Diabetes and Antioxidants

Nutrition Research, Vol. 15, No. 9, 1377-1410, 1995 pp.
Copyright 0 1995 Elsevier Science Ltd

Printed in the USA. All rights reserved
027 I-53 17/95 $29.00 + 60
0271-5317(95)02012-K
MICRONUTRIENTS AND ANTIOXIDANTS IN THE PROGRESSION OF DIABETES
K. H. Thompson, Ph.D. and D. V. Godin, Ph.D.*
Western Human Nutrition Research Center, ARS, US Department of Agriculture
The Presidio of San Francisco, CA, USA 94129-0997
Department of Pharmacology and Therapeutics, Faculty of Medicine
The University of British Columbia, Vancouver, B.C., Canada V6T 123
ABSTRACT
Evidence for changes in trace mineral and vitamin metabolism as a
consequence of diabetes pathophysiology is reviewed. Emphasis is on those
micronutrients which have a recognized antioxidant or prooxidant function in
viva, with consideration of the relevance of these changes to current
hypotheses regarding the onset of secondary complications in the progression
of diabetes. Prospects for re-defining micronutrient requirements specific to
diabetic individuals are discussed.
KEY WORDS: Diabetes Mellitus, Micronutrient, Zinc, Ascorbic Acid, Vitamin E,
Antioxidant
INTRODUCTION
Diabetes mellitus represents a spectrum of disorders, whose primary clinical
manifestation is an absolute or relative lack of insulin, or insulin resistance. It has been
estimated that diabetes mellitus afflicts 30 to 35 million people worldwide (1). The etiology
of diabetes, which is treatable but not curable, is incompletely understood, although it is
known to have an underlying genetic component. Progression of diabetes often leads to
kidney failure and heart disease, as well as to haemotological abnormalities, nephropathy
and a constellation of metabolic abnormalities which are in some ways analagous to signs
of aging (2). Diabetic retinopathy, a frequent secondary complication of diabetes, is the
leading cause of vision impairment and blindness in the developed world (3).
Corresponding Author
1377
1378
K.H. THOMPSON and D.V. GODIN
Investigation of the pathophysiology of the secondary complications of diabetes is
focusing increasingly on the role of oxidative stress in their initiation and progression.
Micronutrients may exert protective or scavenging effects, as well as being essential
components of several key enzymes in intracellular antioxidant defense. Their deficiency,
or excess, may contribute to derangement of the pro-oxidant/anti-oxidant balance, and hence
to the progressive appearance of secondary complications as the disease advances (6). A
cyclic process wherein glycation of proteins causes oxidation of associated lipids, which in
turn stimulates autoxidative reactions of sugars in a continuous positive feedback loop may
be in operation (4).
In this review, we will focus less on assigning a definitive order of events in the
development of secondary complications and progression of diabetes than on the evidence
for potentially useful therapeutic interventions to interrupt this destructive cycle.
BACKGROUND
Two general types of diabetes mellitus can be distinguished: type I (insulin-dependent,
juvenile onset, or IDDM), and type II (insulin-independent, maturity onset, or NIDDM), the
latter comprising 80% or more of clinical cases (7). In the type I form, P-cells of the islets of
Langerhans are totally or partially destroyed, possibly as a result of autoimmune and/or
environmental factors (8). Insulin replacement therapy is the hallmark of this condition. Type
II diabetes, which generally involves both environmental and genetic factors is quite
heterogeneous, with two major abnormalitities being inadequate insulin release in response
to glucose and/or insensitivity of target tissues (such as liver, adipose tissue and muscle) to
the action of insulin (7).
Type I diabetes is usually diagnosed in the mid- to late-teens or early twenties of a
persons lifespan. Because juvenile-onset diabetes requires exogenous insulin for control
of hyperglycemia and other diabetic symptomatology, oscillation between conditions of hypo-
and hyperglycemia is common in this disorder (9). Type II, maturity-onset diabetes may
sometimes be controlled by diet alone; however, many type II diabetic individuals also require
exogenous insulin for adequate blood glucose control. Oral hypoglycemic agents may also
exert beneficial effects, but do not completely prevent hypo- or hyperglycemic episodes on
a daily basis, Hyperinsulinemia is frequently an additional metabolic abnormality in type II
diabetes (10).
Both type I and II diabetes are accompanied by alterations in micronutrient absorption,
tissue uptake, and excretion, some in a time-dependent fashion (1 l-14). A major effect of
these changes may be a worsening of the oxidative balance, with declining capability to
combat endogenously produced free radicals.
MICRONUTRIENTS IN DIABETES 1379
Proaression of diabetes
In a diabetic individual, several organs of the body are affected by a chronic instability
of blood glucose levels and increased oxidative stress (15). In the eyes, this results in
cataract formation and retinal microvascular disease. In the kidney, increased filtration rate
and filtration fraction, excretion of urinary albumin and other proteins, synthesis of mesangial
actomyosin-like material, hypertrophy, glomerular capillary damage and eventual renal failure
are frequent sequelae to both types I and II diabetes (6). Accelerated macrovascular
disease, possibly related to lipid abnormalities, platelet hyperaggregability and abnormalities
in arterial wall function, leads to atherosclerosis and/or arteriosclerosis in a significant
majority of diabetic individuals (6,16,17). In addition, diabetes is associated with
osteoporosis, increased incidence of birth defects, and reduced elasticity of connective tissue
(18).
Free radical oroduction and antioxidant defense
A common feature in most, if not all, of these complications, is the involvement of
reactive oxygen species (ROS) (4,19,20). In general mechanistic terms, common diabetic
complications such as coronary artery disease, atherosclerosis and ischemic tissue injury
associated with microangiopathy may be due to increased or uncontrolled oxidative activity,
given the wealth of evidence implicating reactive oxygen-derived substances (ROS) in the
pathogenesis of both micro- and macro-angiopathy (6,16,20,21).
ROS may cause cell damage by attacking membrane lipids or proteins, interacting with
thiol groups, inactivating enzymes, or inducing modifications in ribonucleic acids (22). Some
ROS, such as superoxide and hydroxyl radical, are free radicals, defined as molecular or
ionic species characterized by an unpaired electron (23). Other ROS, such as hydrogen
peroxide (and probably lipid peroxides), can lead to the formation of a variety of more
reactive ROS in the presence of transition metal ion catalysts (24). Under physiological
conditions, the primary source of ROS is the mitochondrial electron transport chain, with the
region between quinones and cytochrome b, on the internal mitochondrial membrane,
constituting the main production site (25). Partial reduction of mitochondrial oxygen by
electrons that escape from electron carriers in the respiratory chain results in the low level,
but continuous, production of ROS. Additional autoxidizable components on the inner
mitochondrial membrane include NADH and thiols (26).
Although production of oxygen-based free radicals is an inevitable consequence of
oxygen metabolism, safe disposal or deactivation of these metabolites is essential to aerobic
life. Thus, there is an entire cell machinery devoted to detoxification of free radicals (27).
The enzymatic components include copper,zinc superoxide dismutase (CuZnSOD) and
catalase in the cytoplasm, manganese superoxide dismutase (MnSOD) in the mitochondria,
and glutathione peroxidase (GSHPx) in the mitochondria and cytoplasm (22,23,27).
Superoxide dismutases catalyze the dismutation of superoxide ions to hydrogen peroxide and
bimolecular oxygen (28); catalase is the enzyme which catalyzes degradation of hydrogen
peroxide; and glutathione peroxidase scavenges lipid hydroperoxides, requiring the
tripeptide, glutathione (GSH) as a cofactor (5). Glutathione reductase (GRD) reduces
oxidized glutathione (GSSG) and is thus linked to GSHPx activity.
The nonenzymatic components of antioxidant defense are, most notably, ascorbic acid
in the cytoplasm, a-tocopherol in the lipid bilayer of cell membranes, GSH both intra- and
extra-cellularly, and uric acid (20,22,29,30). GSH is in dynamic equilibrium with all cellular
sulfhydryl groups. Decreased tissue levels of GSH can be considered an indicator of
oxidative stress in vivo (31). In detoxifying cellular oxidants, GSH becomes oxidized itself (to
GSSG), and is then reduced back to GSH by GRD, which requires NADPH as a cofactor.
Other dietary and metabolic substances may act in an antioxidant or pro-oxidant capacity,
depending on micronutrient interactions and pathophysiological state (5,22).
It is important to emphasize that both enzymatic and nonenzymatic components of
cellular antioxidant defense systems function in an interactive and interdependent fashion.
Thus, no one of these metabolites, nutrients or enzymes acts in isolation from the others. A
reduction in glutathione may tip the balance towards lipid peroxidation (32) or it could be
covered for by supplemental vitamin E in the cell membrane (33). Conversely, increased
levels of dietary iron (e.g., from indiscriminate use of supplements) may promote autoxidative
processes in vivo (34) but this may be vastly enhanced by concomitant excess of ascorbic
acid in the diet, due to enhanced release of free (decompartmentalized) iron (29, 35). A more
thorough understanding of how these interactions occur on a quantitative basis is necessary
before any nutritional recommendations can be made.
Evidence for increased oxidative stress in diabetes
Oxidant stress is said to be increased in a system when the rate of free radical
production increases and/or the antioxidant mechanisms are impaired, Increased oxidative
stress in diabetes could be the result of an increase in ROS production, an impairment in the
activity of endogenous antioxidant components or a combination of the two. There are
numerous examples of both in diabetic subjects as well as in experimentally diabetic animals.
