Sik
HS
Lee
In-Kyu
IK
D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007340:Insulinoma / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*
D018398:Homeodomain Proteins; D007328:Insulin; C094696:Klrg1 protein, rat; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; C099713:nuclear receptor subfamily 0, group B, member 2; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose