Chen Deqi, Jia Dan, Wu Xia, Shi Kexin, Ren Cui, Dou Yonghui, Guo Mingxin, Wang Juanxia, Ma Min, Wu Zhengzhi, Shi He-Yong, Li Weimin, Feng Yifan, Wu Fuhai
Central Laboratory, Guangdong Pharmaceutical University, Guangzhou, China.
Integrated Chinese and Western Medicine, Post-doctoral Research Station, Jinan University, Guangzhou, China.
Clin Exp Pharmacol Physiol. 2020 Aug;47(8):1382-1392. doi: 10.1111/1440-1681.13302. Epub 2020 Apr 13.
In this study, we investigated the lipid metabolism regulatory activity of a novel metformin derivative (MD568) and its potential mechanism of action in obese rats with type 2 diabetes mellitus (T DM). Previous gene chip analysis of 3T3-L1 cells have shown that MD568 regulates the transcription of genes involved in the peroxisome proliferator-activated receptor (PPAR) signalling pathway, fatty acid metabolism, and glycerolipid metabolism. In this study, obese T DM rats were treated with MD568 (200 mg/kg) for 8 weeks. Results showed that MD568 significantly reduced the body weight gain, plasma glucose, insulin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels. MD568 treatment also improved the insulin resistance of obese T DM model rats. In particular, in white adipose tissue, MD568 inhibited the excessive volume increment of adipose cells by down-regulating the protein levels of CCAAT/enhancer-binding protein-α (C/EBP-α) and PPAR-γ, as well as the transcription of their target lipid metabolism-related genes. In the liver, MD568 inhibited hepatic fatty lesions and interfered with hepatic gluconeogenesis by regulating the expression of lipid metabolism-related genes and glycogen-related kinases. In conclusion, our results suggest that the newly synthesized MD568 affects the maintenance of lipid homeostasis in obese type 2 diabetic rats.
在本研究中，我们调查了一种新型二甲双胍衍生物（MD568）的脂质代谢调节活性及其在2型糖尿病（T2DM）肥胖大鼠中的潜在作用机制。先前对3T3-L1细胞的基因芯片分析表明，MD568可调节参与过氧化物酶体增殖物激活受体（PPAR）信号通路、脂肪酸代谢和甘油脂质代谢的基因转录。在本研究中，给肥胖的T2DM大鼠用MD568（200mg/kg）治疗8周。结果显示，MD568显著降低了体重增加、血糖、胰岛素、总胆固醇、甘油三酯和低密度脂蛋白胆固醇水平。MD568治疗还改善了肥胖T2DM模型大鼠的胰岛素抵抗。特别是，在白色脂肪组织中，MD568通过下调CCAAT/增强子结合蛋白-α（C/EBP-α）和PPAR-γ的蛋白水平及其靶脂质代谢相关基因的转录，抑制了脂肪细胞的过度体积增加。在肝脏中，MD568通过调节脂质代谢相关基因和糖原相关激酶的表达，抑制肝脏脂肪病变并干扰肝脏糖异生。总之，我们的结果表明新合成的MD568影响2型糖尿病肥胖大鼠脂质稳态的维持。