Increased oxidative stress has been implicated in the etiology of type I diabetes and
of spontaneous or chemically induced diabetes in experimental animals (for review and
description of animal models, see 36) as well as in the development of complications in all
types of diabetes (4,6, 27, 37). Autoimmune processes, notably macrophage and
lymphocyte infiltration of the pancreatic islets, play a key role in the induction of type I
diabetes (38). Prevention of diabetes in nonobese diabetic and multiple low-dose
streptozotocin (STZ)-injected mice by treatment with a synthetic antioxidant (MDL 29,311)
supports the hypothesis of a crucial involvement of free radicals in this process (39).
Cytokines produced by activated macrophages (e.g., interleukin-1 and tumor necrosis factor)
and T-lymphocytes (y-interferon) may also initiate oxidative processes resulting in the
destruction of pancreatic P-cells (38). Pretreatment with superoxide dismutase can prevent
damage to pancreatic B-cells by STZ in vitro or protect against the diabetogenic effects of
STZ administration to rats in vivo (40,41). Vitamin E, a nonenzymatic antioxidant, also
prevented induction of diabetes by both STZ and alloxan (42). Direct evidence of the free
radical basis of diabetes induction comes from recent studies showing an increased rate of
oxygen radical secretion from macrophages isolated from diabetes-prone BioBreeding (BB)
rats, a spontaneously diabetic rat model (43). This hyperseceretion of ROS by infiltrating
macrophages may contribute to S-cell destruction.
Increased lipid peroxidation seems to be associated with the development of
secondary complications of type I or II diabetes, underlining the crucial role of oxidative
damage. Numerous reports have documented elevations in peroxide levels in plasma, red
blood cells and tissues of animals with chemically-induced diabetes (44-47). Increases in
blood peroxides (or other indices of oxidative stress, such as diene conjugation products)
have also been reported in human diabetic patients (48-54).
A large body of experimental evidence exists attesting to the presence of increased
oxidative stress in diabetes. Superoxide radical production was reported to be increased in
insulin-dependent, non-ketotic, diabetic subjects (55). Hydrogen peroxide production was
shown to be increased in experimental diabetes (56) and in nondiabetic cataractous lens
(57). Increased glycation end products have also been detected in STZ-diabetic rat lens
crystallin (58). Lipid peroxidation in diabetic VLDL and LDL was preventable by dietary
supplementation with vitamin E (59). Lipid peroxide levels in diabetic individuals with micro-
and macro-angiopathies were elevated compared to non-diabetic controls, and were
significantly correlated with duration of diabetes and the presence of ischemic heart disease
(60). Also, erythrocytes of STZ-induced diabetic rats (61-63) and diabetic patients (64-65)
were more susceptible to peroxidation in vitro. Low-density lipoproteins of diabetic subjects
were also more susceptible to phenylhydrazine-induced oxidation and this was associated
with an increased level of arachidonic acid in the LDLs of diabetic patients (65).
Impaired antioxidant scavenging in types I and II diabetes in humans and experimental
diabetes in animals has also been reported. Both increases and decreases in activities of key
antioxidant enzymes, namely catalase, MnSOD and CuZnSOD, GSHPx, and GRD have been
extensively documented (19,27,64,66-73). The disturbed antioxidant activities in STZ-
diabetic rats could be completely reversed by insulin treatment (61,70) or partially reversed
by vanadate treatment (72). Changes were tissue-specific (62,71), both quantitatively and
qualitatively. Pancreas and heart were noticeably less robust than liver and kidney in
antioxidant enzyme activities, as previously determined in non-diabetic mice (74). Change
in food intake and severe loss of weight with diabetic induction by STZ injection did not
account for the changes in antioxidant enzymes observed (75). In the spontaneously diabetic
BB rat, dramatic shifts in pancreatic antioxidant enzyme activities occurred before any
pancreatic insulitis (which is evidence of onset of diabetic symptomatology) was detectable.
Time-dependent changes included declining CuZnSOD and GSHPx activities in pancreas,
with total SOD remaining high due to elevated activity levels of MnSOD (76). Total
pancreatic SOD activity in BB rats was significantly lower than in Wistar rats, which the
authors concluded may constitute a diabetic proneness factor (77).
Link between hyperqlvcemia and increased oxidative stress
It is now recognized that the autoxidation of glucose and of glycated proteins can
generate ROS, especially in the presence of transition metals (17,78).
Hunt et al. (79) have
demonstrated that peroxidation and glycosylation of LDL occur concomitantly in diabetes
mellitus. An increase in the glycS& form of erythrocyte CuZnSOD was found in diabetic
patients (80). Increased glycation was subsequently shown to be accompanied by enzyme
inactivation (81). Diabetic endothelial cell dysfunction caused by hyperglycemia has been
shown to be free-radical mediated (82,83). Glucose can be a source of superoxide ions (84),
and hence, hyperglycemia, the essential identifying feature of diabetes, may itself contribute
to increased oxidative stress. The mechanism may involve slow enolization of
monosaccharides to produce ene-diols, which react nonenzymatically with oxygen to yield
a semidione radical and superoxide (18). The semidione radical can then decay to a l-
hydroxyalkyl radical and hydrogen peroxide at physiological pH.
Catalysis by excess trace metal ions (e.g., Cu, Fe2) is a prerequisite for most
autoxidation reactions (23,78). Superoxide can reductively mobilize iron ions from ferritin
(85&Z), and is known to be elevated in polymorphonuclear leukocytes of diabetic individuals
(55,87). Superoxide dismutases normally effectively scavenge superoxide radicals (28);
however, this defense may be inadequate in the diabetic state, due either to reduced
synthesis, or to inactivation by glycosylation (76,80). Increased oxidative stress may result
in Fe2 release from mitochondria (88). In addition, an increase in hydrogen peroxide
production in diabetic tissues (17,27), could lead to release of iron from heme proteins, such
as hemoglobin and myoglobin (89,90). Indirect evidence of increased hydrogen peroxide
formation in diabetes has been obtained from experiments in which albumin solutions were
incubated with varying concentrations of glucose (91) and from studies of insulin-mediated
production of hydrogen peroxide in rat epididymal fat cells (92). Thus, highly-reactive
hydroxyl radicals could be formed in vivo (29) and mechanistic explanations exist for the
increased activity of ROS in diabetes mellitus (6,19, 79).
Another possible link between hyperglycemia and oxidative stress relates to the
aldose reductase-catalyzed formation of sorbitol from glucose in the presence of
hyperglycemia, a process implicated in certain diabetic complications, notably those involving
the eye (93). The action of aldose reductase utilizes NADPH, a reducing co-factor for GRD
(22). As a result, levels of NADPH may become limiting, with an ensuing impairment in
antioxidant capacity (83,94). A detailed understanding of the complex interrelationships of
glycation, flux through the polyol pathway, arachidonic acid metabolism, trace metal ion
release and autoxidation of proteins is gradually emerging (29,83,95), but many uncertainties
still remain.
Hvperalvcemia and development of complications
There has been much controversy concerning the extent to which rigorous control of
blood glucose levels can influence the rate and extent to which various diabetic complications
develop. In both experimental and clinical diabetes, correlations have been noted between
indices of oxidative damage in plasma, red blood cells and other tissues of diabetic subjects
and experimentally diabetic animals and the severity of diabetic complications
(19,33,45,46,52,54,60,64). A detailed study by Pirart (96) involving 4,400 patients followed
for a period of 26 years suggested a causal link between hyperglycemia and the development
of retinopathy, neuropathy and nephropathy. On the other hand, a report by Raskin and
Rosenstock (97) pointed out that there are wide variations in the occurrence of diabetic
complications, with some individuals never developing them regardless of the extent of
diabetic control and others showing severe complications despite apparently good diabetic
MICRONUTRIENTS IN DIABETES
control. The results of the Diabetes Control and Complications Trial (DCCT) demonstrate
unequivocally that improved glycemic control delays the onset and slows the progression of
retinopathy, nephropathy and neuropathy in type I diabetes (98); however, the application
of these findings to type II diabetes is somewhat problematic, since rigorous blood glucose
control requires insulin levels which may themselves be pathology-producing (10, 99). What
does seem clear is that persistent hyperglycemia is highly correlated with an increased
incidence and severity of complications - especially retinopathy, nephropathy and neuropathy
(15, 100,101).
ALTERATIONS IN MICRONUTRIENT STATUS IN DIABETES
Micronutrients are involved in the complex processes of development of the secondary
complications of diabetes mellitus in a number of different areas. They may be integral
components of antioxidant enzymes (e.g., Cu, Zn and Mn in the case of the superoxide
dismutases, and Se for GSHPx), cofactors in a variety of enzymatic processes of importance
in glucose and lipid metabolism (e.g., Zn, Mn, Cu), or potential pro-oxidant catalysts (e.g., Cu,
Fe). Other micronutrients which may influence the progression of diabetes are themselves
recognized antioxidants, especially ascorbic acid (vitamin C) and a-tocopherol (vitamin E).
Still other micronutrients are relevant to diabetes since it has been shown that glucose
intolerance developed when these elements were deficient, either experimentally or due to
nutritional inadequacy (e.g. chromium, copper, manganese, and possibly selenium).
