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In Vivo Effect of Bis(Maltolato)Zinc(II) Complex on Akt Phosphorylation in Adipose Tissues of Mice

  • Yuki NaitoEmail author
  • Hiroaki Yamamoto
  • Yutaka Yoshikawa
  • Hiroyuki Yasui
Article
  • 19 Downloads

Abstract

The risk of serious complication gradually increases as diabetes mellitus (DM) progresses. Thus, strategies for the prevention and delay of symptom progression are urgently needed. Previously, we synthesized zinc (Zn) complexes estimated to have a high bioavailability and evaluated their insulin-like anti-DM effects. However, in vivo studies of the effects of Zn compounds on the insulin signaling pathway and the molecular mechanisms underlying the anti-diabetic activities of Zn complexes were unresolved. In this study, we evaluated the effect of bis(maltolato)zinc(II) complex [Zn(mal)2] on male ICR mice (6-week-old) that received intraperitoneal (i.p.) injection of [Zn(mal)2]. The liver, skeletal muscle, and adipose tissues were collected from mice under anesthesia with isoflurane 40 or 90 min after i.p. injection. The [Zn(mal)2]-treatment did not affect Akt phosphorylation in the liver or skeletal muscle. In contrast, in adipose tissues, [Zn(mal)2]-treatment showed increased Akt phosphorylation at 40 min and 90 min after injection (p < 0.01 vs. control). The Zn distribution in the organs was evaluated using inductively coupled plasma mass spectrometry. Notably, high Zn accumulation was observed in the adipose tissue (4.5 ± 2.7 μg Zn/g wet weight), and this value was about six times higher than in the control mice (p < 0.01). Based on the observed organ-specific distribution of [Zn(mal)2], we suggest that it does not directly promote glycogen synthesis in the liver but may impact the insulin signaling pathway in adipose tissues. Our results may contribute to the clinical use of zinc compounds for the treatment of diabetes.

Keywords

Diabetes Zinc Zinc complex [Zn(mal)2Insulin-like effect Akt phosphorylation 

Notes

Acknowledgements

The authors would like to thank the members of the Analytical Center of KPU for the elemental analysis and mass spectra measurements. We would like to thank Editage (www.editage.jp) for English language editing.

