DIFFERENTIAL EXPRESSION OF THE INSULIN GENE TRANSCRIPTIONAL REPRESSORCCAAT ENHANCER-BINDING PROTEIN-BETA AND TRANSACTIVATOR ISLET DUODENUMHOMEOBOX-1 IN RAT PANCREATIC BETA-CELLS DURING THE DEVELOPMENT OF DIABETES-MELLITUS/

Impairment of insulin secretion due to prolonged hyperglycemia is beli eved to contribute to the manifestation of diabetes mellitus, often re ferred to as glucose toxicity of pancreatic beta cells, In addition, i mpaired beta cell function has been associated with elevated islet tri glyceride content (lipotoxicity), Impaired functions of the transactiv ating factors islet duodenum homeobox-l (IDX-1) and RIPE3b-binding pro teins have been implicated in the pathological dawnregulation of insul in gene transcription by high glucose levels in pancreatic beta cell l ines in vitro, and, similarly, the exposure of pancreatic islets to fa tty acids decreases IDX-1, expression. Previously, we identified the b asic leucine zipper transcription factor CCAAT/enhancer-binding protei n beta (C/EBP beta) as an inhibitor of insulin gene transcription in p ancreatic beta cells and showed that the expression of C/EBP beta is u pregulated in insulinoma-derived beta cell lines by sustained high glu cose concentrations. Here we describe the regulation of the expression of IDX-1, C/EBP beta, and insulin at the mRNA and protein levels in p ancreatic islets in animal models of diabetes mellitus, Concomitant wi th a downregulation of IDX-1 and insulin expression, C/EBP beta is upr egulated in association with the manifestation of hyperglycemia during the development of diabetes in the Zucker diabetic fatty (fa/fa) rat and in the 90% pancreatectomy rat model of diabetes. This regulation i s demonstrated to influence both the amount of cellular protein and th e level of steady state messenger RNA. Our findings indicate that the differential dysregulation of both IDX-1 and C/EBP beta, in response t o sustained hyperglycemia or hyperlipidemia, may be involved in the im pairment of insulin gene expression during the manifestation of diabet es mellitus.