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Human Nutrition & Food Management, The Ohio State University, Columbus, OH 43210
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONOxidant stress in rats...Type 2 diabetes: A...REFERENCES |
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KEY WORDS: • mild zinc deficiency • rats • humans • diabetes • oxidant stress
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONOxidant stress in rats...Type 2 diabetes: A...REFERENCES |
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). Zinc is not an antioxidant in
the same sense as vitamin E. However, zinc could conceivably limit
oxidant-induced damage in other ways. Listed in Table 1
are some possible indirect antioxidant roles for zinc; this list is not
necessarily complete. Among the roles that are listed, there may be
overlaps. For example, restriction of free radical production may
contribute to protection against vitamin E depletion. In addition,
stabilization of membranes, which may make membranes more resistant to
oxidant damage, may down-regulate radical production.
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Oxidant stress in rats with mild zinc deficiency |
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TOPABSTRACTINTRODUCTIONOxidant stress in rats...Type 2 diabetes: A...REFERENCES |
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, suggest that the answer is yes. In each case, zinc deficiency is
defined as mild based primarily on the following four criteria.
(1) The dietary treatment is less severe than that typically
used to induce more severe zinc deficiency (more zinc in the diet,
shorter feeding time and the use of older rats). (2) Rats
show much less anorexia than they do with more severe zinc restriction.
(3) Serum zinc values, although below normal, are not as low
as reported for other studies of zinc deficiency in rats.
(4) Liver metallothionein concentrations, which fall with
zinc deficiency (Cousins 1985
), are normal. The first
observation from Table 2
indicates that mildly zinc
deficient rats can exhibit high serum levels of the acute phase protein
ceruloplasmin (DiSilvestro and Carlson 1994
,
Parsons and DiSilvestro 1994
). Elevated levels of this
protein can be a sign of inflammation (Cousins 1985
),
which is associated with above-normal phagocyte secretion rates of
free radicals (Kehrer 1993
).
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suggests that mildly
zinc-deficient rats show very high vulnerability to chemical
hepatitis. The particular chemicals used, carbon tetrachloride and
galactosamine, are thought to produce hepatitis through processes that
involve oxidative stress (Recknagel and Glende 1989
,
Shedlofsky and McClain 1991
). The mechanism or
mechanisms involved in the effects of zinc status on the hepatitis
remain unclear. It is unlikely that metallothionein plays a role
because values are not low in the mildly zinc-deficient rats
(DiSilvestro and Carlson 1994
, Parsons and DiSilvestro 1994
). Extracellular superoxide dismutase is also
not likely to be involved; serum activities of this enzyme, although
low, are still nearly normal in the mildly zinc-deficient rats
(unpublished results). This enzyme activity may be more vulnerable to
mild zinc deficiency in humans than in rats (Davis et al. 1998
).
The third observation from Table 2
is that mildly
zinc-deficient rats show partial loss of acute phase response
protection against hepatitis induced by carbon tetrachloride. This may
be mediated by restricted liver metallothionein elevation. Although
liver metallothionein content is normal in nonstressed rats in this
study, the rise during an acute phase response is greatly limited
(DiSilvestro and Carlson 1994
). At the same time,
protection against carbon tetrachloride–induced liver damage, which
was virtually 100% in zinc-adequate rats, is reduced in rats with
mild zinc deficiency.
The fourth observation from Table 2
notes that mildly
zinc-deficient rats exhibit plasma LDL and VLDL with poor
resistance to oxidation. A striking effect is seen for both lag time
and propagation rates, despite a fairly short time on the low zinc diet
(DiSilvestro and Blostein-Fujii 1997
). Although the
oxidation is assessed in vitro, it is generally assumed that such
assessments reflect blood donor differences in the lipoprotein
properties (Halliwell 1995
). An example of such
differences is the amount of preformed lipid hydroperoxides. Another
possibility is lipoprotein fatty acid profile; this is not likely to be
a factor in the zinc study. Based on other work (Walldius et al. 1983
), if low zinc intake had any effect on fatty acid profile,
it should produce a fatty acid profile that would make lipoproteins
more resistant to oxidation (Halliwell 1995
,
Scaccini et al. 1992
).