Funding Information

This work was supported by JSPS KAKENHI grant number JP17K18231.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Watkins P, Amiel S, Howell S, Turner E (2008) Epidemiology of diabetes. Blackwell Publishing, Oxford, pp 16–22Google Scholar
  2. 2.
    International Diabetes Federation E-library guidelines. https://www.idf.org/e-library/guidelines.html. Accessed 20 July 2018
  3. 3.
    Hojyo S, Fukada T (2016) Zinc transporters and signaling in physiology and pathogenesis. Arch Biochem Biophys 611:43–50.  https://doi.org/10.1016/j.abb.2016.06.020 CrossRefPubMedGoogle Scholar
  4. 4.
    Nishida M, Kawada J (1992) Hormonal control of manganese transport in the mouse thyroid. Experientia 48:262–265CrossRefGoogle Scholar
  5. 5.
    Crul M, van Waardenburg RC, Beijnen JH, Schellens JH (2002) DNA-based drug interactions of cisplatin. Cancer Treat Rev 28:291–303CrossRefGoogle Scholar
  6. 6.
    Gunatilleke SS, de Oliveira CA, McCammon JA, Barrios AM (2008) Inhibition of cathepsin B by Au(I) complexes: a kinetic and computational study. J Biol Inorg Chem 13:555–561.  https://doi.org/10.1007/s00775-008-0344-0 CrossRefPubMedGoogle Scholar
  7. 7.
    Medici V, Santon A, Sturniolo GC, D'Inca R, Giannetto S, Albergoni V, Irato P (2002) Metallothionein and antioxidant enzymes in Long-Evans cinnamon rats treated with zinc. Arch Toxicol 76:509–516CrossRefGoogle Scholar
  8. 8.
    Katayama K, Saito M, Kawaguchi T, Endo R, Sawara K, Nishiguchi S, Kato A, Kohgo H, Suzuki K, Sakaida I, Ueno Y, Habu D, Ito T, Moriwaki H, Suzuki K (2014) Effect of zinc on liver cirrhosis with hyperammonemia: a preliminary randomized, placebo-controlled double-blind trial. Nutrition 30:1409–1414.  https://doi.org/10.1016/j.nut.2014.04.018 CrossRefPubMedGoogle Scholar
  9. 9.
    Sakurai H, Yoshikawa Y, Yasui H (2008) Current state for the development of metallopharmaceutics and anti-diabetic metal complexes. Chem Soc Rev 37:2383–2392.  https://doi.org/10.1039/b710347f CrossRefPubMedGoogle Scholar
  10. 10.
    Yoshikawa Y, Yasui H (2012) Zinc complexes developed as metallopharmaceutics for treating diabetes mellitus based on the bio-medicinal inorganic chemistry. Curr Top Med Chem 12:210–218CrossRefGoogle Scholar
  11. 11.
    Yoshikawa Y, Ueda E, Kawabe K, Miyake H, Sakurai H, Kojima Y (2000) New insulin-mimetic zinc(II) complexes; bis-maltolato zinc(II) and bis-2-hydroxypyridine-N-oxido zinc(II) with Zn(O4) coordination mode. Chem Lett 29:874–875.  https://doi.org/10.1246/cl.2000.874 CrossRefGoogle Scholar
  12. 12.
    Yoshikawa Y, Ueda E, Miyake H, Sakurai H, Kojima Y (2001) Insulinomimetic bis(maltolato)zinc(II) complex: blood glucose normalizing effect in KK-Ay mice with type 2 diabetes mellitus. Biochem Biophys Res Commun 281:1190–1193CrossRefGoogle Scholar
  13. 13.
    Kadowaki S, Munekane M, Kitamura Y, Hiromura M, Kamino S, Yoshikawa Y, Saji H, Enomoto S (2013) Development of new zinc dithiosemicarbazone complex for use as oral antidiabetic agent. Biol Trace Elem Res 154:111–119.  https://doi.org/10.1007/s12011-013-9704-x CrossRefPubMedGoogle Scholar
  14. 14.
    Kawarada H, Yoshikawa Y, Yasui H, Kuwahara S, Habata Y, Saito R (2011) Synthesis and in vitro insulin-mimetic activities of zinc(II) complexes of ethyl 2,5-dihydro-4-hydroxy-5-oxo-1H-pyrrole-3-carboxylates. Metallomics 3:675–679.  https://doi.org/10.1039/c1mt00009h CrossRefPubMedGoogle Scholar
  15. 15.
    Murakami H, Yasui H, Yoshikawa Y (2012) Pharmacological and pharmacokinetic studies of anti-diabetic tropolonatoZn(II) complexes with Zn(S2O2 ) coordination mode. Chem Pharm Bull (Tokyo) 60:1096–1104CrossRefGoogle Scholar
  16. 16.
    Fujimoto S, Yasui H, Yoshikawa Y (2013) Development of a novel antidiabetic zinc complex with an organoselenium ligand at the lowest dosage in KK-A(y) mice. J Inorg Biochem 121:10–15.  https://doi.org/10.1016/j.jinorgbio.2012.12.008 CrossRefPubMedGoogle Scholar
  17. 17.
    Tang X, Shay NF (2001) Zinc has an insulin-like effect on glucose transport mediated by phosphoinositol-3-kinase and Akt in 3T3-L1 fibroblasts and adipocytes. J Nutr 131:1414–1420CrossRefGoogle Scholar
  18. 18.
    Basuki W, Hiromura M, Sakurai H (2007) Insulinomimetic Zn complex (Zn(opt)2) enhances insulin signaling pathway in 3T3-L1 adipocytes. J Inorg Biochem 101:692–699CrossRefGoogle Scholar
  19. 19.
    Naito Y, Yoshikawa Y, Yasui H (2011) Cellular mechanism of zinc-hinokitiol complexes in diabetes mellitus. Bull Chem Soc Jpn 84:298–305.  https://doi.org/10.1246/bcsj.20100262 CrossRefGoogle Scholar
  20. 20.
    Naito Y, Yoshikawa Y, Masuda K, Yasui H (2016) Bis(hinokitiolato)zinc complex ([Zn(hkt)2]) activates Akt/protein kinase B independent of insulin signal transduction. J Biol Inorg Chem 21:537–548.  https://doi.org/10.1007/s00775-016-1364-9 CrossRefPubMedGoogle Scholar
  21. 21.
    Naito Y, Ikuta N, Okano A, Okamoto H, Nakata D, Terao K, Matsumoto K, Kajiwara N, Yasui H, Yoshikawa Y (2015) Isomeric effects of anti-diabetic α-lipoic acid with γ-cyclodextrin. Life Sci 136:73–78.  https://doi.org/10.1016/j.lfs.2015.06.016 CrossRefPubMedGoogle Scholar
  22. 22.
    Hider RC, Ejim L, Taylor PD, Gale R, Huehns E, Porter JB (1990) Facilitated uptake of zinc into human erythrocytes. Relevance to the treatment of sickle-cell anaemia. Biochem Pharmacol 39:1005–1012CrossRefGoogle Scholar
  23. 23.
    Scavone JM, Friedman H, Greenblatt DJ, Shader RI (1987) Effect of age, body composition, and lipid solubility on benzodiazepine tissue distribution in rats. Arzneimittelforschung 37:2–6PubMedGoogle Scholar
  24. 24.
    McClung JP, Tarr TN, Barnes BR, Scrimgeour AG, Young AJ (2007) Effect of supplemental dietary zinc on the mammalian target of rapamycin (mTOR) signaling pathway in skeletal muscle and liver from post-absorptive mice. Biol Trace Elem Res 118:65–76CrossRefGoogle Scholar
  25. 25.
    Bühler RH, Kägi JH (1974) Human hepatic metallothioneins. FEBS Lett 39:229–234CrossRefGoogle Scholar
  26. 26.
    Trayhurn P, Duncan JS, Wood AM, Beattie JH (2000) Metallothionein gene expression and secretion in white adipose tissue. Am J Phys Regul Integr Comp Phys 279:R2329–R2335Google Scholar
  27. 27.
    Beattie JH, Wood AM, Trayhurn P, Jasani B, Vincent A, McCormack G, West AK (2000) Metallothionein is expressed in adipocytes of brown fat and is induced by catecholamines and zinc. Am J Phys Regul Integr Comp Phys 278:R1082–R1089Google Scholar
  28. 28.
    Davis SR, Cousins RJ (2000) Metallothionein expression in animals: a physiological perspective on function. J Nutr 130:1085–1088CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Analytical & Bioinorganic Chemistry, Division of Analytical & Physical SciencesKyoto Pharmaceutical UniversityKyotoJapan
  2. 2.Department of Health, Sports, and Nutrition, Faculty of Health and WelfareKobe Women’s UniversityKobeJapan

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