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      Effect of berberine on the HPA-axis pathway and skeletal muscle GLUT4 in type 2 diabetes mellitus rats

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          Abstract

          Purpose

          Activation of the hypothalamus-pituitary-adrenal (HPA) axis pathway is closely related to insulin resistance (IR), glucose, and lipid metabolism disorders in type 2 diabetes mellitus (T2DM). Berberine (BBR) has effect on regulating disorder of glucose and lipid metabolism in T2DM. In fact, activation of the HPA axis pathway is closely related to IR, glucose, and lipid metabolism disorders in T2DM. Here, we investigated whether the therapeutic effect of BBR on T2DM rats is acted through the HPA axis pathway.

          Methods

          In this research, we investigated the effects of BBR on the HPA-axis pathway-related indicators and expression of skeletal muscle glucose transporter 4 (GLUT4) in the high-fat diet and streptozotocin-induced T2DM rats, and identify its possible mechanism of improving IR in T2DM.

          Results

          BBR significantly reduced fasting blood glucose, total cholesterol, and low-density lipoprotein cholesterol in model rats. It also improved the abnormalities of the high-density lipoprotein cholesterol, the insulin resistance index, the insulin sensitivity index, glucagon, and insulin levels. BBR decreased levels of hypothalamic Orexin-A, the OX2R receptor, the corticotropin-releasing hormone, the pituitary and the plasma adrenocorticotropic hormone, as well as serum and urine corticosterone. At the same time, BBR increased mRNA and protein expressions of GLUT4 in skeletal muscles of model rats as well.

          Conclusion

          Those results suggested that BBR can exert inhibition on the HPA-axis and increased skeletal muscle expression of GLUT4 proteins, which may be one of the important mechanisms in BBR to improve IR and regulating glucose and lipid metabolism in T2DM rats.

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          Most cited references31

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          The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization.

          R DeFronzo, E Jacot, E Jéquier … (1981)
          Article 0 comments Cited 302 times – based on 0 reviews     Review now
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            Efficacy of berberine in patients with type 2 diabetes mellitus.

            Jun Yin, Huili Xing, Jianping Ye (2008)
            Berberine has been shown to regulate glucose and lipid metabolism in vitro and in vivo. This pilot study was to determine the efficacy and safety of berberine in the treatment of type 2 diabetes mellitus patients. In study A, 36 adults with newly diagnosed type 2 diabetes mellitus were randomly assigned to treatment with berberine or metformin (0.5 g 3 times a day) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (from 9.5%+/-0.5% to 7.5%+/-0.4%, P<.01), fasting blood glucose (from 10.6+/-0.9 mmol/L to 6.9+/-0.5 mmol/L, P<.01), postprandial blood glucose (from 19.8+/-1.7 to 11.1+/-0.9 mmol/L, P<.01), and plasma triglycerides (from 1.13+/-0.13 to 0.89+/-0.03 mmol/L, P<.05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes mellitus were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering fasting blood glucose and postprandial blood glucose from 1 week to the end of the trial. Hemoglobin A1c decreased from 8.1%+/-0.2% to 7.3%+/-0.3% (P<.001). Fasting plasma insulin and homeostasis model assessment of insulin resistance index were reduced by 28.1% and 44.7% (P<.001), respectively. Total cholesterol and low-density lipoprotein cholesterol were decreased significantly as well. During the trial, 20 (34.5%) patients experienced transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed for all patients. In conclusion, this pilot study indicates that berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.
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              Exercise, GLUT4, and skeletal muscle glucose uptake.

              Mark Hargreaves, V. Richter (2013)
              Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction. Here we discuss the current understanding of how exercise-induced muscle glucose uptake is regulated. We briefly discuss the role of glucose supply and metabolism and concentrate on GLUT4 translocation and the molecular signaling that sets this in motion during muscle contractions. Contraction-induced molecular signaling is complex and involves a variety of signaling molecules including AMPK, Ca(2+), and NOS in the proximal part of the signaling cascade as well as GTPases, Rab, and SNARE proteins and cytoskeletal components in the distal part. While acute regulation of muscle glucose uptake relies on GLUT4 translocation, glucose uptake also depends on muscle GLUT4 expression which is increased following exercise. AMPK and CaMKII are key signaling kinases that appear to regulate GLUT4 expression via the HDAC4/5-MEF2 axis and MEF2-GEF interactions resulting in nuclear export of HDAC4/5 in turn leading to histone hyperacetylation on the GLUT4 promoter and increased GLUT4 transcription. Exercise training is the most potent stimulus to increase skeletal muscle GLUT4 expression, an effect that may partly contribute to improved insulin action and glucose disposal and enhanced muscle glycogen storage following exercise training in health and disease.
              Article 0 comments Cited 218 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Metab Syndr Obes
                Journal ID (iso-abbrev): Diabetes Metab Syndr Obes
                Journal ID (publisher-id): DMSO
                Journal ID (pmc): dmso
                Title: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
                Publisher: Dove
                ISSN (Electronic): 1178-7007
                Publication date (Electronic): 03 September 2019
                Publication date Collection: 2019
                Volume: 12
                Pages: 1717-1725
                Affiliations
                [1 ]School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine , Guangzhou, People’s Republic of China
                [2 ]Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou, People’s Republic of China
                Author notes
                Correspondence: Heqing Huang; Shijian QuanDepartment of School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine , No. 232 East Wai Huan Road, Guangzhou510006, People’s Republic of ChinaTel +86 1 392 211 9719Email Huangheq@mail.sysu.edu.cn; quansj@gzucm.edu.cn
                [*]

                These authors contributed equally to this work

                Article
                Publisher ID: 211188
                DOI: 10.2147/DMSO.S211188
                PMC ID: 6731988
                SO-VID: 3c9369b4-d34f-4e38-a263-5b51b201b05b
                Copyright © © 2019 Mi et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 05 April 2019
                Date accepted : 10 July 2019
                Page count
                Figures: 5, References: 36, Pages: 9
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: berberine,type 2 diabetes mellitus,insulin resistance,the hpa-axis,glut4
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: berberine, type 2 diabetes mellitus, insulin resistance, the hpa-axis, glut4

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