Au Wo-Shing, Lu Li-Wei, Tam Sidney, Ko Otis King Hung, Chow Billy K C, He Ming-Liang, Ng Samuel S, Yeung Chung-Man, Liu Ching-Chiu, Kung Hsiang-Fu, Lin Marie C
Department of Chemistry, Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Kadoorie Biological Science Building, Hong Kong, China.
World J Gastroenterol. 2009 Jun 28;15(24):2987-94. doi: 10.3748/wjg.15.2987.
To test whether oral L-81 treatment could improve the condition of mice with diabetes and to investigate how L-81 regulates microsomal triglyceride transfer protein (MTP) activity in the liver.
Genetically diabetic (db/db) mice were fed on chow supplemented with or without L-81 for 4 wk. The body weight, plasma glucose level, plasma lipid profile, and adipocyte volume of the db/db mice were assessed after treatment. Toxicity of L-81 was also evaluated. To understand the molecular mechanism, HepG2 cells were treated with L-81 and the effects on apolipoprotein B (apoB) secretion and mRNA level of the MTP gene were assessed.
Treatment of db/db mice with L-81 significantly reduced and nearly normalized their body weight, hyperphagia and polydipsia. L-81 also markedly decreased the fasting plasma glucose level, improved glucose tolerance, and attenuated the elevated levels of plasma cholesterol and triglyceride. At the effective dosage, little toxicity was observed. Treatment of HepG2 cells with L-81 not only inhibited apoB secretion, but also significantly decreased the mRNA level of the MTP gene. Similar to the action of insulin, L-81 exerted its effect on the MTP promoter.
L-81 represents a promising candidate in the development of a selective insulin-mimetic molecule and an anti-diabetic agent.
检测口服L - 81治疗是否能改善糖尿病小鼠的病情，并研究L - 81如何调节肝脏微粒体甘油三酯转运蛋白（MTP）的活性。
给遗传性糖尿病（db/db）小鼠喂食添加或不添加L - 81的普通饲料4周。治疗后评估db/db小鼠的体重、血糖水平、血脂谱和脂肪细胞体积。还评估了L - 81的毒性。为了解分子机制，用L - 81处理HepG2细胞，并评估其对载脂蛋白B（apoB）分泌和MTP基因mRNA水平的影响。
用L - 81治疗db/db小鼠可显著降低其体重、多食和多饮，并使其接近正常水平。L - 81还显著降低空腹血糖水平，改善糖耐量，并减轻血浆胆固醇和甘油三酯水平的升高。在有效剂量下，未观察到明显毒性。用L - 81处理HepG2细胞不仅抑制apoB分泌，还显著降低MTP基因的mRNA水平。与胰岛素的作用相似，L - 81对MTP启动子发挥作用。
L - 81是开发选择性胰岛素模拟分子和抗糖尿病药物的有前景的候选物。
