Wang Zhen-ji, Liu Quan, Li Ping-ping, Zou Chen-hui, Shen Zhu-fang
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Eur J Pharmacol. 2008 Feb 2;580(1-2):277-83. doi: 10.1016/j.ejphar.2007.10.042. Epub 2007 Oct 25.
This paper reports on the effect of GCP-02, a dual activator of the peroxisome proliferator-activated receptors alpha/gamma (PPARalpha/gamma), on glucose and lipid metabolism in insulin-resistant obese mice induced by monosodium glutamate. The mice were divided into four groups on the basis of treatment: control group, rosiglitazone (positive control) (7 micromol/kg), and low- and high-dosage GCP-02 (7 micromol/kg and 3.5 micromol/kg, respectively). Drugs were given orally once a day for 19 days, and mice underwent testing for insulin tolerance, oral glucose tolerance and gluconeogenesis, and plasma cholesterol, triglyceride and free fatty acid levels. Mice were sacrificed, and body length and weight were measured; intraperitoneal adipose, heart and liver weighed; and plasma alanine aminotransferase (ALT) level and aspartate aminotransferase (AST) activity measured. Liver, soleus muscle and myocardium were assayed for glycogen, triglyceride and free fatty acid content and myocardia tested for superoxide dismutase (SOD) activity and malonaldehyde content. RT-PCR revealed expression of insulin receptor substrate 1 and 2 (IRS1, IRS2) and related genes in liver. GCP-02 had a more powerful effect than rosiglitazone on improving insulin sensitivity, ameliorating glucose tolerance, suppressing L-alanine-induced gluconeogenesis, and decreasing plasma levels of cholesterol, triglyceride and free fatty acid. It reduced body weight in control mice, significantly lowered hepatic content of glycogen, triglyceride and free fatty acid and myocardial content of triglyceride, and increased myocardial SOD activity. IRS2 mRNA was down-regulated in control mice but up-regulated by GCP-02. Thus, GCP-02 is a potential candidate for the prevention and therapy of diseases associated with insulin resistance such as type 2 diabetes mellitus and cardiovascular disease.
本文报道了过氧化物酶体增殖物激活受体α/γ（PPARα/γ）双重激活剂GCP-02对味精诱导的胰岛素抵抗肥胖小鼠糖脂代谢的影响。根据治疗方法将小鼠分为四组：对照组、罗格列酮（阳性对照）（7微摩尔/千克）以及低剂量和高剂量GCP-02组（分别为7微摩尔/千克和3.5微摩尔/千克）。每天口服给药一次，持续19天，然后对小鼠进行胰岛素耐受性、口服葡萄糖耐受性和糖异生测试，以及检测血浆胆固醇、甘油三酯和游离脂肪酸水平。处死小鼠后，测量体长和体重；称量腹腔脂肪、心脏和肝脏重量；检测血浆丙氨酸转氨酶（ALT）水平和天冬氨酸转氨酶（AST）活性。测定肝脏、比目鱼肌和心肌中的糖原、甘油三酯和游离脂肪酸含量，并检测心肌中的超氧化物歧化酶（SOD）活性和丙二醛含量。逆转录聚合酶链反应（RT-PCR）检测肝脏中胰岛素受体底物1和2（IRS1、IRS2）及相关基因的表达。GCP-02在改善胰岛素敏感性、改善葡萄糖耐受性、抑制L-丙氨酸诱导的糖异生以及降低血浆胆固醇、甘油三酯和游离脂肪酸水平方面比罗格列酮具有更强的作用。它降低了对照小鼠的体重，显著降低了肝脏中糖原、甘油三酯和游离脂肪酸的含量以及心肌中甘油三酯的含量，并提高了心肌SOD活性。对照小鼠中IRS2 mRNA表达下调，但GCP-02可使其上调。因此，GCP-02是预防和治疗与胰岛素抵抗相关疾病（如2型糖尿病和心血管疾病）的潜在候选药物。