That the concentrations of these trace elements and vitamins may be altered in
diabetes has been well-established (11!12,14, 102-l 08). Surveys of human diabetic subjects
have revealed a variety of significant changes in trace metal status (109-l 11). The following
sections will focus on changes in micronutrient status which could affect oxidative status, and
hence the development of diabetic complications. We will also review some investigations
of the effects of micronutrient supplementation on micro- and macrovascular changes in types
I and II diabetes. First we will consider those micronutrients, namely zinc, ascorbic acid, a-
tocopherol and selenium, whose role in the progression of diabetes can clearly be linked to
their behavior as antioxidants; and then we will review other micronutrients of potential
interest in the pathogenesis of diabetes and its secondary complications.
Numerous studies have found decreases in physiological measures of zinc status,
hyperzincuria and indications of zinc malabsorption in both type I and type II diabetic
individuals (112-123). Experimental investigations of altered zinc excretion and distribution
in diabetic animals have demonstrated a close association between the onset of diabetes and
alterations in zinc metabolism (106,124-l 27). Diabetic patients with congestive heart failure
(CHF) had significantly lower serum zinc levels and increased zinc excretion compared to
diabetic patients without CHF (128). Similarly, zinc excretion was found to be greatly
increased in patients with incipient diabetic nephropathy, as detected by appearance of
microalbuminuria (129).
In vitro studies (130,131) and investigations of the effects of zinc deficiency on glucose
intolerance (132-l 36) have corroborated an interaction of zinc in insulin sensitivity and as
a modulator of insulin action. However, the involvement of zinc in the progression of diabetes
is most likely related to its role as an antioxidant micronutrient (137). Zinc protects sulfhydryl
groups against oxidation and inhibits the production of ROS by pro-oxidant transition metals,
presumably by competing with Fe and Cu for binding sites on cell membranes and some
proteins (138).
In viva, a marginal deficiency of zinc increased the teratogenic effects of STZ-induced
diabetes in rats (139). Although zinc stimulated hydrogen peroxide production in isolated rat
adipocytes (140); this is unlikely to occur in viva (141). lntraperitoneal (i.p.) administration
of zinc, 100 mg/kg body weight, normalized hyperglycemia in STZdiabetic rats within 3 hours
(141). Oral administration of ZnCI,, 210 mg/kg body weight, lowered blood glucose by an
average of 50% within 2 hours. However, a hyperglycemic effect in both diabetic and non-
diabetic rats was observed when zinc sulfate, 25 umol i.p., was administered acutely (142).
Zinc inhibited hydroxyl ion formation catalyzed by a citrate-iron complex in the
hypoxanthine/xanthine oxidase reaction in vitro (143) enhanced immune function (144) and
stimulated hexose uptake in rat adipocytes in vitro (141) alone, or in combination with other
trace metals (145).
Studies of zinc supplementation of diabetic individuals have yielded mixed results
(123,146). Zinc supplementation (50 mglday for 1 month) in type I diabetic subjects resulted
in significantly increased percent glycosylated hemoglobin (123) a measure of diabetic
control (147). This was an unanticipated negative finding, but consistent with the
hyperglycemic effect noted above (142). In type II diabetics, zinc sulfate, 220 mg 3 times/day
for 6-8 weeks produced no effect on glycosylated hemoglobin, but did increase lymphocyte
response to phytohemagglutinin, especially in those patients who had shown low serum zinc
values initially (146).
Ascorbic acid
Numerous studies have documented decreases in plasma and tissue levels of
ascorbic acid in animals with chemically-induced diabetes (149-l 50). Levels of plasma
ascorbic acid were found to be significantly lower in both type I and type II diabetic subjects
compared to nondiabetic controls in most studies (151-l 57). However, in one study in which
both diabetic and non-diabetic subjects had markedly higher than usual dietary vitamin C
intakes, no differences between groups were detected (158). Mononuclear leukocyte
ascorbic acid (MN-AA) levels were reduced by 33% in type I diabetics as compared to
nondiabetic individuals (155). MN-AA levels are generally considered as an indicator of
tissue vitamin C status; thus, this result suggests an impaired tissue ascorbate storage
associated with diabetes.
Ascorbic acid is known as a prominent plasma antioxidant (159); therefore, a negative
correlation between plasma aswrbate and increased oxidative stress might be expected. In
fact, in the one study which did not demonstrate significantly decreased plasma aswrbate
in association with diabetes, plasma aswrbate levels were negatively correlated with percent
glywsylated hemoglobin. This result could be interpreted as suggesting that poor diabetic
1385
control results in a faster rate of ascorbate depletion (158). Nonetheless, studies of the
relationship between reduced ascorbate status and the degree of metabolic control in
diabetics have shown a positive correlation in one case (160) but none in another (161).
Diabetic patients affected with microalbuminuria were shown to have a greatly
increased ratio of urinary ascorbic acid excretion to creatinine and an impaired tubular
reabsorption of ascorbic acid, which could be a marker of renal tubular damage (157).
Another possible source of compromised ascorbate status in diabetic individuals is
competitive inhibition between glucose and ascorbic acid, which share a close structural
homology and possibly occupy common membrane transport sites (153). It has been
postulated that the low plasma ascorbate levels in diabetes are a consequence of high
turnover rates, with increased oxidation to the oxidized form, dehydroascorbate (DHA)
(148,151).
Ascorbic acid is a co-factor of proline hydroxylase, an enzyme involved in the
biosynthesis and post-translational modification of collagen; thus, ascorbic acid deficiency
could be expected to adversely affect capillary membrane integrity (162). In fact,
abnormalities of DHAlAA metabolism were more pronounced in type II diabetic patients with
microangiopathy as compared to those without (161). Altered metabolic turnover of
ascorbate in various tissues of experimentally diabetic animals have also been reported
(161).
The general consensus that ascorbate levels are reduced in diabetes has given rise
to numerous investigations of the possible beneficial effects of ascorbate supplementation
in this condition. Supplementation of diabetic subjects with ascorbic acid for varying lengths
of time has confirmed that ascorbate handling in diabetics is defective (161) and therefore
does not necessarily improve tissue ascorbate levels. Some studies have provided evidence
for partial reversal of some diabetes-related abnormalities, such as the accumulation of
sorbitol in red cells (163) and the leakage of lens proteins in aqueous and vitreous humor of
STZdiabetic rats (164). Other investigators suggest that diets adequate in vitamin C for the
general population may be inadequate for the diabetic population, which may suffer from a
virtual state of intracellular scurvy unless dietary intakes are well above the recommended
levels (158).
Vitamin C supplementation mitigated against glycation of hemoglobin and other
proteins (164,165). Ascorbate supplementation of STZ-diabetic rats resulted in increased
plasma levels of tocopherol and retinol, but did not alleviate elevations of malondialdehyde
(MDA) or diene conjugates, both measures of lipid susceptibility to peroxidation (167).
Overall, despite some antioxidant effects of supplemental vitamin C, results are not generally
encouraging (161,167,168). Indeed, it has been suggested that the pro-oxidant properties
of ascorbic acid (35,169) and the defective ascorbate handling in diabetes (161) may
seriously compromise any beneficial effects of ascorbate supplementation in diabetes.
Tocooherols and Selenium
In contrast to the situation with ascorbic acid, plasma levels of vitamin E (a mixture of
tocopherols, principally a- and y-tocopherols) tend to be increased in chemically-induced or
genetic diabetes in experimental animals (71,150,170,171) and in human diabetic subjects
(172,173). Levels of vitamin E in other tissues are not consistently affected in diabetes (12).
Elevated levels of vitamin E have been noted in liver of STZ-diabetic rats (71) and in serum,
heart, testes and thymus of spontaneously diabetic BB rats (171). However, a lack of vitamin
E in particular tissues may be involved in an increased propensity for platelet aggregation
in type I diabetic individuals and contribute to the development of macroangiopathy and
atherosclerosis.
Vitamin E content of platelets was shown to be inversely correlated with ADP-induced
platelet aggregability and TXA, production in STZ-diabetic rats (174) and in human diabetic
subjects (33). Vitamin E is the only lipophilic antioxidant in blood (175) and the principal
chain-breaking antioxidant within mammalian membranes (23). Vitamin E deficiency in rats
resulted in decreased pancreatic MnSOD (108,176) heart GSHPx and hepatic catalase (5)
but increases in muscle and adipose tissue GSHPx activity levels and a significant increase
in oxidant stress, as measured by thiobarbituric acid reactive substances and/or diene
conjugates (22,108,177). Vitamin E-deficient, diabetic rats were shown to have significantly
elevated percent glycosylated hemoglobin levels compared to vitamin-E sufficient diabetic
animals, suggesting a close link between glycation and oxidant stress (108).
In the BB rat, elevated vitamin E levels could be restored to normal by insulin
treatment, suggesting that the raised tocopherol concentrations were a consequence of the
diabetic state (171). The failure of Vrano et al. (178) to demonstrate increases in plasma
tocopherol levels in a group of elderly (aged 70-80) diabetics receiving intensive insulin
therapy may have been due to an effect of insulin on plasma vitamin E. The level of plasma
lipoproteins, which are the principal carriers of vitamin E in the blood, may also affect plasma
vitamin E levels (179). A recent study in types I and II diabetics has suggested that variability
in plasma vitamin E levels in diabetes may be related to the associated hyperlipidemia and,
in particular, to levels of non-HDL cholesterol (179).
