Department of Pharmacology, School of Basic Medicine and Life Science, Hainan Medical University, Haikou 571199, China.
Key Laboratory of Tropical Translational Medicine of the Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmacy, Hainan Medical University, No.3 Xueyuan Road, Chengxi Town, Haikou City, Hainan Province 571199, China.
Phytomedicine. 2022 Nov;106:154423. doi: 10.1016/j.phymed.2022.154423. Epub 2022 Aug 31.
Type 2 diabetes mellitus (DM) is a highly prevalent chronic metabolic disease. Effective antidiabetic drugs are needed to improve and expand the available treatments. Using the ob/ob diabetic mouse model, we previously demonstrated that the alkaloid-rich extract from Litsea glutinosa bark (CG) has potent antidiabetic effects and that laurolitsine (LL) is the richest alkaloid in CG.
We conducted a systematic investigation of the antidiabetic effects and potential mechanisms of LL in vitro and in vivo.
The antidiabetic effects of LL and its mechanisms of action were explored in HL-7702 hepatocytes in vitro and in db/db mice in vivo by a series of experiments, including cellular toxicity analysis, glucose consumption analysis, serum/liver biochemical analysis, pathological examinations, Western blots, RNA-seq analysis, and gut microbiota analysis.
LL stimulated glucose consumption and activated AMP-activated protein kinase (AMPK) without inducing lactic acid production or cytotoxicity in vitro. LL had potent antidiabetic effects with hypoglycemic activity in vivo. It improved insulin resistance, glucose tolerance and lipid metabolism; protected liver, renal and pancreatic functions; and promoted weight loss in db/db mice. Transcriptomic analysis suggested that the antidiabetic effects of LL involved the regulation of mitochondrial oxidative phosphorylation. We further demonstrated that LL effectively activated the hepatic liver kinase B1 (LKB1)/AMPK pathway by regulating the ADP/ATP ratio. Simultaneously, LL significantly modulated the gut microbial community, specifically decreasing the abundances of Mucispirillum schaedleri and Anaerotruncus_sp_G3_2012, which might also contribute to its antidiabetic effects.
These results suggest that LL is a promising antidiabetic drug candidate that may improve glucolipid metabolism via modulation of the hepatic LKB1/AMPK pathway and the gut microbiota.
2 型糖尿病（DM）是一种高发的慢性代谢性疾病。需要有效的抗糖尿病药物来改善和扩大现有治疗方法。我们之前使用 ob/ob 糖尿病小鼠模型证明，从乌药（Litsea glutinosa）树皮中提取的富含生物碱的提取物（CG）具有很强的抗糖尿病作用，而劳洛昔林（LL）是 CG 中最丰富的生物碱。
我们对 LL 的体外和体内抗糖尿病作用及其潜在机制进行了系统研究。
通过一系列实验，包括细胞毒性分析、葡萄糖消耗分析、血清/肝脏生化分析、病理检查、Western blot、RNA-seq 分析和肠道微生物群分析，在 HL-7702 肝细胞体外和 db/db 小鼠体内研究了 LL 的抗糖尿病作用及其作用机制。
LL 在体外刺激葡萄糖消耗并激活 AMP 激活的蛋白激酶（AMPK），而不会产生乳酸生成或细胞毒性。LL 在体内具有很强的抗糖尿病作用，具有降血糖活性。它改善胰岛素抵抗、葡萄糖耐量和脂质代谢；保护肝、肾和胰腺功能；并促进 db/db 小鼠体重减轻。转录组分析表明，LL 通过调节 ADP/ATP 比，参与调节线粒体氧化磷酸化。我们进一步证明，LL 通过调节 ADP/ATP 比，有效激活肝激酶 B1（LKB1）/AMPK 通路。同时，LL 显著调节肠道微生物群落，特别是降低 Mucispirillum schaedleri 和 Anaerotruncus_sp_G3_2012 的丰度，这也可能有助于其抗糖尿病作用。
这些结果表明，LL 是一种有前途的抗糖尿病药物候选物，可能通过调节肝 LKB1/AMPK 通路和肠道微生物群来改善糖脂代谢。
