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: Berberine is a natural alkaloid with hypoglycemic properties. However, its therapeutic use is limited by a very low oral bioavailability. Here we developed a new oral formulation of berberine based on Sucrosomial technology and tested its effect on insulin resistance. : Sucrosomial berberine was first tested in vitro in the hepatoma cell line Huh7 to assess its effect on proteins involved in glucose homeostasis and insulin resistance. The pharmacokinetics and efficacy on insulin resistance were then studied in C57BL/6 mice fed with standard (SD) and high-fat diet (HFD) for 16 weeks and treated daily during the last 8 weeks with oral gavage of Sucrosomial berberine or berberine. : Sucrosomial berberine did not affect Huh7 cell viability at concentrations up to 40 µM. Incubation of Huh7 with 20 µM of Sucrosomial and control berberine induced glucokinase (GK) and the phosphorylation of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), both known targets for the control of insulin resistance. In vivo, we observed an 8-fold higher plasma concentration after 3 weeks of oral administration of 50 mg/kg/day of Sucrosomial formulation compared to berberine. HFD, compared to SD, induced insulin resistance in mice as determined by oral glucose tolerance test (OGTT). The treatment with a 6.25 mg/kg/daily dose of Sucrosomial berberine significantly reduced the area under the curve (AUC) of OGTT (73,103 ± 8645 vs. 58,830 ± 5597 mg/dL × min), while control berberine produced the same effects at 50 mg/Kg/day (51518 ± 1984 mg/dL × min). Under these conditions, the two formulations resulted in similar berberine plasma concentration in mice. Nevertheless, a different tissue distribution of metabolites was observed with a significant accumulation of reduced, demethylated and glucuronide berberine in the brain after the oral administration of the Sucrosomial form. Glucuronide berberine plasma concentration was higher with Sucrosomial berberine compared to normal berberine. Finally, we observed similar increases of AMPK phosphorylation in the liver in response to the treatment with Sucrosomial berberine and berberine. : The Sucrosomial formulation is an innovative and effective technology to improve berberine gastrointestinal (GI) absorption with proven in vitro and in vivo activity on insulin resistance.

小檗碱是一种具有降血糖作用的天然生物碱。然而，其治疗用途受到口服生物利用度极低的限制。在这里，我们开发了一种基于蔗糖酯技术的新的小檗碱口服制剂，并测试了它对胰岛素抵抗的影响。

首先，在肝癌细胞系 Huh7 中进行体外试验，以评估蔗糖酯小檗碱对葡萄糖稳态和胰岛素抵抗相关蛋白的作用。然后，在标准（SD）和高脂肪饮食（HFD）喂养 16 周的 C57BL/6 小鼠中研究其药代动力学和胰岛素抵抗疗效，并在最后 8 周每天用蔗糖酯小檗碱或小檗碱进行口服灌胃治疗。

蔗糖酯小檗碱在高达 40µM 的浓度下不影响 Huh7 细胞活力。在 Huh7 细胞中孵育 20µM 的蔗糖酯和对照小檗碱诱导葡萄糖激酶（GK）和 5'-腺苷一磷酸（AMP）激活的蛋白激酶（AMPK）磷酸化，这两者都是控制胰岛素抵抗的已知靶点。在体内，我们观察到口服 50mg/kg/天的蔗糖酯制剂 3 周后，血浆浓度增加了 8 倍。与 SD 相比，HFD 诱导小鼠胰岛素抵抗，如口服葡萄糖耐量试验（OGTT）所示。用 6.25mg/kg/d 的蔗糖酯小檗碱治疗可显著降低 OGTT 的曲线下面积（AUC）（73,103±8645 与 58,830±5597mg/dL×min），而对照小檗碱在 50mg/kg/天的剂量下产生相同的效果（51518±1984mg/dL×min）。在这些条件下，两种制剂在小鼠中产生了相似的小檗碱血浆浓度。然而，在口服蔗糖酯形式后，观察到代谢物的不同组织分布，在大脑中明显积累了还原、去甲基和葡萄糖醛酸小檗碱。与正常小檗碱相比，葡萄糖醛酸小檗碱的血浆浓度更高。最后，我们观察到在肝脏中，对蔗糖酯小檗碱和小檗碱的治疗有类似的 AMPK 磷酸化增加。

蔗糖酯制剂是一种创新且有效的技术，可改善小檗碱的胃肠道（GI）吸收，并在体外和体内对胰岛素抵抗具有已知的活性。