In terms of vitamin E supplementation in diabetes, Ross et al. (180) have
demonstrated beneficial effects on cataractogenesis in diabetic rats. Also, thrombin-induced
platelet thromboxane A, (TxAJ, vascular prostacyclin (PGI,) and lipid peroxide levels in STZ-
diabetic rats were restored to normal levels by 2-3 months on a high vitamin E diet (174).
Supplemental vitamin E decreased plasma triglycerides, platelet lipid biosynthesis and urine
ketone bodies but did not affect platelet reactivity in the STZ-diabetic animal model (181).
In type I human diabetics given 400 mg D,La-tocopherol acetate daily for 4 weeks,
metabolic control was not affected but a lesser diabetes-associated elevation in platelet
thromboxane & production in response to ADP or collagen stimulation was observed (182).
The functional significance of this finding is uncertain, however, since platelet function
(aggregation) was not detectably abnormal in the patients studied and was not affected by
vitamin E supplementation. However, at 1 g/day supplementation, elevated platelet
aggregability (which is commonly associated with diabetes) was restored to normal (183).
Moreover, low levels of platelet vitamin E were found in a group of type I diabetic subjects
(compared to age- and sex-matched controls) and a significantly negative correlation with
TxAz was discovered (33).
In a recent 4 month supplementation trial of type II diabetic subjects, 900 mg of vitamin
E/day lowered insulin resistance and improved glucose uptake as shown by euglycemic
1387
glucose clamp assays performed both before and after the supplementation period (184).
The authors conclusion that vitamin E may be a useful adjunct in reducing oxidative stress
in type II diabetics confirms the findings from an earlier study by Ceriello et al. (185) in which
glycosylated hemoglobin and other proteins were significantly decreased after 2 months
treatment with either 600 or 1200 mg/d vitamin E. The potential for vitamin E in
pharmacological doses to be used as a means to delay or prevent secondary complications
of diabetes seems well established but requires further testing for long term efficacy.
The biochemical functions of selenium and vitamin E are interrelated, in that both are
essential components of the antioxidant defense system, and they appear to have synergistic
and compensatory effects in induced deficiency states of one or the other (175,186,187).
Selenium is normally present as part of the metalloenzyme, glutathione peroxidase,
or as selenoprotein P (188-190). At high levels, selenium is both toxic and carcinogenic
(188) yet its essentiality at low concentrations has been conclusively demonstrated both in
humans and in animals. Selenium deficiency has been definitively linked to Keshans
disease, which is endemic in selenium-poor areas of China and is one of the few diseases
definitively linked to ROS damage (191,192). Tissue-dependent changes in selenium
concentrations in STZdiabetic rats (193) and increases in serum selenium levels in diabetic
children (194) have been observed. A negative correlation between lipid peroxide levels and
selenium concentration in blood of type II diabetics suggests that a marginal deficiency of
selenium would tend to increase oxidant stress in viva (195).
Animals rendered deficient in either vitamin E or selenium show a marked increase in
susceptibility to the diabetogenic effects of STZ (42) with a combined deficiency of both
having additive effects. By contrast, vitamin E supplementation protected against STZ
diabetes induction (42).
In a tissue slice study of protection against lipid peroxidation by micronutrients (177)
vitamin E afforded the greatest protection in liver, heart and spleen; however, selenium was
more effective in kidney. The two were not synergistic in this experiment; however, when
administered at intermediate dosage levels of 200 IU/kg and 0.2 mg/kg, respectively, vitamin
E and selenium synergistically protected rats against lipid peroxidation, measured in vitro in
brain tissue (196).
Although vitamin C and E exert their primary antioxidant effects in distinct cellular
compartments (aqueous, for ascorbate, and lipophilic, for a-tocopherol), it is believed that
ascorbate plays an important role in preserving and recycling tocopherol by an action at
water/lipid interfaces (175,186,197).
Chromium
Chromium is necessary for normal carbohydrate metabolism (198). Its deficiency
results in glucose intolerance and insulin resistance both in experimental animals (199) and
in humans (200). Chromium supplementation improved glucose tolerance and insulin
resistance in 12 out of 15 controlled investigative trials (201,202) (or, for review, see 203).
In a 16-month study of supplementation with inorganic chromium (204) no change in
fasting blood glucose was seen; however, increased HDL and decreased VLDL levels in both
diabetic and nondiabetic subjects suggested a potential for improving lipid profiles of type II
diabetics with chromium, thereby lowering the risk of atherogenic complications. A significant
finding was the wide range of initial serum chromium values, all of which were assumed to
be within the normal range. It is not currently possible to accurately determine chromium
status (205); hence chromium deficiency can only be inferred (206,207). In vitro studies
have shown that chromium potentiates insulin action best when supplied in a biologically
active form, otten termed glucose tolerance factor (GTF), which seems to be a complex
containing nicotinic acid, trivalent chromium and glutathione (208). This might explain the
greater effectiveness of chromium-rich yeast supplementation (209) compared to inorganic
chromium supplementation (210). Other liganded forms of chromium are being proposed as
alternative biologically available chromium supplements (21 l), but these have only been tried
in vitro thus far.
The regulatory role of chromium in glucose and insulin metabolism appears to be more
of a nutritional, as distinct from a pharmacological, effect. Thus, chromium appears to be
most effective if at least a marginal chromium deficiency state exists, as shown in a study by
Polansky et al. (212). Supplementa!~chromiurn (200 ug/day) was given to type II diabetic
subjects on a low-chromium diet, with consequent beneficial effects on plasma glucose,
insulin and glucagon (212).
Mannanese
Manganese is actively accumulated within mammalian liver and pancreas, where it
is concentrated within the mitochondria and forms an integral and essential component of
a key mitochondrial antioxidant enzyme, MnSOD (213). Dietary deficiency of manganese
has been shown to reduce tissue MnSOD activities in rats (214) mice and chickens (215)
and also to enhance lipid peroxidation in rat tissue homogenates (216) and decrease
kidney GSHPx activity in pigs (217).
Manganese deficient, STZ-diabetic rats had compromised antioxidant enzyme
defenses, with further decreases in kidney and heart MnSOD and kidney CuZnSOD, as
compared to manganese sufficient diabetic animals (71). In addition, manganese
deficiency has been associated with diabetes-like glucose intolerance (218,219). In
guinea pigs, glucose intolerance induced by dietary manganese deficiency could be
reversed by manganese supplementation (220). Dietary supplementation prior to STZ
induction of diabetes prevented the development of hyperglycemia in rats (221); however,
acute intravenous administration of manganese resulted in hyperglycemia and
hypoinsulinemia (222) reminiscent of the situation with zinc (142).
Addition of 55 ppm manganese together with 1 ppm chromium (but not manganese
alone) to the feed of STZ-diabetic rats resulted in restoration of normoglycemia (223). In
oWbb mica, manganese supplementation (at 10 times normal levels) normalized activities of
the mitochondrial enzymes, succinate dehydrogenase and MnSOD, in brown adipose tissue,
as compared to the depressed levels of these enzymes in unsupplemented ob/ob mice (224).
In short-term studies, experimental diabetes has been associated with significant
increases in liver and kidney manganese as compared to insulin-treated or diabetic rats
(103,106). An increased urinary excretion of Mn in human diabetic subjects (225) and both
increases and decreases in blood Mn (12) have been reported. Some of the variability
reported may be due to differing macronutrient and/or protein content of the diets of trace
metal study subjects (104,226).
The mechanism by which manganese regulates cell function may relate to its effects
on calcium homeostasis (227) or it may be more closely allied with its known antioxidant
functions (228230). A liganded manganese complex, Desferal-Mn, was used successfully
to inhibit diquat-induced cataract formation in rabbit lenses (231) suggesting that manganese
can act as an effective antioxidant in viva. In that light, manganese supplementation may be
of more interest for long-term effects with regard to onset of complications than in short-term
glucose control. An acute study of manganese supplementation showed no effect of 15-30
mg manganese gluconate peros on plasma glucose in type II diabetic subjects (232). To our
knowledge, this is the only follow-up study to an intriguing anecdotal report (233) in which
MnCI, supplementation (at a dose of 3-5 mg) appeared to correct hyperglycemia within hours
in a severely insulin-resistant diabetic patient.
Comer and Iron
Copper has been shown to be elevated in experimentally diabetic rats, especially in
the kidney cortex (234,235). Kidney copper was 3-fold higher than normal at 2 weeks, and
7-fold higher at 4 weeks, following STZ injection (234). As copper is an enhancer of lipid
peroxidation and oxidative damage, this increase in copper concentration could exacerbate
oxidative stress in diabetes and the increased renal copper content may contribute to diabetic
nephropathy (12). Accumulation of copper in diabetic rats has been shown to be
independent of food intake (106) but may be due to enhanced intestinal absorption of copper
ions (124). In this regard, it is noteworthy that serum levels of copper were elevated in
diabetes mellitus and were highest in individuals with angiopathy and/or alterations in lipid
metabolism (113,236). Increases in serum copper (especially in combination with low Se
levels) have been shown to be associated with common carotid intimal media thickening
(237). In the presence of copper, glucose has been shown to promote the oxidation of
plasma low density lipoproteins, thereby markedly increasing their atherogenicity (79). Both
serum copper and the copper protein, ceruloplasmin, were elevated in type II diabetic
patients (113) compared to non-diabetic controls.