The vitamin E–zinc connection, although not a new idea, has just begun
to draw substantial attention. Unfortunately, none of the work noted in
Table 2
included any assessments of vitamin E. In
retrospect, this seems to be an obvious omission.
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Type 2 diabetes: A test case for zinc status–oxidative stress relationship in humans |
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TOPABSTRACTINTRODUCTIONOxidant stress in rats...Type 2 diabetes: A...REFERENCES |
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, Oberley 1988
,
Sinclair et al. 1992
). Diabetes is also associated with
a surprisingly broad range of signs of moderate zinc deficiency
(Mooradian and Morely 1986
, Moutschen et al. 1992
, Pai and Prasad 1988
, Strain 1991
), including low zinc in plasma and blood cells,
abnormal taste acuity and low plasma activity of thymulin (an
immunoregulatory peptide that requires zinc for activity). In addition,
many of the specific impairments in immune function found in diabetes
are the same as those seen with zinc deficiency in humans and
rats and mice (reviewed in Moutschen et al. 1992
). Pilot study results.
Forty postmenopausal type 2 diabetic women were found to show signs of
zinc deficiency based on low values for plasma zinc and 5'-nucleotidase
activities (Blostein-Fujii et al. 1997
). Previous work
in our laboratory suggested that plasma 5'-nucleotidase activities are
sensitive indicators of zinc status (Bales et al. 1994
).
In the type 2 diabetic women, the activities were extremely low
compared with those of control subjects (Blostein-Fujii et al. 1997
). Short-term zinc supplementation (30 mg/d as amino
acid chelate for 3 wk) in 20 of the type 2 diabetic women elevated
values for plasma zinc and plasma activities of 5'-nucleotidase
(Blostein-Fujii et al. 1997
). As another monitor of zinc
function, plasma insulin-like growth factor-l was also
monitored. Subjects with low initial values (13 of the 20 subjects)
showed an increase with zinc supplementation. Placebo administered to
the other 20 diabetic women produced no effects on any of these
measurements.
The 5'-nucleotidase activities, although elevated by zinc treatment,
were still found to be well below values obtained for nondiabetic
control subjects (Blostein-Fujii et al. 1997
).
Therefore, based on this criterion, the particular zinc supplementation
protocol used is not sufficient to restore normal zinc status. The zinc
supplementation did not alter vulnerability of LDL and VLDL to
oxidation (Blostein-Fujii et al. 1997
). Possibly, the
supplementation protocol of this study does not sufficiently improve
zinc status to have an effect. Another possible explanation involves
the multiple nutrient problems that can be present in thc diabetic
subjects studied. Supplementation of just one nutrient, like zinc,
might not be able to substantially affect lipoprotein oxidation.
Based on our previous findings, a new research project is under way in our laboratory that is intended to deal with the two issues raised in the previous paragraph. Zinc will be administered for a longer time period at a higher dose. In addition, some subjects will be administered vitamin C, with or without the zinc treatment. We hope that this study will further define the potential antioxidant role of zinc in mildly zinc-deficient subjects.
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONOxidant stress in rats...Type 2 diabetes: A...REFERENCES |
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1. Bales C. W., DiSilvestro R. A., Currie K. L., Plaisted C. S., Joung H., Galanos A. N., Lin P. H. Marginal zinc deficiency in older adults: responsiveness of zinc status indicators. J. Am. Coll. Nutr. 1994;13:455-462[Abstract]
2.
Blostein-Fujii A., DiSilvestro R. A., Frid D., Katz C., Malarkey W. Short term zinc supplementation in type II diabetic women: effects on plasma 5'-nucleotidase activities, insulin-like growth factor levels and lipoprotein oxidation rates in vitro. Am. J. Clin. Nutr. 1997;66:639-642
3. Bray T. M., Bettger W. J. The physiological role of zinc as an antioxidant. Free Radic. Biol. Med. 1990;8:281-291[Medline]
4. Bunk M. J., Dnistrain A. M., Schwartz M. K., Rivlin R. S. Dietary zinc deficiency decreases plasma concentrations of vitamin E. Proc. Soc. Exp. Biol. Med. 1989;190:379-384[Medline]
5. Burton G. W., Traber M. G. Vitamin E: antioxidant activity, biokinetics, and bioavailability. Annu. Rev. Nutr. 1989;10:357-382[Medline]
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Cousins R. J. Absorption, transport and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Phys. Rev. 1985;65:238-309
7. Davis C. D., Klevay L. M., Milne D. B., Nielsen F. H. Extracellular superoxide dismutase activity: a promising indicator of zinc status in humans. FASEB J 1998;12:A346(abs.)
