{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T19:38:06Z","timestamp":1770061086074,"version":"3.49.0"},"reference-count":35,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T00:00:00Z","timestamp":1661904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alesco S.r.l."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: 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\u00ae technology and tested its effect on insulin resistance. Methods: Sucrosomial\u00ae 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\u00ae berberine or berberine. Results: Sucrosomial\u00ae berberine did not affect Huh7 cell viability at concentrations up to 40 \u00b5M. Incubation of Huh7 with 20 \u00b5M of Sucrosomial\u00ae and control berberine induced glucokinase (GK) and the phosphorylation of 5\u2032-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\u00ae 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\u00ae berberine significantly reduced the area under the curve (AUC) of OGTT (73,103 \u00b1 8645 vs. 58,830 \u00b1 5597 mg\/dL \u00d7 min), while control berberine produced the same effects at 50 mg\/Kg\/day (51518 \u00b1 1984 mg\/dL \u00d7 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\u00ae form. Glucuronide berberine plasma concentration was higher with Sucrosomial\u00ae berberine compared to normal berberine. Finally, we observed similar increases of AMPK phosphorylation in the liver in response to the treatment with Sucrosomial\u00ae berberine and berberine. Conclusions: The Sucrosomial\u00ae formulation is an innovative and effective technology to improve berberine gastrointestinal (GI) absorption with proven in vitro and in vivo activity on insulin resistance.<\/jats:p>","DOI":"10.3390\/nu14173595","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T01:50:51Z","timestamp":1661997051000},"page":"3595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["In Vitro and In Vivo Sucrosomial\u00ae Berberine Activity on Insulin Resistance"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-4414","authenticated-orcid":false,"given":"Maria Giovanna","family":"Lupo","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Brilli","sequence":"additional","affiliation":[{"name":"R&D Department, PharmaNutra S.p.A., 56122 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"De Vito","sequence":"additional","affiliation":[{"name":"R&D Department, Alesco S.r.l., 56122 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Germano","family":"Tarantino","sequence":"additional","affiliation":[{"name":"R&D Department, PharmaNutra S.p.A., 56122 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Sut","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Ferrarese","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Panighel","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2247-8227","authenticated-orcid":false,"given":"Daniela","family":"Gabbia","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6398-8237","authenticated-orcid":false,"given":"Sara","family":"De Martin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8264-6953","authenticated-orcid":false,"given":"Stefano","family":"Dall\u2019Acqua","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8898-7441","authenticated-orcid":false,"given":"Nicola","family":"Ferri","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Padova, 35128 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1055\/s-0032-1328321","article-title":"The effects of berberine on blood lipids: A systemic review and meta-analysis of randomized controlled trials","volume":"79","author":"Dong","year":"2013","journal-title":"Planta Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2074610","DOI":"10.1155\/2021\/2074610","article-title":"The Effect of Berberine on Metabolic Profiles in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials","volume":"2021","author":"Guo","year":"2021","journal-title":"Oxid Med. Cell Longev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1074\/jbc.M114.597229","article-title":"Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1alpha protein expression through the ubiquitin-proteasome degradation pathway","volume":"290","author":"Dong","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1038\/nm1135","article-title":"Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins","volume":"10","author":"Kong","year":"2004","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/j.numecd.2019.06.001","article-title":"Differential effects of red yeast rice, Berberis aristata and Morus alba extracts on PCSK9 and LDL uptake","volume":"29","author":"Lupo","year":"2019","journal-title":"Nutr. Metab. Cardiovasc. Dis. NMCD"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"105686","DOI":"10.1016\/j.bioorg.2022.105686","article-title":"Evaluation of the effects of natural isoquinoline alkaloids on low density lipoprotein receptor (LDLR) and proprotein convertase subtilisin\/kexin type 9 (PCSK9) in hepatocytes, as new potential hypocholesterolemic agents","volume":"121","author":"Maharjan","year":"2022","journal-title":"Bioorganic Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Adorni, M.P., Zimetti, F., Lupo, M.G., Ruscica, M., and Ferri, N. (2020). Naturally Occurring PCSK9 Inhibitors. Nutrients, 12.","DOI":"10.3390\/nu12051440"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1194\/jlr.M600020-JLR200","article-title":"Inhibition of lipid synthesis through activation of AMP kinase: An additional mechanism for the hypolipidemic effects of berberine","volume":"47","author":"Brusq","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.2337\/db06-0006","article-title":"Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states","volume":"55","author":"Lee","year":"2006","journal-title":"Diabetes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E148","DOI":"10.1152\/ajpendo.00211.2007","article-title":"Berberine improves glucose metabolism through induction of glycolysis","volume":"294","author":"Yin","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"8003","DOI":"10.1038\/s41598-019-44576-7","article-title":"Berberine alleviates hyperglycemia by targeting hepatic glucokinase in diabetic db\/db mice","volume":"9","author":"Li","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1507\/endocrj.K11E-024","article-title":"Berberine ameliorates hyperglycemia in alloxan-induced diabetic C57BL\/6 mice through activation of Akt signaling pathway","volume":"58","author":"Xie","year":"2011","journal-title":"Endocr. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.fitote.2016.02.001","article-title":"Research progress on berberine with a special focus on its oral bioavailability","volume":"109","author":"Liu","year":"2016","journal-title":"Fitoterapia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1208\/s12249-010-9520-y","article-title":"Physicochemical characterization of berberine chloride: A perspective in the development of a solution dosage form for oral delivery","volume":"11","author":"Battu","year":"2010","journal-title":"AAPS PharmSciTech"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sut, S., Faggian, M., Baldan, V., Poloniato, G., Castagliuolo, I., Grabnar, I., Perissutti, B., Brun, P., Maggi, F., and Voinovich, D. (2017). Natural Deep Eutectic Solvents (NADES) to Enhance Berberine Absorption: An In Vivo Pharmacokinetic Study. Molecules, 22.","DOI":"10.3390\/molecules22111921"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gomez-Ramirez, S., Brilli, E., Tarantino, G., and Munoz, M. (2018). Sucrosomial((R)) Iron: A New Generation Iron for Improving Oral Supplementation. Pharmaceuticals, 11.","DOI":"10.3390\/ph11040097"},{"key":"ref_17","first-page":"425","article-title":"Sucrosomial(R) iron absorption studied by in vitro and ex-vivo models","volume":"111","author":"Fabiano","year":"2018","journal-title":"Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/0277-5379(91)90142-Z","article-title":"Comparison of the sulforhodamine B protein and tetrazolium (MTT) assays for in vitro chemosensitivity testing","volume":"27","author":"Keepers","year":"1991","journal-title":"Eur. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Xia, X., Yan, J., Shen, Y., Tang, K., Yin, J., Zhang, Y., Yang, D., Liang, H., Ye, J., and Weng, J. (2011). Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016556"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.metabol.2009.07.029","article-title":"Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression","volume":"59","author":"Zhang","year":"2010","journal-title":"Metab. Clin. Exp."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4181","DOI":"10.1002\/jps.23718","article-title":"Excretion of berberine and its metabolites in oral administration in rats","volume":"102","author":"Ma","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1053\/beha.2002.0003","article-title":"Iron transport across cell membranes: Molecular understanding of duodenal and placental iron uptake","volume":"15","author":"Srai","year":"2002","journal-title":"Best Pr. Res. Cl Ha"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Fabiano, A., Brilli, E., Mattii, L., Testai, L., Moscato, S., Citi, V., Tarantino, G., and Zambito, Y. (2018). Ex Vivo and in Vivo Study of Sucrosomial((R)) Iron Intestinal Absorption and Bioavailability. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092722"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1271\/bbb.60306","article-title":"Enhanced daunomycin accumulation in human intestinal Caco-2 cells from non-ionic food emulsifiers unrelated to the p-glycoprotein inhibitory mechanism","volume":"70","author":"Takaishi","year":"2006","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3109\/02652049809006840","article-title":"Influence of the stabilizer coating layer on the purification and freeze-drying of poly(D,L-lactic acid) nanoparticles prepared by an emulsion-diffusion technique","volume":"15","author":"Allemann","year":"1998","journal-title":"J. Microencapsul"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1124\/dmd.106.011361","article-title":"Pharmacokinetics of berberine and its main metabolites in conventional and pseudo germ-free rats determined by liquid chromatography\/ion trap mass spectrometry","volume":"34","author":"Zuo","year":"2006","journal-title":"Drug Metab. Dispos. Biol. Fate Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1038\/sj.bjp.0704406","article-title":"Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats--pharmacokinetic\/pharmacodynamic modelling","volume":"134","author":"Bouw","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3389\/fncel.2014.00349","article-title":"The UDP-glucuronosyltransferases of the blood-brain barrier: Their role in drug metabolism and detoxication","volume":"8","author":"Ouzzine","year":"2014","journal-title":"Front. Cell Neurosci."},{"key":"ref_29","first-page":"1843","article-title":"Magnesium bioavailability after administration of sucrosomial(R) magnesium: Results of an ex-vivo study and a comparative, double-blinded, cross-over study in healthy subjects","volume":"22","author":"Brilli","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ijpharm.2009.09.013","article-title":"Study of gel-forming properties of sucrose esters for thermosensitive drug delivery systems","volume":"383","author":"Szuts","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3107","DOI":"10.1002\/jps.24085","article-title":"Sucrose esters increase drug penetration, but do not inhibit p-glycoprotein in caco-2 intestinal epithelial cells","volume":"103","author":"Kiss","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ijpharm.2014.03.017","article-title":"Amorphous solid dispersion of berberine with absorption enhancer demonstrates a remarkable hypoglycemic effect via improving its bioavailability","volume":"467","author":"Zhaojie","year":"2014","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kohli, K., Mujtaba, A., Malik, R., Amin, S., Alam, M.S., Ali, A., Barkat, M.A., and Ansari, M.J. (2021). Development of Natural Polysaccharide-Based Nanoparticles of Berberine to Enhance Oral Bioavailability: Formulation, Optimization, Ex Vivo, and In Vivo Assessment. Polymers, 13.","DOI":"10.3390\/polym13213833"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7563889","DOI":"10.1155\/2021\/7563889","article-title":"Development of an Innovative Berberine Food-Grade Formulation with an Ameliorated Absorption: In Vitro Evidence Confirmed by Healthy Human Volunteers Pharmacokinetic Study","volume":"2021","author":"Petrangolini","year":"2021","journal-title":"Evid. Based Complementary Altern. Med. Ecam"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1038\/s41467-019-09852-0","article-title":"Liver-target nanotechnology facilitates berberine to ameliorate cardio-metabolic diseases","volume":"10","author":"Guo","year":"2019","journal-title":"Nat. Commun."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/17\/3595\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:21:05Z","timestamp":1760142065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/17\/3595"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,31]]},"references-count":35,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["nu14173595"],"URL":"https:\/\/doi.org\/10.3390\/nu14173595","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,31]]}}}