On the other hand, copper deficiency can also be atherogenic due to increased
oxidative stress (238). Nonenzymatic glycation has been implicated as the mechanism of
cellular damage in copper deficiency (239). Copper deficiency, but not zinc deficiency,
results in lowered activity of CuZnSOD (189,240). In order to maintain normal activities of
CuZnSOD under conditions of increased oxidative stress, such as inflammation, higher than
usual dietary intakes of copper were required in rats (241). In copper deficiency, a decline
in CuZnSOD activity was accompanied by increased lipid peroxidation in aortic and liver
tissues and erythrocytes of rats (242,243). Two selenium-dependent enzymes, type I S-
deiodinase and GSHPx in rat liver, were also found recently to be negatively affected by
dietary copper deficiency (244).
Iron status is little affected by diabetes per se; however, because of its role as a
catalyst in free radical generation, and the give state of increased oxidant stress in diabetes,
it is probably advisable for diabetic individuals to avoid excess iron. Idiopathic iron overload
may result in diabetic-like symptoms, and can be treated successfully with iron chelation
(245). In transfusion siderosis and idiopathic hemochromatosis, diseases in which
decompartmentalized iron is present in significant quantities, diabetes-like glucose
intolerance and subsequent development of microvascular complications are common (246).
Treatment of high-ferritin diabetes with desferrioxamine, an iron chelator, results in a
reduction in hyperglycemia and lipid abnormalities (247). Presence of free iron under
pathological conditions has been inferred on the basis of studies showing that deferoxamine,
a potent iron chelator, prevented endothelial injury mediated by oxidized LDL (248)
neutrophils (249) or xanthine-oxidase induced free radical generation (250).
Unlike zinc, chromium or copper, iron deficiency does not seem to be associated with
abnormalities of glucose metabolism (13). STZ-induced diabetes results in elevated hepatic
and kidney iron stores, but lower serum iron levels (13,104,106).
Vanadium
As a micronutrient, vanadium may be of little interest in the progression of diabetes,
since normal intakes are clearly well above marginal (251). However, the pharmacological
potential of this ultratrace element to improve glucose tolerance and alleviate insulin
insensitivity is attracting increasing attention (252-254). Both in vitro and in vivo studies have
demonstrated the insulin-mimetic properties of inorganic and organic forms of oxovanadium
compounds (252,255-258). Recent studies suggest a post-receptor mechanism for the in
vivo action of vanadate compounds (259) administered at low doses. At higher doses,
interpretation of results may be complicated by a somewhat variable response and possible
toxic effects (256,257,260). In rat studies, investigators have noted both pro-and anti-oxidant
effects of oxovanadium compounds (257,260). Cataract development, which is at least partly
an oxidative process, was prevented in STZ-rats by vanadium treatment (257,261). Sorbitol
accumulation also was significantly decreased (262). The presence or availability of reduced
glutathione may affect the redox potential of pharmacological doses of vanadium (32,263).
Supplementation with additional antioxidant, such as vitamin E, may also preclude any pro-
oxidant effects of vanadium (261,264).
Molybdenum and tungsten have been shown to have insulin-mimetic properties in rat
adipocyte suspensions in vitro (265). Improved glucose uptake was reminiscent of that seen
with vanadate (265). A recent in vivo trial of tungstate, administered at pharmacological
doses, has demonstrated a hypoglycemic action (probably non-specific) in rats (266). A
combination of lithium and vanadate effectively normalized decreased activities of GSHPx
and CAT, but not total SOD, and normalized hyperglycemia in diabetic rat liver (267). The
two ultratrace elements seemed to act synergistically, leading to a reduction in the effective
dosage of vanadium (267). The potential for amelioration of the oxidative stress of diabetes
by judicious combinations of ultratrace elements administered orally clearly deserves further
experimental evaluation.
CONCLUSIONS
Much progress has been made over the last few years in achieving a better
understanding of the onset and progress of diabetic complications. Several previously
disparate hypotheses of protein glycation, polyol pathway abnormalities, and
hyperinsulinema are increasingly being seen as part of interrelated biochemical processes.
That these processes are susceptible to dietary modulation is increasingly clear; however,
we are still a long way from being able to advise specific micronutrient supplementation for
optimal health in specific disorders, including diabetes (268,269). The overall impression
from studies to date is that diabetic individuals, both types I and II, may have somewhat
different nutrient requirements from the general population (270, 271). The fact of multiple
interactions and the dose-dependent pro- and anti-oxidant activities of many of the
micronutrients (272) require that we proceed with caution and avoid making any premature
recommendations. Future studies which more closely define status and requirements of both
metals and vitamins may enable such recommendations to be put forward on a more sound
scientific basis (273).
REFERENCES
1. Zimmet P. Epidemiology of diabetes. In: Diabetes Mellitus, Theory and Practice. Ellenberg
M, Rifkin H, eds.Medical Examinations Publications:New Hyde Park 1983: 451-92.
2. Entmacher PS. Long-term prognosis in diabetes mellitus. In: Sussman KE, Metz RJS, eds.
Diabetes Mellitus. New York: American Diabetes Association, 1975; 191-6.
3. U.S. Department of Health and Human Services. Diabetes. In: The Surgeon Generals
Report on Nutrition and Health. DHHS (PHS) publication No.88-50210. 1988: 249-73.
4. Baynes J. Role of oxidative stress in development of complications in diabetes. Diabetes
1991; 40: 405-12.
5. Chow CK. Interrelationships in cellular antioxidant defense systems. In: Cellular and
Antioxidant Defense Mechanisms, Vol II. Chow CK, ed. CRC Press, Boca Raton,FL 1988:
217-37.
6. Wolff SP. The potential role of oxidative stress in the diabetic complications: novel
implications for theory and therapy. In: Diabetic Complications, Scientific and Clinical
Aspects. Crabbe, MJC, ed. Churchill Livingstone:Edinburgh 1987: 167-220.
7. Arky RA. Prevention and therapy of diabetes mellitus. Nutr Rev 1983; 41: 165-73.
8. Eisenbarth GS Type I diabetes mellitus: a chronic autoimmune disease. N Engl J Med
1988; 314: 1360-8.
1392 K.H. THOMPSON and D.V. GODIN
9. Decker-t T, Poulsen JE, Larsen M. Prognosis of diabetics with diabetes onset before the
age of thirty-one. Diabetol 1978; 14: 363-70.
10. Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded
definition. Ann Rev Med 1993; 44: 121-31.
11. Failla ML. Trace element metabolism in the chemically diabetic rat. Biol Trace Elem Res
1983; 5: 275-84.
12. Mooradian AD, Morley JE. Micronutrient status in diabetes mellitus. Am J Clin Nutr 1987;
45: 877-95.
13. Strain JJ. Disturbances of micronutrient and antioxidant status in diabetes. Proc Nutr Sot
1991; 50: 591604.
14. Bhanot S, Thompson KH, McNeil1 JH. Essential trace elements of potential importance
in nutritional management of diabetes mellitus. Nutr Res 1994; 14: 593-604.
15. Brownlee M. Glycation products and the pathogenesis of diabetic complications. Diab
Care 1992; 15: 1835-43.
16. Brownlee M, Cerami A. The biochemistry of the complications of diabetes mellitus. Ann
Rev Biochem 1981; 50: 385-432.
17. Wolff SP, Jiang ZY, Hunt JV. Protein glycation and oxidative stress in diabetes mellitus
and ageing. Free Rad Biol Med 1991; IO: 339-52.
18. Monnier VM, Kohn RR, Cerami A. Accelerated age-related browning of human collagen
in diabetes mellitus. Proc Nat1 Acad Sci USA 1984; 81: 583-7.
19. Godin DV, Wohaieb SA. Reactive oxygen radical processes in diabetes. In: Free
Radicals in the Pathophysiology of Heart Disease. Singal PK, ed. Boston: Martinus Nijhoff
Publishing, 1987: 303-22.
20. Halliwell B. Reactive oxygen species in living systems: source, biochemistry, and role in
human disease. Am J Med 1991; 91 (Suppl C): 14S-22s.
21. Godin DV, Wohaieb SA. Nutritional deficiency, starvation, and tissue antioxidant status,
Free Rad Biol & Med 1988; 5:165-176.
22. Chow CK. Nutritional influence on cellular antioxidant defense systems. Am J Clin Nutr
1979; 32: 1066-81.
23. Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in human
disease. Methods Enzymol 1990; 186: l-85.
24. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol
Rev 1979; 59: 527-605.
25. Boveris A, Chance B. The mitochondrial generation of hydrogen peroxide: general
properties and effect of hyperbaric oxygen, Biochem J 1973; 134: 707-l 6.
26. Srivastava SK, Ansari NH, Liu S, lzban A, Das B, Szabor G, Bhatnagar A. The effects of
oxidants on biomembranes and cellular metabolism. Mol Cell Biochem 1989; 91: 149-57.
27. Loven DP, Oberley LW. Free radicals, insulin action, and diabetes. In: Superoxide
dismutases.Vol. II. Pathological States. Oberley, LW, ed. CRC Press, Inc: Boca Raton, FL;
1982: 151-189.
28. Fridovich I. Superoxide dismutases. Ann Rev Biochem 1975; 44: 147-59.
29. Halliwell, B. Free radicals and antioxidants: a personal view. Nutr Rev 1994; 52: 253-65.
30. Stocker R, Frei B. Endogenous antioxidant defenses in human blood plasma. In:
Oxidative Stress: Oxidants and Antioxidants. Sies H, ed. Academic Press: London 1991: 213-
30.
