S. Fujimoto et al. / Journal of Inorganic Biochemistry 121 (2013) 10–15
[4] C.E. Heyliger, A.G. Tahiliani, J.H. McNeill, Science 22 (1985) 1474–1477.
15
In patients and animal models of T2D, abnormalities in homeostasis,
such as zinc deficiency, are well documented [18], and organ zinc con-
centrations decrease in KK-Ay mice relative to healthy C57BL mice, par-
ticularly in the pancreas and muscle, as these are the main organs
responsible for glucose metabolism [32]. Such a low zinc status might
be caused by impaired zinc absorption in the gastrointestinal tract
[20]. If such abnormal zinc metabolism affects the pathogenesis of
T2D, reducing zinc deficiency might be important in the treatment of
DM. With regard to efficient zinc supplementation and administering
zinc complexes, the relationship between zinc distribution and the sta-
bility of zinc complexes is highly important, as indicated by findings in
this study as well as a previous study [42]. Therefore, a zinc complex
with moderate stability and lipophilicity is required to transport zinc ef-
ficiently to the organs responsible for glucose metabolism.
[5] M. Nishida, H. Sakurai, J. Kawada, M. Koyama, J. Takada, Naturwissenschaften 76
(1989) 220–222.
[6] J.H. McNeill, H.L.M. Delgatty, M.L. Battell, Diabetes 40 (1991) 1675–1678.
[7] R.A. Anderson, N. Cheng, N.A. Bryden, M.M. Polansky, J. Chi, J. Feng, Diabetes 46
(1997) 1786–1791.
[8] E.J. Coleman, Annu. Rev. Biochem. 61 (1992) 897–946.
[9] C.T. Chasapis, A.C. Loutsidou, C.A. Spiliopoulou, M.E. Stefanidou, Arch. Toxicol. 86
(2012) 521–534.
[10] P. Zalewski, S. Millard, I. Forbes, O. Kapaniris, S. Slavotinek, W. Betts, A. Ward, S.
Lincoln, I. Mahadevan, J. Histochem. Cytochem. 42 (1994) 877–884.
[11] L. Coulston, P. Dandona, Diabetes 29 (1980) 665–667.
[12] A. Shisheva, D. Gefel, Y. Shechter, Diabetes 41 (1992) 982–988.
[13] M.D. Chen, S.J. Liou, P.Y. Lin, V.C. Yang, P.S. Alexander, W.H. Lin, Biol. Trace Elem.
Res. 61 (1998) 303–311.
[14] O. Ezaki, J. Biol. Chem. 264 (1989) 16118–16122.
[15] H. Haase, W. Maret, Exp. Cell Res. 291 (2002) 289–298.
[16] R. Ilouz, O. Kaidanovich, D. Gurwitz, H. E-Finkelman, Biochem. Biophys. Res.
Commun. 295 (2002) 102–106.
Using the isotope tracer technique, the lower AUCorgan/AUCblood
values of zinc derived from [ZPS] compared to that of ZnCl2 was calcu-
lated. In other words, free zinc is superior to zinc complexes in terms
of tissue penetration. However, gastrointestinal absorption of free
zinc is lower than that of zinc complexes [43], and greater 65Zn levels
were measured in organs treated with [65ZPS] compared to those
treated with 65ZnCl2. Considering a patient's quality of life, oral sup-
plementation of zinc is useful, and complexation of zinc is totally ad-
vantageous for more efficient distribution of oral zinc to any tissue;
i.e., achievement of high zinc uptake by administering [ZPS] orally
might be useful in the treatment of DM.
Several organoselenium compounds are already reported as po-
tential therapeutic agents [44]. This study, however, is the first report
that an organoselenium compound as a metal ligand has potential as
a therapeutic agent for DM. Although dietary levels of the desired
amount of selenium fall within a very narrow range, organoselenium
compounds are characterized by low toxicity, even when used at
supra pharmacological doses [45–47]. Furthermore, the experimental
dose of zinc derived from [ZPS] is less than the clinical dose of zinc ac-
etate used to treat Wilson's disease [48]. Thereby, it is concluded that
[ZPS] is a potential novel antidiabetic agent.
[17] S.F. Simon, C.G. Taylor, Exp. Biol. Med. 226 (2001) 43–51.
[18] J.J. Cunningham, A. Fu, P.L. Mearkle, R.G. Brown, Metabolism 43 (1994)
1558–1562.
[19] E. Ho, N. Quan, Y.H. Tsai, W. Lai, T.M. Bray, Exp. Biol. Med. 226 (2001) 103–111.
[20] M.J. Salgueiro, N. Krebs, M.B. Zubillaga, R. Weill, E. Postaire, A.E. Lysionek, R.A.
Caro, T. De Paoli, A. Hager, J. Boccio, Biol. Trace Elem. Res. 81 (2001) 215–228.
[21] Y. Yoshikawa, H. Yasui, Curr. Top. Med. Chem. 12 (2012) 210–218.
