Skip to main content
SpringerLink
Log in

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

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Watkins P, Amiel S, Howell S, Turner E (2008) Epidemiology of diabetes. Blackwell Publishing, Oxford, pp 16–22

    Google Scholar 

  2. International Diabetes Federation E-library guidelines. https://www.idf.org/e-library/guidelines.html. Accessed 20 July 2018

  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

    Article  CAS  PubMed  Google Scholar 

  4. Nishida M, Kawada J (1992) Hormonal control of manganese transport in the mouse thyroid. Experientia 48:262–265

    Article  CAS  Google Scholar 

  5. Crul M, van Waardenburg RC, Beijnen JH, Schellens JH (2002) DNA-based drug interactions of cisplatin. Cancer Treat Rev 28:291–303

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 76:509–516

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 12:210–218

    Article  CAS  Google Scholar 

  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

    Article  Google Scholar 

  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 281:1190–1193

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  15. Murakami H, Yasui H, Yoshikawa Y (2012) Pharmacological and pharmacokinetic studies of anti-diabetic tropolonato–Zn(II) complexes with Zn(S2O2 ) coordination mode. Chem Pharm Bull (Tokyo) 60:1096–1104

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 131:1414–1420

    Article  CAS  Google Scholar 

  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 101:692–699

    Article  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 39:1005–1012

    Article  CAS  Google Scholar 

  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 37:2–6

    CAS  PubMed  Google Scholar 

  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 118:65–76

    Article  CAS  Google Scholar 

  25. Bühler RH, Kägi JH (1974) Human hepatic metallothioneins. FEBS Lett 39:229–234

    Article  Google Scholar 

  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–R2335

    CAS  Google Scholar 

  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–R1089

    CAS  Google Scholar 

  28. Davis SR, Cousins RJ (2000) Metallothionein expression in animals: a physiological perspective on function. J Nutr 130:1085–1088

    Article  CAS  Google Scholar 

Download references

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

This work was supported by JSPS KAKENHI grant number JP17K18231.

Author information

Authors and Affiliations

  1. Department of Analytical & Bioinorganic Chemistry, Division of Analytical & Physical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto, 607-8414, Japan

    Yuki Naito, Hiroaki Yamamoto, Yutaka Yoshikawa & Hiroyuki Yasui

  2. Department of Health, Sports, and Nutrition, Faculty of Health and Welfare, Kobe Women’s University, 4-7-2 Minatojima-Nakamachi, Chuo-ku, Kobe, 650-0046, Japan

    Yutaka Yoshikawa

Authors
  1. Yuki Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroaki Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yutaka Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyuki Yasui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuki Naito.

Ethics declarations

Conflicts of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Naito, Y., Yamamoto, H., Yoshikawa, Y. et al. In Vivo Effect of Bis(Maltolato)Zinc(II) Complex on Akt Phosphorylation in Adipose Tissues of Mice. Biol Trace Elem Res 192, 206–213 (2019). https://doi.org/10.1007/s12011-019-1648-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-019-1648-3

Keywords

Search

Navigation