31. Meister A, Anderson ME. Glutathione. Ann Rev Biochem 1983; 52: 71 l-60.
32. Younes M, Siegers C-P. Lipid peroxidation as a consequence of glutathione depletion in
rat and mouse liver. Res Comm Chem Pathol & Pharmacol 1980: 27: 119-28.
33. Karpen CW, Cataland S, ODorisio TM, Panganamala R. Intervention of platelet vitamin
E and thromboxane synthesis in type 1 diabetes mellitus. Diabetes 1984; 33: 239-43.
34. Nelson RL. Dietary iron and colorectal cancer risk. Free Rad Biol and Med 1992; 12: 161-
8.
35. Hunt JV, Bottoms MA, Mitchinson MJ. Ascorbic acid oxidation: a potential cause of
elevated severity of atherosclerosis in diabetes mellitus. FEBS lett 1992; 311: 161-4.
36. Bell RH, Hye RJ. Animal models of diabetes mellitus: physiology and pathology, J Surg
Res 1983; 35: 433-60.
37. Oberley LW. Free radicals and diabetes. Free Rad Biol Med 1988; 5: 113-24.
38. Rabinovitch A. Free radicals as mediators of pancreatic islet P-cell injury in autoimmune
diabetes. J Lab Clin Med 1992; 119: 455-6.
39. Heineke EW, Johnson MB, Dillberger JE, Robinson KM. Antioxidant MDL 29,311
prevents diabetes in nonobese diabetic and multiple low-dose STZ-injected mice. Diabetes
1993; 42: 1721-30.
40. Robbins MJ, Sharp RA, Slonim AE, Burr IM. Protection against streptozotocin-induced
diabetes by superoxide dismutase. Diabetol 1980; 18: 55-8.
41. Gandy SE, Buse MG, Crouch RK. Protective role of superoxide dismutase against
diabetogenic drugs. J Clin Invest 1982; 70: 650-8.
42. Slonim AE, Surber ML, Page DL, Sharp RA, Burr IM. Modification of chemically induced
diabetes in rats by vitamin E. J Clin Invest 1983; 71: 1282-8.
43. Brenner HH, Burkart V, Rothe H, Kolb H. Oxygen radical production is increased in
macrophages from diabetes prone BB rats. Autoimmunity 1993; 15: 93-8.
44. Nakakimura H, Mizuno K. Studies on lipid peroxidation in biological systems. II.
Hyperlipoproteinemia in mice induced by alloxan. Chem Pharma Bull 1980; 28: 2207-I 1.
45. Jain SK, Levine SN, Duett J, Hollier B. Reduced vitamin E and increased lipofuscin
products in erythrocytes of diabetic rats. Diabetes 1991; 40: 1241-4.
46. Armstrong D, Al-Awadi F. Lipid peroxidation and retinopathy in streptozotocin-induced
diabetes. Free Rad Biol Med 1991; 11: 433-6.
47. Rungby J, Flyvberg A, Andersen HB, Nyborg K. Lipid peroxidation in early experimental
diabetes in rats: effects of diabetes and insulin. Acta Endocrinol 1992; 126: 378-80.
48. llling EK, Gray CH, Lawrence RD. Blood glutathione and non-glucose substances in
diabetes. Biochem J 1951; 48: 637-40.
49. Sato Y, Hotta N, Sakamoto N, Matsuaka S, Ohishi N, Yagi K. Lipid peroxide level in
plasma of diabetic patients. Biochem Med 1979; 21: 104-7.
50. Nishigaki I, Hagihara H, Trunekawa H, Maseki N, Yagi K. Lipid peroxide levels of serum
lipoprotein fractions of diabetic patients, Biochem Med 1978; 25: 373-6.
51. Bono A, Caimi G, Catania A, Sarno A, Pandolfo L. Red cell peroxide metabolism in
diabetes mellitus. Horm Metabol Res 1987; 19: 264-6.
52. Jennings PE, Jones AF, Florkowski CM, Lunec J, Barnett AH. Increased diene conjugates
in diabetic subjects with microangiopathy. Diabetic Med 1987; 4: 452-6.
53. Uzel N, Sivas A, Uysal M, Oz H. Erythrocyte lipid peroxidation and glutathione peroxidase
activities in patients with diabetes mellitus. Horm Metab Res 1987; 19: 89-90.
54. Mazzanti L, Faloia E, Robini RA, Staffolani R, Kantar A, Fiorini R, Swoboda B, De Pirro
R, Bertoli E. Diabetes mellitus induces red blood cell plasma membrane alterations possibly
affecting the aging process. Clin Biochem 1992; 25: 41-6.
55. Nath N, Chari SN, Rathi AB. Superoxide dismutase in diabetic polymorphonuclear
leukocytes. Diabetes 1984; 33: 586-9.
56. Loven D, Oberley L, Schedl H, Wilson H. Superoxide dismutase activities in jejunum and
kidney of diabetic rats treated with insulin and glutathione. In: Oxy Radicals and Their
1395
Scavenger Systems. Vol. II: Cellular and Molecular Aspects, Greenwald RA, Cohen G, eds.
Elsevier Science Publishing, Amsterdam: 1983: 17-21,
57. Hunt JV, Jiang ZY, Wolff SP. Formation of hydrogen peroxide by lens proteins: protein-
derived hydrogen peroxide as a potential mechanism of oxidative insult to the lens. Free Rad
Biol Med 1992; 13: 319-23.
58. Nakayama H, Mitsuhashi T, Kuwajima S, Aoke S, Kuroda Y, ltoh T, Nakagawa S.
lmmunochemical detection of advanced glycation end products in lens crystallins from
streptozocin-induced diabetic rat. Diabetes 1993; 42: 34550.
59. Morel DW, Chisolm GM. Antioxidant treatment of diabetic rats inhibits lipoprotein
oxidation and cytotoxicity. J Lipid Res 1989; 30: 1827-34.
60. Chittar HS, Nihalani KD, Varthakavi PK, Udipi SA. Lipid peroxide levels in diabetics with
micro- and macro-angiopathies. J Nutr Biochem 1994; 5: 442-5.
61. Wohaieb SA, Godin DV. Alterations in free radical tissue-defence mechanisms in
streptozotocin-induced diabetes in rat. Effects of insulin treatment. Diabetes 1987; 36: 1014-
18.
62. Wohaieb SA, Godin DV. Alterations in tissue antioxidant systems in the spontaneously
diabetic (BB Wistar) rat. Can J Physiol Pharmacol 1987; 65: 2191-5.
63. Jain SK, Levine SN, Duett J, Hollier B. Elevated lipid peroxidation levels in red blood cells
of streptozotocin-treated diabetic rats. Metabolism 1990; 39: 971-5.
64. Godin DV, Wohaieb SA, Garnett ME, Goumeniouk AD. Antioxidant enzyme alterations
in experimental and clinical diabetes. Mol Cell Biochem 1988; 84: 223-31.
65. Rabini RA, Fumelli P, Galassi R, Dousset N, Taus M, Ferretti G, Mazzanti L, Curatola G,
Solera ML, Valdiguie P. Increased susceptibility to lipid oxidation of low-density lipoproteins
and erythrocyte membranes from diabetic patients. Metabolism 1994; 43: 1470-4.
66. Long WK, Carsen PE. Increased erythrocyte glutathione reductase activity in diabetes
mellitus. Biochem Biophys Res Commun 1961; 5: 394-9.
67. Matkovics B, Varga Sz.1, Szabo L, Witas H. The effect of diabetes on the activities of the
peroxide metabolism enzymes. Horm Metab Res 1982; 14: 77-9.
68. Kaji H, Kurasaki M, Ito K, Saito T, Saito K, Niioka T, Kojima Y, Ohsaki Y, Ide H, Tsuji M.
Increased lipoperoxide value and glutathione peroxidase activity in blood plasma of type 2
(non-insulin-dependent) diabetic women. Klin Wochenschr 1985; 63: 765-8.
69. Hagglof B, Marklund SL, Holmgren G. CuZn superoxide dismutase, Mn superoxide
dismutase and glutathione peroxidase in lymphocytes and erythrocytes in insulin-dependent
diabetic children. Acta Endocrinol 1983; 102: 235-9.
70. Tagami S, Kondo T, Yoshida K, Hirokawa J, Ohtsuka Y, Kawakami Y. Effect of insulin on
impaired antioxidant activities in aortic endothelial cells from diabetic rabbits. Metab 1992;
41: 1053-8.
71. Thompson KH, Godin DV, Lee M. Tissue antioxidant status in streptozotocin-induced
diabetes in rats. Effects of dietary manganese deficiency. Biol Trace Elem Res 1992; 35:
213-24.
72. Saxena AK, Srivastava P, Kale RK, Baquer NZ. Impaired antioxidant status in diabetic
rat liver. Effect of vanadate. Biochem Pharmacol 1993; 45: 539-42.
73. Strange RC, Jones P, Bicknell J, Scarpello J. Expression of CuZn-superoxide dismutase
and glutathione peroxidase in erythrocytes from diabetic and nondiabetic subjects. Clin Chim
Acta 1992; 207: 261-3.
74. Grankvist K, Marklund SL, Taljedal IB. CuZn-superoxide dismutase, Mn-superoxide
dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the
mouse. Biochem J 1981; 199: 393-8.
