Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
Pharmacol Res. 2018 Apr;130:466-480. doi: 10.1016/j.phrs.2017.12.026. Epub 2017 Dec 25.
Type 2 diabetes is characterized by insulin resistance in target tissues and hyperglycemia. Catalpol is a natural product isolated from the root of Rehmannia glutinosa, which has been reported to produce the effect of anti-diabetes in recent reports. The goal of the current study is to investigate the therapeutic effects of catalpol on hepatic insulin resistance in type 2 diabetes and elucidate the underlying cellular mechanisms. Type 2 diabetes in vivo was induced by combined high-fat diet (HFD) and streptozotocin (STZ) injection in C57BL/6J mice. Insulin resistance in vitro was induced by glucosamine administration in HepG2 cells. Catalpol exhibited the effects decreasing hepatic gluconeogenesis and increasing hepatic glycogen synthesis both in vivo and in vitro. Additionally, catalpol improved hepatic NADPH oxidase type 4 (NOX4)-mediated oxidative stress and activated hepatic AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathway in vivo and in vitro. The effects of catalpol on preventing gluconeogenesis and increasing glycogen synthesis in glucosamine-induced HepG2 cells were prevented by pretreatment with LY294002, the inhibitor of PI3K. Furthermore, the effect of catalpol on depriving glucosamine-induced insulin resistance was prevented by knockdown of NOX4 or AMPK with short interfering RNA (siRNA) in HepG2 cells. Moreover, the suppressive effect of catalpol on glucosamine-induced NOX4 over-expression was weakened by knockdown of AMPK with siRNA. Taken together, these findings suggested that catalpol ameliorated hepatic insulin resistance in type 2 diabetes through acting on AMPK/NOX4/PI3K/AKT pathway.
2 型糖尿病的特征是靶组织胰岛素抵抗和高血糖。梓醇是从地黄根中分离得到的天然产物，最近的报道称其具有抗糖尿病作用。本研究旨在探讨梓醇对 2 型糖尿病肝胰岛素抵抗的治疗作用，并阐明其潜在的细胞机制。采用高脂饮食（HFD）联合链脲佐菌素（STZ）注射法在 C57BL/6J 小鼠体内诱导 2 型糖尿病，用氨基葡萄糖处理 HepG2 细胞在体外诱导胰岛素抵抗。梓醇在体内和体外均表现出降低肝糖异生和增加肝糖原合成的作用。此外，梓醇改善了肝 NADPH 氧化酶 4（NOX4）介导的氧化应激，并在体内和体外激活了肝 AMP 激活的蛋白激酶（AMPK）和磷脂酰肌醇 3-激酶（PI3K）/AKT 通路。LY294002（PI3K 抑制剂）预处理可阻止梓醇在氨基葡萄糖诱导的 HepG2 细胞中防止糖异生和增加糖原合成的作用。此外，用短发夹 RNA（siRNA）敲低 HepG2 细胞中的 NOX4 或 AMPK 可阻止梓醇对氨基葡萄糖诱导的胰岛素抵抗的作用。此外，用 siRNA 敲低 AMPK 可削弱梓醇对氨基葡萄糖诱导的 NOX4 过表达的抑制作用。综上所述，这些发现表明梓醇通过作用于 AMPK/NOX4/PI3K/AKT 通路改善 2 型糖尿病肝胰岛素抵抗。
