It is well known that zinc is an essential trace element for maintaining human health. However, there is a paucity of literature describing cases of zinc deficiency, leading many physicians to believe that zinc deficiency is a rare occurrence. Nevertheless, we have found many zinc-deficient patients at our Kitamimaki-onsen clinic since 2002, and reported their symptoms at the annual meeting of this BRTE society held in 2005. Their complaints were anorexia, general fatigue, impaired sense of taste, burning mouth, various types of skin lesion, delayed wound healing, emotional instability, and others. Each of these wide ranging complaints can be induced by zinc depletion, though they do not necessarily manifest themselves simultaneously.
The reasons why such a wide range of symptoms appear in cases of zinc deficiency are becoming more apparent, due to recent studies advancing our knowledge on the functions of zinc-related proteins such as zinc transporters and zincrelated metaloenzymes.
In this paper, we offer possible explanations on the relationship between zinc depletion and the onset of the abovenoted symptoms, and discuss the limitations of using serum zinc levels to detect and diagnose zinc deficiency.

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Type 1 diabetes is an organ-specific autoimmune disease characterized by T-cell mediated destruction of pancreatic β-cells and the circulating autoantibodies to multiple islet autoantigens. During the past decade investigators have identified a series of islet autoantigens, including glutamic acid decarboxylase (GAD), insulinoma-associated antigen-2 (IA-2), and insulin. Recently, one of the zinc transporters, ZnT8, which is specifically expressed in the pancreatic β-cells, has identified as a major autoantigen in human type 1 diabetes. On the other hand, genome-wide association studies identified an association between a nonsynonymous variant in the ZnT8 gene (SLC30A8 rs13266634 ; Arg325Trp) and susceptibility to type 2 diabetes in various ethnic groups. We have investigated the association between humoral autoreactivity to ZnT8 and the SLC30A8 polymorphism and their clinical roles as an additional diagnostic marker of Japanese type 1 diabetes.
In the present study, we found that ZnT8 autoantibodies recognize the cytoplasmic domain of the molecule and SLC30A8 polymorphism regulates humoral autoreactivity to ZnT8 in patients with type 1 diabetes. Furthermore, ZnT8 autoantibodies were detected in 60% of Japanese patients with type 1 diabetes and diagnostic sensitivity for combined analysis of autoantibodies to ZnT8, GAD, IA-2, and insulin was > 90%. These results indicate that variant residue at aa325 is a key determinant of humoral autoreactivity to ZnT8, SLC30A8 genotype is an important determinant of autoantibody specificity, and ZnT8 auoantibodies are an additional useful marker for Japanese type 1 diabetes.

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Zinc (Zn), one of the essential trace elements, is crucially involved in numbers of mammalian physiological events, thereby its dysregulation is causative of pathogenesis. Zn homeostasis is regulated by Zn transporter family members. Studies using gene-manipulated mice and human genetics revealed dysfunction of Zn transporters is potently associated with several statuses of human diseases. In this review, I will describe the role of the Zn transporter Slc39a13/Zip13 in bone, tooth and the connective tissue development based on comprehensive strategies using knockout mice and clinical cases, and also discuss the biological relevance of regulation of intracellular Zn distribution for physiological and pathological development in mouse and human.

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A number of secretory, membrane-bound or organelle-resident enzymes are properly folded and become functional active forms by binding with zinc during their itinerary in the secretory pathway. Zinc homeostasis within the pathway, therefore, has to be strictly regulated. In vertebrate cells, it is regulated through the coordinated zinc mobilization by specific ZnT (Zn transporter, SLC30A) and ZIP (Zrt, Irt-related protein, SLC39A) transporters. This article reviews the recent progress in cellular and functional properties of such zinc transporters including those expressed in cell-specific manner, and shortly discusses future perspectives based on current data.