75. Wohaieb SA, Godin DV. Starvation-related alterations in free radical tissue defense
mechanisms in rats. Diabetes 1987; 36: 169-73.
76. LAbbe MR, Trick DT. Changes in pancreatic glutathione peroxidase and superoxide
dismutase activities in the prediabetic diabetes-prone BB rat. Proc Sot Exp Biol & Med 1994;
207: 206-212.
77. Pisanti FA, Frascatore S, Papaccio G. Superoxide dismutase activity in the BB rat: a
dynamic time-course study. Life Sci 1988; 43: 1625-32.
78. Stadtman ER, Oliver CN. Metal-catayzed oxidation of proteins. Physiological
consequences. J Biol Chem 1991; 266: 2005-8.
79. Hunt JV, Smith CCT, Wolff SP. Autooxidative glycosylation and possible involvement of
peroxides and free radicals in LDL modification by glucose. Diabetes 1990; 39: 14204.
80. Kawamura N, Ookawara T, Suzuki K, Konishi K, Mino M, Taniguchi N. Increased glycated
Cu,Zn-superoxide dismutase levels in erythrocytes of patients with insulin-dependent
diabetes mellitus. J Clin Endocrinol Metab 1992; 74: 1352-4.
81. Oda A, Bannai C, Yamaoka T, Katori T, Matsuchima T, Yamashita K. lnactvation of
Cu,Zn-superoxide dismutase by in vitro glycosylation and in erythrocytes of diabetic patients.
Horm Metab Res 1994; 26: 14.
82. Tesfamariam B, Cohen RA. Free radicals mediate endothelial cell dysfunction caused by
elevated glucose. Am J Physiol (Heart Circ Phsyiol 32) 1992: 263: H321-6.
83. Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Rad Biol Med
1994; 16: 383-91.
84. Thornalley PJ. Monosaccharide autoxidation in health and disease. Environ Health
Perspect 1985; 64: 297-307.
85. Biemond P, Van Eijk HG, Swaak AJG, Koster JF. Iron mobilization from ferritin by
superoxide derived from stimulated polymorphonuclear leukocytes. Posible mechanism in
inflammation diseases. J Clin Invest 1984; 73: 1576-9.
86. Bolann BJ, Ulvik RJ. On the limited ability of superoxide to release iron from ferritin. Eur
J Biochem 1990; 193: 899-904.
87. Ceriello A, Guigliano D, Qatraro A, Donzella C, Dipalo G, Lefebvre PJ. Vitamin E
reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic
complications? Diab Care 1991; 14: 68-72.
88. Merryfield MI, Lardy HA. Ca* mediated activation of phosphoenolpyruvate carboxykinase
occurs via release of Fe* from rat liver mitochondria. J Biol Chem 1982; 257: 3628-35.
89. Gutteridge JMC. Iron promoters of the Fenton reaction and lipid peroxidation can be
released from haemoglobin by peroxides. FEBS Lett 1986; 201: 291-5.
90. Puppo A, Halliwell B. Formation of hydroxyl radicals in biological systems. Does
myoglobin stimulate hydroxyl radical production from hydrogen peroxide? Free Rad Res
Commun 1988; 4: 41522.
91. Jiang Z-Y, Woollard ACS, Wolff SP. Hydrogen peroxide production during experimental
protein glycation. FEBS Lett 1990; 268: 69-71.
92. May JM, DeHaen C. Insulin-stimulated intracellular hydrogen peroxide production in rat
epidydymal fat cell. J Biol Chem 1979; 254:2214-6.
93. Kinoshita JH, Fukoshi S, Kador P, Merola LO. Aldose reductase in diabetic complications
of the eye. Metab 1979; 28: 462-8.
94. Kehrer JP, Lund LG. Cellular reducing equivalents and oxidative stress. Free Rad Biol
Med 1994: 17: 65-75.
95. Henning B, Toborek M, Cader AA, Decker EA. Nutrition, endothelial cell metabolism, and
atherosclerosis. Crit Rev Food Sci & Nutr 1994: 34: 253-82.
96. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of
4400 patients observed between 1947 and 1973. Diabetes Care 1987; 1: 168-263.
97. Raskin P, Rosenstock J. Blood glucose control and diabetic complications. Ann Intern
Med 1986; 105: 254-63.
98. Diabetes Control and Complications Trial Research Group. The effect of intensive
treatment of diabetes on the development and progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977-86.
99. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose
control on late complications of type I diabetes. Lancet 1993; 341: 1306-g.
100. Pell S, DAlonzo C. Factors associated with long-term survival of diabetics. J Am Diab
Assoc 197 I; 214: 1833-40.
101. Reichard P, Nilsson B-Y, Rosenqvist U. The effect of long-term intensified insulin
treatment on the development of microvascular complications of diabetes mellitus. N Engl J
Med 1993; 329: 304-9.
102. Pidduck HG, Wien PJJ, Evans DAP. Plasma zinc and copper in diabetes mellitus.
Diabetes 1970; 19: 234-9.
103. Bond JS, Failla ML, Unger DF. Elevated manganese concentration and arginase activity
in livers of streptozotocin induced diabetic rats. J Biol Chem 1983; 258: 8004-09.
104. Johnson WT, Evans GW. Effects of the inter-relationship between dietary proteins and
minerals on tissue content of trace minerals in streptozotocin diabetic rats. J Nutr 1984;
114: 180-90.
105. Raz I, Adler JH, Havivi E. Altered tissue content of trace metals in diabetic
hyperinsulinaemic sand rats (psammomys obesus). Diabetologia 1988; 31: 329-33.
106. Failla ML, Kiser RA. Altered tissue content and cytosol distribution of trace metals in
experimental diabetes. J Nutr 1981; 111: 1900-9.
107. Nakagawa M, Kobayashi S, Kimura I, Kimura M. Diabetic state-induced modification of
Ca, Mg, Fe and Zn content of skeletal; cardiac and smooth muscles. Endocrinol Japon 1989;
36: 795807.
108. Thompson KH, Lee M. Effects of manganese and vitamin E deficiencies on antioxidant
enzymes in streptozotocin-diabetic rats. J Nutr Biochem 1993; 4: 47681.
109. Kanabrocki EL, Case LF, Graham L, Fields T, Miller EB, Oester VT, Kaplan E. Non
dialyzable manganese and copper levels in serum of patients with various diseases. J Nucl
Med 1967; 8: 166-72.
110. Kosenko LG. Concentration of trace elements in blood of patients with diabetes mellitus.
Fed Proc 24 (Suppl.). 1965: 237-8.
11 I. Kulerich S. Trace elements in health and disease. Bostrom and Ljungstedt, eds. 1984;
96-l 03.
112. Kumar S, Jaya RKS. Blood and urinary zinc levels in diabetes mellitus. Nutr Metab
1974; 17: 231-5.
113. Mateo MCM, Bustamante JB, Cantalapiedra MAG. Serum zinc, copper and insulin in
diabetes mellitus. Biomed 1978: 29: 56-8.
114. Chooi MK, Todd JK, Boyd ND. Influence of age and sex on plasma zinc levels in normal
and diabetic individuals Nutr Metab 1976; 20: 135-42.
115. Khandelwal PD, Bhu N. A study of serum Zn in uncontrolled diabetics. J Assoc Phys
India 1981; 29: 715-9.
116. Hagglof B, Hallmans G, Holmgren G, Ludvigsson J, Falkmer S. Prospective and
retrospective studies of zinc concentrations in serum, blood clots, hair and urine in young
patients with insulin dependent diabetes mellitus. Acta Endocrinol (Copen) 1983; 102: 88-95.
117. Kinlaw WB, Levine AS, Morley JE, Silvius SE, McClain CJ. Abnormal zinc metabolism
in type II diabetes mellitus. Am J Med 1983; 75: 273-7.
118. Canfield WK, Hambidge KM, Johnson LK. Zinc nutriture in type I diabetes mellitus:
relationship to growth measures and metabolic control. J Ped Gastroenter Nutr 1984; 3: 577-
84.
119. Sjdgren A, Edvinsson L, Floren C-H, Abdulla M. Zinc and copper in striated muscle and
body fluids from subjects with diabetes mellitus type I. Nutr Res 1986; 6: 147-54.
120. Sjogren A, Floren CH, Nilsson A. Magnesium, potassium and zinc deficiency in subjects
with type II diabetes mellitus. Acta Med Stand 1988; 224: 461-5.
121. Car N, Car A, Granik M, Skrabalo Z, MomEiliovid B. Zinc and copper in the serum of
diabetic patients. Biol Trace Elem Res 1992; 32: 325-9
122. Honnorat J, Accominotti M, Brousolle C, Fleuret A-C, Vallon J-J, Orgiazzi J. Effects of
diabetes type and treatment on zinc status in diabetes mellitus. Biol Trace Elem Res 1992,
32: 31 l-23.
123. Cunningham JJ, Fu A, Mearkle MS, Brown RG. Hyperzincuria in individuals with insulin-
dependent diabetes mellitus: concurrent zinc status and the effect of high-dose zinc
supplementation. Metabolism 1994; 43: 1558-62.
124. Craft NE, Failla ML. Zinc, iron and copper absorption in the streptozotocin diabetic rat.
Am J Physiol 1983; 244: E122-28.
