Khan Sabbir, Kumar Sandeep, Jena Gopabandhu
Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160062, India.
Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab 160062, India.
Biochimie. 2016 Jun;125:42-52. doi: 10.1016/j.biochi.2016.02.014. Epub 2016 Mar 2.
Recent evidences highlighted the role of histone deacetylases (HDACs) in insulin-resistance, gluconeogenesis and islet function. HDACs can modulate the expression of various genes, which directly or indirectly affect glucose metabolism. This study was aimed to evaluate the role of valproic acid (VPA) on fat deposition, insulin-resistance and gluconeogenesis in type-2 diabetic rat. Diabetes was developed in Sprague-Dawley rats by the combination of high-fat diet and low dose streptozotocin. VPA at the doses of 150 and 300 mg/kg/day and metformin (positive control) 150 mg/kg twice daily for 10 weeks were administered by oral gavage. Insulin-resistance, dyslipidemia and glycemia were evaluated by biochemical estimations, while fat accumulation and structural alteration were assessed by histopathology. Protein expression and insulin signaling were evaluated by western blot and immunohistochemistry. VPA treatment significantly reduced the plasma glucose, HbA1c, insulin-resistance, fat deposition in brown adipose tissue, white adipose tissue and liver, which are comparable to metformin treatment. Further, VPA inhibited the gluconeogenesis and glucagon expression as well as restored the histopathological alterations in pancreas and liver. Our findings provide new insights on the anti-diabetic role of VPA in type-2 diabetes mellitus by the modulation of insulin signaling and forkhead box protein O1 (FOXO1)-mediated gluconeogenesis. Since VPA is a well established clinical drug, the detailed molecular mechanisms of the present findings can be further investigated for possible clinical use.
近期证据突显了组蛋白去乙酰化酶（HDACs）在胰岛素抵抗、糖异生及胰岛功能中的作用。HDACs可调节多种基因的表达，这些基因直接或间接影响葡萄糖代谢。本研究旨在评估丙戊酸（VPA）对2型糖尿病大鼠脂肪沉积、胰岛素抵抗及糖异生的作用。通过高脂饮食和低剂量链脲佐菌素联合诱导斯普拉格-道利大鼠患糖尿病。通过灌胃给予剂量为150和300 mg/kg/天的VPA以及作为阳性对照的二甲双胍，二甲双胍剂量为150 mg/kg，每日两次，持续10周。通过生化检测评估胰岛素抵抗、血脂异常和血糖水平，同时通过组织病理学评估脂肪堆积和结构改变。通过蛋白质印迹法和免疫组织化学评估蛋白质表达和胰岛素信号传导。VPA治疗显著降低了血浆葡萄糖、糖化血红蛋白、胰岛素抵抗，以及棕色脂肪组织、白色脂肪组织和肝脏中的脂肪沉积，其效果与二甲双胍治疗相当。此外，VPA抑制了糖异生和胰高血糖素表达，并恢复了胰腺和肝脏的组织病理学改变。我们的研究结果通过调节胰岛素信号传导和叉头框蛋白O1（FOXO1）介导的糖异生，为VPA在2型糖尿病中的抗糖尿病作用提供了新的见解。由于VPA是一种成熟的临床药物，本研究结果的详细分子机制可进一步研究以便可能用于临床。
