In the last years there is a crescent number of evidences suggesting the role of epigenetic factors in the pathogenesis of type 2 diabetes (T2D). However, the current understanding of the molecular mechanisms that connect the environmental and genetic factors is still limited. The Wistar rat strain Goto-Kakizaki (GK) is considered one of the best animal models of T2D because it shows similar metabolic, hormonal and vascular disorders observed in humans. Despite its genetic character, the spontaneous type 2 diabetes observed in GK rats is manifested only in adulthood, which indicates the presence of epigenetic components in the genesis of the disease. These exhibit high hepatic expression of miR-29a-c, which has as direct target genes G6Pase and ±-PGC1. In a recent study of our group we demonstrated that pregnant rats treated with dexamethasone show a late onset of glucose intolerance and the loss of pancreatic function, which is associated with the over-expression of miR-29a-c. These findings indicate that there may be a unique repertoire of miRNA associated with diabetes, regardless of its etiology. Thus, the objective of this project is to identify common patterns of hepatic miRNA expression between the genetic model of type 2 diabetes (GK rats) and WKY subjected to metabolic imprinting (prenatal exposure to excess GC with subsequent metabolic insult). Among the most common metabolic insults of modern life is the high consumption of fructose in industrialized drinks. Four experimental groups will be used in the hepatic miRNA expression profile analysis: (1) neonatal GK rats; (2) adult diabetic GK rats; (3) neonatal WKY rats exposed to fetal GC excess; and (4) adult WKY rats exposed to fetal GC excess and to fructose ingestion. Metabolic parameters (ITT, GTT, PTT, body weight and composition) will me monitored until the gene expression analysis. The miRNA differentially expressed in the large-scale analysis will be confirmed by qPCR; the putative target genes will be searched using in silico analysis and confirmed by immunoblotting.
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