Exendin-4 may improve type 2 diabetes by modulating the epigenetic modifications of pancreatic histone H3 in STZ-induced diabetic C57BL/6 J mice

ABSTRACT

Type 2 diabetes (T2D) is a complicated systemic disease that might be improved by exendin-4, although the epigenetic role remains unclear. In the current study, C57BL/6 J mice were used to generate a T2D model, followed by treatment with exendin-4 (10 μg/kg). Histone H3K9 and H3K23 acetylation, H3K4 mono-methylation, and H3K9 di-methylation were explored by western blot analysis of pancreatic histone extracts. Real-time polymerase chain reaction (PCR) was used to examine the expression levels of pancreatic beta cell development-related genes, and chromatin immunoprecipitation (ChIP) was applied to analyze H3 and H3K9 acetylation, H3K4 mono-methylation, and H3K9 di-methylation in the promoter region of the pancreatic and duodenal homeobox 1 (Pdx1) gene. The results showed that total H3K9 di-methylation and H3K9 and H3K23 acetylation increased in pancreatic tissues of diabetic mice, whereas H3K4 mono-methylation was reduced. All of these changes could be abrogated by treatment with exendin-4. Our data indicated that T2D progression might be improved by exendin-4 treatment through the reversal of global pancreatic histone H3K9 and H3K23 acetylation, H3K4 mono-methylation, and H3K9 di-methylation. A better understanding of these epigenetic alterations may, therefore, lead to novel therapeutic strategies for T2D. (AU)