2176-P: miRNA-374 Improves Glucotoxicity-Induced Beta-Cell Dysfunction and Glucose Metabolism Dysfunction through the Regulation of PGC-1 Alpha

Glucotoxicity plays a major role in the progressive deterioration of β-cell function and development of type 2 diabetes mellitus. MicroRNAs (miRNAs) represent small noncoding RNAs that play a role in many diseases, including diabetes. This study was to search the common gene mechanism between liver and pancreas in diabetic condition such as glucotoxicity and to search the miRNAs related to glucotoxicity-induced β-cell dysfunction and glucose metabolism dysfunction in liver. To study the role of miRNAs in glucotoxicity-induced β-cell dysfunction and glucose metabolism dysfunction, we analyzed the miRNA expression patterns of primary rat islets and hepatocytes for three days after exposure to glucotoxicity and confirmed up-regulated and down-regulated miRNAs. Overexpression of miR-374 suppressed PGC-1α expression in glucotoxicity. miR-374 was found to target the 3'-untranslated region (3'UTR) of PGC-1α through miR-374 binding sites and to downregulated PGC-1α protein abundance at the post-transcriptional level by luciferase activity assay combined with mutational analysis. Here we demonstrate that miR-374 mediated suppression of PGC-1α gene expression is an important initiation step of glucotoxicity induced β-cell dysfunction and glucose metabolism dysfunction in liver and appropriate new target for early treatment.