8. DiSilvestro R. A., Blostein-Fujii A. Moderate zinc deficiency in rats enhances lipoprotein oxidation in vitro. Free Radic. Biol. Med. 1997;22:739-742[Medline]
9. DiSilvestro R. A., Carlson G. P. Effects of mild zinc deficiency, plus or minus acute phase response, on CC14 hepatotoxicity. Free Radic. Biol. Med. 1994;16:57-61[Medline]
10.
Halliwell B. Oxidation of low-density lipoproteins: questions of initiation, propagation, and the effect of antioxidants. Am. J. Clin. Nutr. 1995;61:670.S-677S
11. Kehrer J. P. Free radicals as mediators of tissue injury and disease. Crit. Rev. Toxicol. 1993;23:21-48[Medline]
12. Lyons T. J. Oxidized low density lipoproteins: a role in the pathogenesis of atherosclerosis in diabetes?. Diab. Med 1991;8:411-419[Medline]
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Marklund S. L. Human copper-containing superoxide dismutase of high molecular weight. Proc. Natl. Acad. Sci. U.S.A. 1982;79:7634-7638
14.
Mooradian A. D., Morely J. E. Micronutrient status in diabetes mellitus. Am. J. Clin. Nutr. 1986;45:877-895
15. Moutschen M. P., Scheen A. J., Lefebvre P. J. Impaired immune responses in diabetes mellitus: analysis of the factors and mechanisms involved: relevance to the increased susceptibility of diabetic patients to specific infections. Diab. Metab. 1992;18:187-201[Medline]
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Noh S. K., Koo S. I. Feeding of a marginally low level of dietary zinc lowers the concentration of 
-tocopherol (-P) in selected organs. FASEB J 1998;12:A217(abs.)
17. Oberley L. W. Free radicals and diabetes. Free Radic. Biol. Med. 1988;5:113-124[Medline]
18. Pai L., Prasad A. S. Cellular zinc in patients with diabetes mellitus. Nutr. Res. 1988;8:889-897
19. Parsons S., DiSilvestro R. A. Effects of mild zinc deficiency, plus or minus an acute phase response, on galactosamine-induced hepatitis in rats. Br. J. Nutr. 1994;72:611-618[Medline]
20. Recknagel R. O., Glende E. A. The carbon tetrachloride hepatotoxicity model: free radicals and calcium homeostasis. Miquel J. Quintanilha A. T. Weber H. eds. Handbook of Free Radicals and Antioxidants in Biomedicine 1989;Vol. 3:3-16 CRC Press Boca Raton, FL.
21. Sakanashi T. M., Keen C. L., Hong K. H., Gershwin M. E., Fletcher M. P. Zinc deficiency associated alterations in the chemotactic and respiratory burst responses of rat peripheral blood neutrophils. FASEB J 1993;7:A723(abs.)
22. Scaccini C., Nardini M., D’Aquino M., Gentili V., Di Felice M. Effect of dietary oils on lipid peroxidation and on antioxidant parameters of rat plasma and lipoprotein fractions. J. Lipid Res. 1992;33:627-633[Abstract]
23. Shedlofsky S. I., McClain C. J. Hepatic dysfunction due to cytokines. Kimbal E. S. eds. Cytokines and Inflammation 1991:235-273 CRC Press Boca Raton, FL.
24. Sinclair A. J., Lunec J., Girling J., Barnett A. H. Modulators of free radical activity in diabetes mellitus: role of ascorbic acid. Free Radic. Aging 1992;2:342-352
25. Strain J. J. Disturbances of micronutrient and antioxidant status in diabetes. Proc. Nutr. Soc. 1991;50:591-604[Medline]
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Walldius G., Michaelsson G., Hardell L. I., Aberg H. The effects of diet and zinc treatment on the fatty acid composition of serum lipids and adipose tissue and on serum lipoproteins in two adolescent patients with acrodermatitis enteropathica. Am. J. Clin. Nutr. 1983;38:512-522
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