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α-Methyl artoflavanocoumarin from Juniperus chinensis exerts anti-diabetic effects by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant HepG2 cells

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Abstract

Diabetes mellitus is one of the greatest global health issues and much research effort continues to be directed toward identifying novel therapeutic agents. Insulin resistance is a challenging integrally related topic and molecules capable of overcoming it are of considerable therapeutic interest in the context of type 2 diabetes mellitus (T2DM). Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling transduction and is regarded a novel therapeutic target in T2DM. Here, we investigated the inhibitory effect of α-methyl artoflavanocoumarin (MAFC), a natural flavanocoumarin isolated from Juniperus chinensis, on PTP1B in insulin-resistant HepG2 cells. MAFC was found to potently inhibit PTP1B with an IC50 of 25.27 ± 0.14 µM, and a kinetics study revealed MAFC is a mixed type PTP1B inhibitor with a K i value of 13.84 µM. Molecular docking simulations demonstrated MAFC can bind to catalytic and allosteric sites of PTP1B. Furthermore, MAFC significantly increased glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells, down-regulated the phosphorylation of insulin receptor substrate (IRS)-1 (Ser307), and dose-dependently enhanced the protein levels of IRS-1, phosphorylated phosphoinositide 3-kinase (PI3K), Akt, and ERK1. These results suggest that MAFC from J. chinensis has therapeutic potential in T2DM by inhibiting PTP1B and activating insulin signaling pathways.

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Acknowledgements

This work was supported by a research grant from Pukyong National University (2017). We also thank Aging Tissue Bank for providing research information.

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Authors and Affiliations

  1. Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea

    Hee Jin Jung, Su Hui Seong, Md Yousof Ali & Jae Sue Choi

  2. College of Pharmacy, Catholic University of Daegu, Gyeongsan, 38430, Republic of Korea

    Byung-Sun Min

  3. Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju, 54896, Republic of Korea

    Hyun Ah Jung

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  1. Hee Jin Jung
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Correspondence to Hyun Ah Jung or Jae Sue Choi.

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Jung, H.J., Seong, S.H., Ali, M.Y. et al. α-Methyl artoflavanocoumarin from Juniperus chinensis exerts anti-diabetic effects by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. Arch. Pharm. Res. 40, 1403–1413 (2017). https://doi.org/10.1007/s12272-017-0992-0

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