[22] Y. Yoshikawa, A. Murayama, Y. Adachi, H. Sakurai, H. Yasui, Metallomics 3 (2011)
686–692.
[23] L.A. Daniels, Biol. Trace Elem. Res. 54 (1996) 185–199.
[24] M.P. Rayman, Lancet 356 (2005) 233–241.
[25] S.R. Stapleton, Cell. Mol. Life Sci. 57 (2000) 1874–1879.
[26] O. Ezaki, J. Biol. Chem. 265 (1990) 1124–1128.
[27] N.B.V. Barbosa, J.B.T. Rocha, D.C. Wondracek, J. Perottoni, G. Zeni, C.W. Nogueira,
Chem. Biol. Interact. 163 (2006) 230–238.
[28] C.O. Kienitz, C. Thöne, P.G. Jones, Inorg. Chem. 35 (1996) 3990–3997.
[29] D.H. Barton, D. Crich, Y. Herye, P. Potier, J. Thierry, Tetrahedron 41 (1985)
4347–4357.
[30] R.C. Hider, R. Ejim, P.D. Gale, E. Huehns, J.B. Porter, Biochem. Pharmacol. 39
(1990) 1005–1012.
[31] M. Nakai, H. Watanabe, C. Fujiwara, H. Kakegawa, T. Satoh, J. Takeda, R.
Matsushita, H. Sakurai, Biol. Pharm. Bull. 18 (1995) 719–725.
[32] Y. Adachi, J. Yoshida, Y. Kodera, T. Kiss, T. Jakusch, E.A. Enyedy, Y. Yoshikawa, H.
Sakurai, Biochem. Biophys. Res. Commun. 351 (2006) 165–170.
[33] J. Bailer, J. Pharmacokinet. Biopharm. 16 (1987) 303–309.
[34] S. Karmaker, T.K. Saha, Y. Yoshikawa, H. Sakurai, Chem. Med. Chem. 2 (2007)
1607–1612.
[35] Y. Adachi, J. Yoshida, Y. Kodera, T. Kiss, T. Jakusch, E.A. Enyedy, Y. Yoshikawa, H.
Sakurai, Biochem. Biophys. Res. Commun. 351 (2006) 165–170.
[36] Y. Yoshikawa, Y. Adachi, H. Sakurai, Life Sci. 80 (2007) 759–766.
[37] H. Murakami, H. Yasui, Y. Yoshikawa, Chem. Pharm. Bull. 60 (2012) 1096–1104.
[38] C. Jacob, W. Maret, B.L. Vallee, Biochem. Biophys. Res. Commun. 248 (1998)
569–573.
[39] C. Jacob, W. Maret, B.L. Vallee, Proc. Natl. Acad. Sci. 96 (1999) 1910–1914.
[40] Calculated using Advanced Chemistry Development (ACD/Labs) Software V8.14
(1994-2010 ACD/Labs).
5. Conclusion
The hypoglycemic effects of [ZPS] in KK-Ay mice were apparent at
lower doses than previously studied zinc complexes. In addition, greatly
elevated gastrointestinal absorption of zinc by [ZPS], and no intravital
toxicity of [ZPS] was observed, suggesting the possibility of the
organoselenium ligand as a new metal delivery system for treating DM.
[41] N.F. Krebs, J. Nutr. 130 (2000) 1374S–1377S.
[42] R.M. Epand, A.R. Stafford, M. Tyers, E. Nieboer, Mol. Pharm. 27 (1985) 366–374.
[43] J.C. King, D.M. Shames, L.R. Woodhouse, J. Nutr. 130 (2000) 1360S–1366S.
[44] M.S. Garcia, Curr. Med. Chem. 11 (2004) 1657–1669.
[45] R. Fachinetto, L.A. Pivetta, M. Farina, R.P. Pereira, C.W. Nogueira, J.B. Rocha, Food
Chem. Toxicol. 44 (2006) 588–594.
[46] J. Perottoni, F.C. Meotti, V. Folmer, L. Pivetta, C.W. Nogueira, G. Zeni, J.B.T. Rocha,
Environ. Toxicol. Pharmacol. 19 (2005) 239–248.
[47] H. Masumoto, H. Hakusui, M. Takaichi, T. Yokota, T. Honda, Y. Esumi, Xenobiotic
Metabol. Dispos. 12 (1997) 610–618.
Acknowledgments
The authors are grateful to the members of the Analytical Center of
KPU for the elemental analysis and mass spectra measurements.
References
[48] T. Mizuochi, A. Kimura, N. Shimizu, H. Nishiura, M. Matsushita, M. Yoshino, J.
Pediatr. Gastroenterol. Nutr. 53 (2011) 365–367.
[1] J.E. Shaw, R.A. Sicree, P.Z. Zimmet, Diab. Res. Clin. Pract. 87 (2009) 4–14.
[2] A. Amos, D.G. McCarthy, P. Zimmet, Diabet. Med. 14 (1997) S5–S85.
[3] R.M. Sapolsky, L.C. Krey, B.S. McEwen, Endocr. Rev. 7 (1986) 284–301.