Valproic Acid Improves Glucose Homeostasis by Increasing Beta-Cell Proliferation, Function, and Reducing its Apoptosis through HDAC Inhibition in Juvenile Diabetic Rat

Sabbir Khan; Gopabandhu Jena

doi:10.1002/jbt.21807

Valproic Acid Improves Glucose Homeostasis by Increasing Beta-Cell Proliferation, Function, and Reducing its Apoptosis through HDAC Inhibition in Juvenile Diabetic Rat

J Biochem Mol Toxicol. 2016 Sep;30(9):438-46. doi: 10.1002/jbt.21807. Epub 2016 Apr 15.

Authors

Sabbir Khan¹, Gopabandhu Jena²

Affiliations

¹ Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India. gbjena@gmail.com.
² Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India. gbjena@niper.ac.in.

PMID: 27079868
DOI: 10.1002/jbt.21807

Abstract

Recent evidence highlighted that there is a link between type-1 diabetes mellitus and histone deacetylases (HDACs) due to their involvement in beta-cell differentiation, proliferation, and function. The present study aimed to investigate the protective role of valproic acid (VPA) on beta-cell proliferation, function, and apoptosis in juvenile diabetic rat. Diabetes was induced in juvenile Sprague-Dawley rats by streptozotocin (75 mg/kg, i.p.) and VPA was administered at the doses of 150 and 300 mg/kg/day for 3 weeks by oral route. Various biochemical parameters, cellular alterations, and protein expression as well as apoptosis were assessed using different assays. VPA treatment significantly decreased plasma glucose, beta-cell damage, and apoptosis as well as increased the beta-cell function, insulin level/expression. The present study demonstrated that VPA improves beta-cell proliferation and function as well as reduces beta-cell apoptosis through HDAC inhibition. Our findings provide evidence that VPA may be useful for the treatment of juvenile diabetes.

Keywords: Apoptosis; Beta-Cell; Diabetes; HDAC inhibitor; Sodium Valproate.

MeSH terms

Animals
Apoptosis / drug effects
Blood Glucose / metabolism
Cell Proliferation / drug effects
Diabetes Mellitus, Experimental / drug therapy*
Diabetes Mellitus, Experimental / genetics
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / mortality
Diabetes Mellitus, Type 1 / drug therapy
Diabetes Mellitus, Type 1 / genetics
Diabetes Mellitus, Type 1 / metabolism
Diabetes Mellitus, Type 1 / pathology
Disease Models, Animal
Drug Administration Schedule
Gene Expression Regulation
Glycated Hemoglobin / metabolism
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / genetics*
Histone Deacetylases / metabolism
Histones / genetics
Histones / metabolism
Homeostasis
Humans
Hypoglycemic Agents / pharmacology*
Insulin / biosynthesis
Insulin / genetics
Insulin-Secreting Cells / drug effects*
Insulin-Secreting Cells / metabolism
Insulin-Secreting Cells / pathology
Male
Rats
Rats, Sprague-Dawley
Streptozocin
Survival Analysis
Valproic Acid / pharmacology*

Substances

Blood Glucose
Glycated Hemoglobin A
Histone Deacetylase Inhibitors
Histones
Hypoglycemic Agents
Insulin
Streptozocin
Valproic Acid
Histone Deacetylases