Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes.

摘要: Preservation of insulin-secreting β-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and β-cell apoptosis vitro. In this report, we demonstrate efficacy HDAC inhibitors (HDACi) vivo. We show that daily administration BRD3308, isoform-selective HDAC3 inhibitor, 2 weeks female nonobese diabetic (NOD) mice, beginning 3 age, followed by twice-weekly injections until age 25 weeks, protects animals from The preservation was because a significant decrease infiltration mononuclear cells. Moreover, BRD3308 treatment increased basal insulin secretion islets cultured All metabolic tissues tested vehicle- or BRD3308-treated groups showed virtually no sign immune cell infiltration, except minimal white adipose tissue treated highest dose (10 mg/kg), providing additional evidence protection attack groups. Furthermore, pancreata 10 mg/kg exhibited significantly decreased numbers apoptotic compared those vehicle low-dose BRD3308. Finally, 1 had enhanced proliferation. These vivo results point potential use selective as therapeutic approach prevent death long-term limiting progression type