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      Kampo medicines, Rokumigan, Hachimijiogan, and Goshajinkigan, significantly inhibit glucagon-induced CREB activation

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          Abstract

          The pathophysiology of type 2 diabetes mellitus (T2DM) is characterized by not only insulin resistance, but also the abnormal regulation of glucagon secretion, suggesting that antagonizing the glucagon-induced signaling pathway has therapeutic potential in the treatment of T2DM. Although various Kampo medicines (traditional herbal medicines) are often utilized to ameliorate the symptoms of T2DM, their effects on glucagon signaling have not yet been clarified. In the present study, we examined the effects of nine types of representative Kampo formulations prescribed for T2DM on glucagon-induced CREB activation in HEK293T cells stably expressing glucagon receptor (Gcgr) and a hepatic cell line HepG2. Among these Kampo medicines, Rokumigan, Hachimijiogan, and Goshajinkigan significantly suppressed the glucagon-induced transactivation of the cAMP-responsive element (CRE)-binding protein (CREB) by inhibiting its interaction with CREB-binding protein (CBP), which led to a reduction in the expression of phosphoenolpyruvate carboxykinase (PEPCK) mRNA. Furthermore, among the crude drugs commonly contained in these three Kampo medicines, Rehmannia Root (Jio), Moutan Bark (Botampi), and Cornus Fruit (Shanzhuyu) exerted inhibitory effects on glucagon-induced CREB activation. Collectively, the present results provide a novel mechanism, the inhibition of glucagon signaling, by which Rokumigan, Hachimijiogan, and Goshajinkigan improve the symptoms of T2DM.

          Abstract

          Cell biology; Pharmaceutical science; Biochemistry; Molecular biology; Health sciences; Pharmacology; Type 2 diabetes mellitus; Kampo medicines; Glucagon; CREB; PEPCK

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          Most cited references29

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          Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133.

          G. Gonzalez, M Montminy (1989)
          In this paper, we demonstrate that phosphorylation of CREB at Ser-133 is induced 6-fold in vivo, following treatment of PC12 cells with forskolin. By contrast, no such induction was observed in the kinase A-deficient PC12 line A126-1B2 (A126). Using F9 teratocarcinoma cells, which are unresponsive to cAMP, we initiated a series of transient expression experiments to establish a causal link between phosphorylation of CREB and trans-activation of cAMP-responsive genes. Inactivating the kinase A phosphorylation site by in vitro mutagenesis of the cloned CREB cDNA at Ser-133 completely abolished CREB transcriptional activity. As CREB mutants containing acidic residues in place of the Ser-133 phosphoacceptor were also transcriptionally inactive, these results suggest that phosphorylation of CREB may stimulate transcription by a mechanism other than by simply providing negative charge.
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            Phosphorylated CREB binds specifically to the nuclear protein CBP.

            J C Chrivia, R Kwok, N. Lamb … (1993)
            Cyclic AMP-regulated gene expression frequently involves a DNA element known as the cAMP-regulated enhancer (CRE). Many transcription factors bind to this element, including the protein CREB, which is activated as a result of phosphorylation by protein kinase A. This modification stimulates interaction with one or more of the general transcription factors or, alternatively, allows recruitment of a co-activator. Here we report that CREB phosphorylated by protein kinase A binds specifically to a nuclear protein of M(r) 265K which we term CBP (for CREB-binding protein). Fusion of a heterologous DNA-binding domain to the amino terminus of CBP enables the chimaeric protein to function as a protein kinase A-regulated transcriptional activator. We propose that CBP may participate in cAMP-regulated gene expression by interacting with the activated phosphorylated form of CREB.
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              Glucagon and regulation of glucose metabolism.

              Guoqiang Jiang, B. Zhang (2003)
              As a counterregulatory hormone for insulin, glucagon plays a critical role in maintaining glucose homeostasis in vivo in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Compared with healthy subjects, diabetic patients and animals have abnormal secretion of not only insulin but also glucagon. Hyperglucagonemia and altered insulin-to-glucagon ratios play important roles in initiating and maintaining pathological hyperglycemic states. Not surprisingly, glucagon and glucagon receptor have been pursued extensively in recent years as potential targets for the therapeutic treatment of diabetes.
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                Author and article information

                Contributors
                Megumi Funakoshi-Tago
                Journal
                Journal ID (nlm-ta): Heliyon
                Journal ID (iso-abbrev): Heliyon
                Title: Heliyon
                Publisher: Elsevier
                ISSN (Print): 2405-8440
                ISSN (Electronic): 2405-8440
                Publication date PMC-release: 20 March 2020
                Publication date Collection: March 2020
                Publication date (Electronic): 20 March 2020
                Volume: 6
                Issue: 3
                Electronic Location Identifier: e03598
                Affiliations
                [a ]Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan
                [b ]Cosmic Corporation Co., Ltd., Tomisaka Building, 7-3 Koishikawa 2-chome, Bunkyo-ku, Tokyo 112-0002, Japan
                Author notes
                [∗ ]Corresponding author. tago-mg@ 123456pha.keio.ac.jp
                [1]

                These authors contributed equally to the study.

                Article
                Publisher ID: S2405-8440(20)30443-6 Publisher ID: e03598
                DOI: 10.1016/j.heliyon.2020.e03598
                PMC ID: 7090351
                SO-VID: 905bc518-7f81-4d97-909a-06566f41ef75
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 6 September 2019
                Date revision received : 28 November 2019
                Date accepted : 11 March 2020
                Categories
                Subject: Article

                Keywords: cell biology,pharmaceutical science,biochemistry,molecular biology,health sciences,pharmacology,type 2 diabetes mellitus,kampo medicines,glucagon,creb,pepck
                Data availability:
                Keywords: cell biology, pharmaceutical science, biochemistry, molecular biology, health sciences, pharmacology, type 2 diabetes mellitus, kampo medicines, glucagon, creb, pepck

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