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We developed the ratio of apo/holo activities of angiotensin converting enzyme (ACE ratio) in the serum as an index of the zinc nutrition status. The zinc nutrition in patients with taste impairment was then estimated by dietary zinc intake, zinc concentration and ACE ratio in the serum. The results obtained in a series of our studies suggested that zinc deficiency is predominant factor underlying taste impairment even when zinc concentrations are within normal ranges in the serum and that ACE ratio is a more sensitive indicator of the zinc nutrition status than measuring zinc concentration in the serum. There were no differences of dietary intake of zinc after adjusting for energy and zinc concentration in the serum between patients and age-matched healthy subjects. But, ACE ratio in patients with taste impairment was significantly higher than that in age-matched healthy subjects. It is suggested that zinc deficiency in patients with taste impairment is due to malabsorption of dietary zinc from the duodenum and jejunum, but not low intake of dietary zinc.

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Zinc deficiency induces growth retardation, reduced reproductive function, dermatitis, taste abnormality, immune dysfunction, and so on. In the present paper we summarize the effects of dietary zinc deficiency and carbonic anhydrase (CA) on the taste function were studied in SD rats. At an early stage of zinc deficiency after 3 to 7 days of the feeding, it was shown that abnormal increase of taste preference for NaCl solution were observed, though this occurred before any change in the chorda tympani (taste) nerve sensitivity to NaCl. This suggested the contribution of the central nervous system might be involved in this behavioral change. Actually, we observed the decreased oxytocin secretion through the hypophysis, which was paralleled well with the increase of salt preference. After 7 to 14 days feeding of zinc-deficient diet, the rats showed the decreased chorda tympani and lingual trigeminal nerves sensitivity to carbonated water, in addition to the decreased CA activity in the submandibular gland. At a severe stage, i.e., after 3 weeks or much longer-term of the zinc deficiency, it was shown the decrease in the chorda tympani nerve sensitivity to most of the basic tastes except for sweet taste (sucrose), the degenerative histological changes in the lingual trigeminal nerve fibers, the decreased CA II protein expression in the submandibular gland, and the decreased salivary secretion (28 days or later). We have also undertaken the tongue surface CA inhibition studies, and found out that the CA activity is indispensable factor to maintain the taste perception normally. Finally, we investigated the role of zinc in food intake regulation using rats during earlystage zinc deficiency without decreased zinc concentrations in plasma and tissues. The results showed that orally administered zinc may stimulate food intake via orexigenic peptides coupled to the afferent vagal stimulation through the gastrointestinal tract in rats after short-term treatment with a zinc-deficient diet.

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Plasmid DNA damage induced by 2, 2'-azobis (2-amidinopropane) dihydrochloride (AAPH) and the effects of Co(II) and Fe(II) ions on this damage were investigated under aerobic conditions by agarose gel electrophoresis. DNA singlestrand breaks were observed depending on AAPH concentration and treatment time. DNA damage induced by treatment with 10 mM AAPH for 2 hours at 37°C was not inhibited by superoxide dismutase (<200 U), catalase (<200 U), or mannitol (<200 mM), although the damage slightly tended to be decreased by 200 U superoxide dismutase. Damage was inhibited by EDTA or deferoxamine in a concentration-dependent manner. These results suggested the involvement of superoxide anion and metal ions in damage formation. When DNA was incubated with 1mM AAPH, DNA damage was enhanced by 0.001-0.1 mM Fe(II) ion, whereas damage induced by AAPH and Fe(II) ion was totally resolved by 0.1 mM deferoxamine. In contrast, ≥1 mM concentration of Co(II) ion had a suppressive effect on AAPH-induced damage. Co(II) ion in the concentration range of 0.01-0.1 mM suppressed DNA damage induced by both 5 mM AAPH and 0.1 mM Fe(II) ion ; however, a higher concentration (≥5 mM) of Co(II) ion enhanced DNA damage and caused severe DNA breaks, making the DNA bands invisible even in the absence of AAPH. Spectrophotometric analysis suggested the direct interaction of AAPH and Co(II) ion. The above results suggested that Co(II) ion has biphasic effects on DNA damage induced by AAPH depending on its concentration, although Fe(II) ion simply enhances the AAPH-induced DNA damages.

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