Background

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.

Purpose

We conducted a systematic investigation of the antidiabetic effects and potential mechanisms of LL in vitro and in vivo.

Methods

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.

Results

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.

Conclusion

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.

中文翻译：

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月桂核苷通过调节肝脏 LKB1-AMPK 通路和肠道菌群改善 2 型糖尿病

背景

2 型糖尿病 (DM) 是一种高度流行的慢性代谢性疾病。需要有效的抗糖尿病药物来改善和扩大可用的治疗方法。使用 ob/ob 糖尿病小鼠模型，我们之前证明了来自山苍子树皮 (CG) 的富含生物碱的提取物具有强大的抗糖尿病作用，而月桂核苷 (LL) 是 CG 中最丰富的生物碱。

目的

我们对 LL在体外和体内的抗糖尿病作用和潜在机制进行了系统研究。

方法

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，探讨了 LL在体外HL-7702 肝细胞和 db/db 小鼠体内的抗糖尿病作用及其作用机制、蛋白质印迹、RNA-seq 分析和肠道微生物群分析。

结果

LL 刺激葡萄糖消耗并激活 AMP 活化蛋白激酶 (AMPK)，而不会在体外诱导乳酸产生或细胞毒性。LL具有有效的抗糖尿病作用和体内降血糖活性。改善胰岛素抵抗、糖耐量和脂质代谢；保护肝、肾、胰功能；并促进 db/db 小鼠体重减轻。转录组学分析表明，LL 的抗糖尿病作用涉及线粒体氧化磷酸化的调节。我们进一步证明 LL 通过调节 ADP/ATP 比率有效激活肝肝激酶 B1 (LKB1)/AMPK 通路。同时，LL 显着调节肠道微生物群落，特别是降低Mucispirillum schaedleri和Anaerotruncus_sp _G3_2012，这也可能有助于其抗糖尿病作用。

结论

这些结果表明，LL 是一种有前途的抗糖尿病候选药物，可以通过调节肝脏 LKB1/AMPK 通路和肠道微生物群来改善糖脂代谢。