Prolonged elevations of glucose concentration have deleterious effects on -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 -cell dysfunction induced by glucotoxicity.
In patients with residual hypertriglyceridemia despite statin treatment, a combination of ω-3 fatty acids and rosuvastatin produced a greater reduction of TGs and non-HDL-C than rosuvastatin alone. Further study is needed to determine whether the advantages of this lipid profile of ω-3 fatty acids actually leads to the prevention of cardiovascular event. ClinicalTrials.gov identifier: NCT03026933.
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