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      Enhanced Anti-diabetic Effect of Berberine Combined With Timosaponin B2 in Goto-Kakizaki Rats, Associated With Increased Variety and Exposure of Effective Substances Through Intestinal Absorption

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          Objective: Inspired by the traditionally clinical application of herb pair Zhimu- Huangbo to treat diabetes, a combination of plant ingredients, timosaponin B2 (TB-2) and berberine (BBR), was evaluated for their anti-diabetic efficacy and cooperative mechanisms.

          Methods: The efficacy and pharmacokinetics of orally administered TB-2 (33.3 mg/kg/day), BBR (66.7 mg/kg/day), and TB-2+BBR (100 mg/kg/day) were evaluated in spontaneously non-obese diabetic Goto-Kakizaki (GK) rats, and metformin (200 mg/kg/day) was used as a positive control. The comparative exposure of the parent drugs, timosaponin A3 (TB-2 metabolite), and M1–M5 (BBR metabolites) was quantified in the portal vein plasma (before hepatic disposition), liver, and systemic plasma (after hepatic disposition) of normal rats on single and combination treatments. Cooperative mechanism of TB-2 and BBR on intestinal absorption and hepatic metabolism was investigated in Caco-2 cells and primary hepatocytes, respectively.

          Results: After a 6-week experiment, non-fasting and fasting blood glucose levels and oral glucose tolerance test results showed that TB-2+BBR treatments (100 mg/kg/day) displayed significantly anti-diabetic efficacy in GK rats, comparable to that on metformin treatments. However, no significant improvement was observed on TB-2 or BBR treatments alone. Compared to single treatments, combination treatments led to the increased circulating levels of BBR by 107% in GK rats. In normal rats, the hepatic exposure of BBR, timosaponin A3, and M1–M5 was several hundred folds higher than their circulating levels. Co-administration also improved the levels in the plasma and liver by 41–114% for BBR, 141–230% for TB-2, and 12–282% for M1–M5. In vitro, the interaction between TB-2 and BBR was mediated by intestinal absorption, rather than hepatic metabolism.

          Conclusion: Combining TB-2 and BBR enhanced the anti-diabetic efficacy by increasing the in vivo variety of effective substances, including the parent compounds and active metabolites, and improving the levels of those substances through intestinal absorption. This study is a new attempt to assess the effects of combined plant ingredients on diabetes by scientifically utilizing clinical experience of an herb pair.

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          Most cited references 52

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          Global estimates of diabetes prevalence for 2013 and projections for 2035.

          Diabetes is a serious and increasing global health burden and estimates of prevalence are essential for appropriate allocation of resources and monitoring of trends. We conducted a literature search of studies reporting the age-specific prevalence for diabetes and used the Analytic Hierarchy Process to systematically select studies to generate estimates for 219 countries and territories. Estimates for countries without available source data were modelled from pooled estimates of countries that were similar in regard to geography, ethnicity, and economic development. Logistic regression was applied to generate smoothed age-specific prevalence estimates for adults 20-79 years which were then applied to population estimates for 2013 and 2035. A total of 744 data sources were considered and 174 included, representing 130 countries. In 2013, 382 million people had diabetes; this number is expected to rise to 592 million by 2035. Most people with diabetes live in low- and middle-income countries and these will experience the greatest increase in cases of diabetes over the next 22 years. The new estimates of diabetes in adults confirm the large burden of diabetes, especially in developing countries. Estimates will be updated annually including the most recent, high-quality data available. Copyright © 2013. Published by Elsevier Ireland Ltd.
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            Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy

            The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.
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              Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states.

              Berberine has been shown to have antidiabetic properties, although its mode of action is not known. Here, we have investigated the metabolic effects of berberine in two animal models of insulin resistance and in insulin-responsive cell lines. Berberine reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice. Similarly, berberine reduced body weight and plasma triglycerides and improved insulin action in high-fat-fed Wistar rats. Berberine downregulated the expression of genes involved in lipogenesis and upregulated those involved in energy expenditure in adipose tissue and muscle. Berberine treatment resulted in increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and L6 myotubes, increased GLUT4 translocation in L6 cells in a phosphatidylinositol 3' kinase-independent manner, and reduced lipid accumulation in 3T3-L1 adipocytes. These findings suggest that berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                24 January 2019
                : 10
                1Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, China
                2University of Chinese Academy of Sciences , Beijing, China
                3West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University , Chengdu, China
                Author notes

                Edited by: Paul Roos Ernsberger, Case Western Reserve University, United States

                Reviewed by: Medardo Hernández, Complutense University of Madrid, Spain; Weidong Xie, Tsinghua University, China

                *Correspondence: Guoyu Pan, gypan@ Chenggang Huang, cghsimm@

                These authors have contributed equally to this work

                This article was submitted to Integrative and Regenerative Pharmacology, a section of the journal Frontiers in Pharmacology

                Copyright © 2019 Tian, Liu, Li, Lin, Liu, Hu, Chen, Sun, Xu, Zhang, Han, Zhang, Pan and Huang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 7, Tables: 4, Equations: 3, References: 52, Pages: 15, Words: 0
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