Berberine (BBR) is a promising anti-diabetic isoquinoline alkaloid from Rhizoma coptidis, while its bioavailability was extremely low. Here, the existing form and pharmacokinetics of BBR were comparatively characterized in conventional and antibiotic-induced pseudo germ-free (PGF) rats. Furthermore, we comparatively investigated the antidiabetic effect and potential mechanism of BBR and its intestinal oxidative metabolite oxyberberine (OBB) in STZ-induced diabetic rats. Results showed that BBR and OBB existed mainly as protein-bound form in blood, while protein-bound OBB was significantly depleted in PGF rats. Treatment with OBB and BBR effectively decreased clinical symptoms of diabetic rats, reduced blood glucose level, ameliorated the pancreatic damage, and mitigated oxidative stress and inflammatory markers. However, the anti-diabetes effect of BBR was obviously compromised by antibiotics. In addition, OBB exerted superior anti-diabetes effect to BBR of the same dose, significantly up-regulated the mRNA expression of Nrf2 signaling pathway and substantially promoted the pancreatic levels of PI3K/Akt signaling pathway. In conclusion, BBR and its absorbed oxidative metabolite OBB were mainly presented and transported in the protein-bound form in vivo. The gut microbiota may play an important role in the anti-diabetes effect of BBR through transforming itself into the superior hypoglycemic metabolite OBB. OBB possessed favorable hypoglycemic and pancreatic β-cells protective effects, which may stand a huge potential to be further developed into a promising anti-diabetes candidate.

小ber碱（BBR）是黄连的抗糖尿病异喹啉生物碱，其生物利​​用度极低。在这里，BBR的现有形式和药代动力学在常规和抗生素诱导的假无菌（PGF）大鼠中得到了比较表征。此外，我们比较研究了STZ诱导的糖尿病大鼠中BBR及其肠氧化代谢产物小ber碱（OBB）的抗糖尿病作用及其潜在机制。结果表明，BBR和OBB主要以蛋白结合形式存在于血液中，而蛋白结合的OBB在PGF大鼠中显着减少。OBB和BBR的治疗有效地减轻了糖尿病大鼠的临床症状，降低了血糖水平，减轻了胰腺损害，并减轻了氧化应激和炎性标志物。然而，BBR的抗糖尿病作用明显受到抗生素的损害。此外，OBB对相同剂量的BBR发挥卓越的抗糖尿病作用，显着上调了Nrf2信号通路的mRNA表达，并显着提高了PI3K / Akt信号通路的胰腺水平。总之，BBR及其吸收的氧化代谢产物OBB主要以蛋白结合形式存在和运输。体内。肠道菌群可能通过将自身转化为优越的降血糖代谢产物OBB，在BBR的抗糖尿病作用中发挥重要作用。OBB具有良好的降血糖和胰岛β细胞保护作用，这可能具有巨大的潜力，可以进一步发展成为有希望的抗糖尿病候选药物。