title: Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats.
abstract: Failure of pancreatic β cells to compensate for insulin resistance is a prerequisite for the development of type 2 diabetes. Sustained elevated circulating levels of free fatty acids and glucose contribute to β-cell failure. Selective inhibition of histone deacetylase (HDAC)-3 protects pancreatic β cells against inflammatory and metabolic insults in vitro. In the present study, we tested the ability of a selective HDAC3 inhibitor, BRD3308, to reduce hyperglycaemia and increase insulin secretion in a rat model of type 2 diabetes. At diabetes onset, an ambulatory hyperglycaemic clamp was performed. HDAC3 inhibition improved hyperglycaemia over the study period without affecting weight gain. At the end of the hyperglycaemic clamp, circulating insulin levels were significantly higher in BRD3308-treated rats. Pancreatic insulin staining and contents were also significantly higher. These findings highlight HDAC3 as a key therapeutic target for β-cell protection in type 2 diabetes.
authors.affiliation: Chemical Biology Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.|Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Lundh
authors.affiliation: Department of Internal Medicine, Yale University, New Haven, CT, USA.
authors.forename: T
authors.initials: T
authors.lastname: Galbo
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: S S
authors.initials: SS
authors.lastname: Poulsen
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.|Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Mandrup-Poulsen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D015309:Glucose Clamp Technique; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000378:metabolism* / Q000627:therapeutic use; D006943:Hyperglycemia / Q000188:drug therapy; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D051381:Rats; D011924:Rats, Zucker; D015430:Weight Gain; D000099186:Histone Deacetylase 3
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D007328:Insulin; D000099186:Histone Deacetylase 3
keywords: Zucker diabetic fatty rat; antidiabetic drug; beta cell; endocrine therapy; insulin secretion; type 2 diabetes