Transcriptional regulation of healthy and diabetic pancreatic beta-cell gene expression

摘要: Hyperglycemia, deficient insulin secretion, and resistance are the characteristic pathogenetic features of type 2 diabetes (T2D), hallmarked by functional survival defects insulin-producing islet -cell. The primary pathogenesis T2D probably involves both genetic environmental forces, hyperglycemia very commonly hyperlipidemia might further aggravate -cell dysfunction. To gain a deeper understanding precise nature cellular molecular responsible for T2D, it is necessary to pin down mechanisms which glucotoxicity lipotoxicity adversely impact rodent human -cells. This was over-arching aim current work. Additionally, influence antidiabetic drugs, with alleged ability protect preserve function viability, on above pathways addressed. Paper I, II Long term exposure free fatty acids (FFAs) may alter signaling gene expression, precipitating failure through impaired synthesis secretion in combination apoptosis, phenomenon referred as lipotoxicity. It still unclear whether apoptosis induced increased FFAs alone, synergy glucose, or if predisposing factors required. Also, protective effects PPAR agonist pioglitazone (a thiazolidinedione) GLP-1 receptor exenatide (an incretin mimetic) against FFA-induced dysfunction debated. We sought investigate long effect global alterations with/out palmitate evoke lipotoxicity, rat diabetic non-diabetic islets. Microarray interrogation qRT-PCR analyses revealed several categories, most importantly epigenetic regulation expression that seem regulate survival. Furthermore, contribute play an important role development hyperglycemia, obese individuals, subjects who genetically more predisposed T2D. Considering nutritional state directly induces modifications, appear normalize these misregulations from lipotoxic insult. modifications genome provide new promising targets clinical diagnostics also therapeutic purposes III Chronic believed be determinant become irreversible over time (known glucotoxicity). objective this study glucose-regulated key genes islets spontaneously Goto-Kakizaki (GK) rats compared normoglycemic Wistar rats, using microarray technology. identified significant changes mRNAs involved glucose sensing, phosphorylation, action, glucocorticoid handling, ion transport, mitogenesis clearly distinguish animals controls. Our results identify elements -cells, revealing substantial qualitative quantitative differences between healthy have implications our etiology treatment Such markers predictive therapeutical value settings efforts aiming at conferring protection regenerative capacity suppression occurring diabetes. IV Pancreatic duodenal homeobox-1 (PDX-1) transcription factor critical embryonic pancreas normal function. In PDX-1 regulates number maintaining identity function, including insulin. Glucose homeostasis requires tight secretion. homeodomain protein plays DNA binding glucose-dependent transcription. basis nuclear translocation, however, remains poorly understood. study, we aimed amino acid sequences translocation mouse site-directed mutagenesis putative phosphorylation sites positively charged residues localization signal (NLS) motifs GFP-tagged PDX-1. demonstrate NLS motif RRMKWKK necessary, conjunction integrity helix 3` domain sufficient, import LIST OF PUBLICATIONS I. Ghanaat-pour H, Sjoholm A. Gene regulated exposed Diab/Metab Res Rev, press. II. Exenatide acid-induced Manuscript. III. Huang Z, Lehtihet M, Global profiling pancreatic rats. J Mol Endocrinol 2007 Aug; 39(2):135-50. IV. Moede T, Leibiger B, Berggren P, IB. Identification localisation signal, RRMKWKK, FEBS Lett 1999; 461:229-34.