Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga, 1006, Latvia.
Faculty of Pharmacy, Rīga Stradiņš University, Dzirciema Str. 16, Riga, 1007, Latvia.
Sci Rep. 2020 Sep 3;10(1):14555. doi: 10.1038/s41598-020-71470-4.
The current study aimed to explore whether metformin, the most widely prescribed oral medication for the treatment of type 2 diabetes, alters plasma levels of cardiometabolic disease-related metabolite trimethylamine N-oxide (TMAO) in db/db mice with type 2 diabetes. TMAO plasma concentration was up to 13.2-fold higher in db/db mice when compared to control mice, while in db/db mice fed choline-enriched diet, that mimics meat and dairy product intake, TMAO plasma level was increased 16.8-times. Metformin (250 mg/kg/day) significantly decreased TMAO concentration by up to twofold in both standard and choline-supplemented diet-fed db/db mice plasma. In vitro, metformin significantly decreased the bacterial production rate of trimethylamine (TMA), the precursor of TMAO, from choline up to 3.25-fold in K. pneumoniae and up to 26-fold in P. Mirabilis, while significantly slowing the growth of P. Mirabilis only. Metformin did not affect the expression of genes encoding subunits of bacterial choline-TMA-lyase microcompartment, the activity of the enzyme itself and choline uptake, suggesting that more complex regulation beyond the choline-TMA-lyase is present. To conclude, the TMAO decreasing effect of metformin could be an additional mechanism behind the clinically observed cardiovascular benefits of the drug.
本研究旨在探讨二甲双胍（治疗 2 型糖尿病最常用的口服药物）是否会改变 2 型糖尿病 db/db 小鼠血浆中心血管疾病相关代谢物三甲胺 N-氧化物（TMAO）的水平。与对照小鼠相比，db/db 小鼠的 TMAO 血浆浓度高出 13.2 倍，而在喂食富含胆碱的饮食（模拟肉类和乳制品摄入）的 db/db 小鼠中，TMAO 血浆水平增加了 16.8 倍。二甲双胍（250mg/kg/天）可使标准饮食和胆碱补充饮食喂养的 db/db 小鼠的 TMAO 浓度分别降低高达 2 倍和 1.68 倍。体外实验表明，二甲双胍可使肺炎克雷伯菌和奇异变形杆菌中 TMA（TMAO 的前体）的细菌产量分别降低 3.25 倍和 26 倍，而仅显著减缓奇异变形杆菌的生长速度。二甲双胍不影响编码细菌胆碱-TMA 裂解酶微区室亚基的基因表达、酶本身的活性和胆碱摄取，表明存在比胆碱-TMA 裂解酶更为复杂的调控机制。总之，二甲双胍降低 TMAO 的作用可能是该药物在临床上观察到的心血管益处的另一个机制。