125. Levine AS, McClain CJ, Handwerger BS, Brown DM, Morley JE. Tissue zinc status of
genetically diabetic and streptozotocin-induced diabetic mice. Am J Clin Nutr 1983; 37: 382-
6.
126. Lau AL, Failla ML. Urinary excretion of zinc, copper and iron in the streptozotocin
diabetic rat. J Nutr 1984; 114:224-33.
127. Cordova A. Zinc content in selected tissues in streptozotocin-diabetic rats after maximal
exercise. Biol Trace Elem Res 1994; 42: 209-16.
128. Golik A, Cohen N, Ramot Y, Maor J, Moses R, Weissgarten J, Leonov Y, Modai D, Type
II diabetes mellitus, congestive heart failure and zinc metabolism. Biol Trace Elem Res 1993;
39: 171-5.
129. Brun J-F, Fons C, Fussellier M, Bardet L, Orsetti A. Urinary zinc and its relationships
with microalbuminuria in type I diabetics. Biol Trace Elem Res 1992; 32: 317-23.
130. Coulston L, Dandona P. Insulin like effects of zinc on adipocytes. Diabetes 1980; 29:
665-7.
131. Ezaki 0. IIB group metal ions (Zn*, Cd*, Hg) stimulate glucose transport activity by
post-insulin receptor kinase mechanism in rat adipocytes. J Biol Chem 1989; 264: 16118-22.
132. Huber AM, Gershoff SN. Effect of zinc deficiency in rats on insulin release from the
pancreas. J. Nutr. 1973; 103:1739-44.
133. Quarterman J, Mills CF, Humphries WR. The reduced secretion of and sensitivity to
insulin in zinc deficient rats. Biochem Biophys Res 1966; 25: 356-8.
134. Quarterman J, Florence E. Observations on glucose tolerance and plasma levels of free
fatty acids and insulin in the zinc deficient rat. Br J Nutr 1972; 28: 75-9.
135. Brown ED, Penhos JC, Recant L, Smith, JC, Jr. Glucose tolerance, plasma and
pancreatic insulin levels in zinc deficient rats. Proc Sot Exp Biol Med 1975; 150: 55760.
136. Arquilla ER, Packer S, Tarmas W, Miyamoto S. The effect of zinc on insulin metabolism.
Endocrinology 1978; 103: 1440-99.
137. Bray TM, Bettger WJ. The physiological role of zinc as an antioxidant, Free Rad Biol
Med 1990; 8: 281-97.
138. Bettger WJ. Zinc and selenium, site-specific versus general oxidation. Can J Physiol
Pharmacoll993; 71: 721-4.
139. Uriu-Hare JY, Stern JS, Keen CL. Influence of maternal dietary Zn intake on expression
of diabetes-induced teratogenicity in rats. Diabetes 1989; 38: 1282-90.
140. May JM, Contoreggi CS. The mechanism of the insulin-like effects of ionic Znt2. J Biol
Chem 1982; 257: 4362-8.
141. Shisheva A, Gefel D, Shechter Y. Insulinlike effects of zinc ion in vitro and in vivo.
Preferential effects on desensitized adipocytes and induction of normoglycemia in
streptozocin-induced rats. Diabetes 1992; 41: 982-8.
142. Etzel KR, Cousins RJ. Hyperglycemic action of zinc in rats. J Nutr 1983; 113: 1657-63.
143. Coudray C, Rachidi S, Favier A. Effect of zinc on superoxidedependent hydroxyl radical
production in vitro. Biol Trace Elem Res 1993; 38: 273-87.
1401
144. Cook-Mills JM, Fraker PJ. The role of metals in the production of toxic oxygen
metabolites by mononuclear phagocytes. In: Nutrient Modulation of the Immune Response,
Cunningham-Rundles S, ed., Marcel Dekker, Inc.: New York; 1993: 127-40.
145. Rossetti L, Giaccari A, Robbenhaar EK, Vogel LR. lnsulinomimetic properties of trace
elements and characterisation of their in viva mode of action. Diabetes 1990; 39: 1243-50.
146. Niewoehner CB, Allen JI, Boosalis M, Levine AS, Morley JE. The role of zinc
supplementation in type II diabetes mellitus. Am J Med 1986; 81: 63-8.
147. Tze WJ, Thompson KH, Leichter J. HbAlc - an indicator of diabetic control. J Pediatrics
1978; 93: 13-16.
148. Yew MS. Effect of streptozotocin diabetes on tissue ascorbic acid and dehydroascorbic
acid. Horm Metab Res 1983; 15: 158-63.
149. Schlosser MJ, Kapeghian JC, Verlangieri AJ. Selected physical and biochemical
parameters in the streptozotocin-treated guinea pig: insights into the diabetic guinea pig
model. Life Sci 1987; 41: 134553.
150. Selvam R, Anuradha CV. Effect of oral methionine on blood lipid peroxidation and
antioxidants in alloxan-induced diabetic rats. J Nutr Biochem 1990; 1: 653-8.
151, Som S, Basu S, Mukherjee D, Deb S, Choudhury PR, Mukherjee S, Chatterjee SN,
Chatterjee IB. Ascorbic acid metabolism in diabetes mellitus. Metabolism 1981; 30: 572-7.
152. Stankova L, Riddle M, Larned J, Burry K, Menashe D, Hart J, Bigley R. Plasma
ascorbate concentrations and blood cell dehydroascorbate transport in patients with diabetes
mellitus. Metabolism 1984; 33: 347-53.
153. Pecoraro RE, Chen MS. Ascorbic acid metabolism in diabetes. Ann NY Acad Sci 1989;
86: 248-58.
154. McLennan S, Yue DK, Fisher E, Capogreco C, Heffernan S, Ross GR, Turtle JR.
Deficiency of ascorbic acid in experimental diabetes. Relationship with collagen and polyol
pathway abnormalities. Diabetes 1988; 37: 359-61.
155. Cunningham JJ, Ellis SL, McVeigh KL, Levine RE, Calles-Escandon J. Reduced
mononuclear ascorbic acid content in adults with insulin-dependent diabetes mellitus
consuming adequate dietary vitamin C. Metabolism 1991; 40: 146-9.
156. Asayama K, Uchida N, Nakane T, Hayashibe H, Dobashi K, Amemiya S, Kiyohiko K,
Nakazawa S Antioxidants in the serum of children with insulin-dependent diabetes mellitus.
Free Rad Biol and Med 1993; 15. 597-602.
157. Seghieri G, Maninoli L, Micelli M, Ciuti M, DAlessandri G, Gironi A, Palmieri L, Anichini
R, Bartolomei G, Franconi F. Renal excretion of ascorbic acid in insulin dependent diabetes
mellitus. Int J Vit Nutr Res 1993; 64: 119-24.
158. Lysy J, Zimmerman J. Ascorbic acid status in diabetes mellitus. Nutr Res 1992; 12: 713-
20.
159. Frei 8, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood
plasma. Proc Nat1 Acad Sci USE 1989; 86: 6377-81.
160. Yue DK, McLennan S, McGill M, Fisher E, Hefferman S, Capogreco C, Turtle JR.
Abnormalities of ascorbic acid metabolism and diabetic control: differences between diabetic
patients and diabetic rats. Diab Res and Clin Practice 1990; 9: 23944.
161. Sinclair AJ, Girling AJ, Gray L, Le Guen C, Lunec J, Barnett AH. Disturbed handling of
ascorbic acid in diabetic patients with and without microangiopathy during high dose
ascorbate supplementation. Diabetol 1991; 34: 171-5.
162. Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med
1986; 314: 892-902.
163. Vinson JA, Staretz ME, Bose P, Kassm HM, Basalyga BS. In vitro and in vivo reduction
of erythrocyte sorbitol by ascorbic acid. Diabetes 1989; 38: 1036-41.
164. Linklater HA, Dzialoszynski T, McLeod HL, Sanford SE, Trevithick JR. Modelling
cortical cataractorgenesis. Xl. Vitamin Creduces Y-crystalline linkage from lenses in diabetic
rats. Exp Eye Res 1990; 51: 241-7.
165. Davie SJ, Gould BJ, Yudkin JS. Effect of vitamin C on glycosylation of proteins.
Diabetes 1992: 41: 167-73.
166. Svoboda P, Stolba P, Hegenbartova M, StraSkovl J, Adam M. The mechanism of
lowering of nonenzymatic glycation by vitamin C. Diabetolog 1992; 35(Suppl 1): A55.
167. Young IS, Torney JJ, Trimble ER. The effect of ascorbate supplementation on oxidative
stress in the streptozotocin diabetic rat. Free Rad Biol Med 1992; 13 :41-6.
168. Bates CJ, Cowan TD, Evans PH. Effect of vitamin C on sorbitol in the lens of guinea-
pigs made diabetic with streptozotocin. Br J Nutr 1992; 67: 445-6.
169. Chen LH. An increase in vitamin E requirement induced by high supplementation of
vitamin C in rats. Am J Clin Nutr 1981; 34: 1036-41.
170. Pritchard, Jr. KA, Pate1 ST, Karpen CW, Newman HAI, Panganamala RV. Triglyceride-
lowering effects of dietary vitamin E in streptozotocin-induced diabetic rats. Increased
lipoprotein lipase activity in livers of diabetic rats fed high dietary vitamin E. Diabetes 1986;
35: 278-81.
171. Behrens WA, Scott FW, Madere R. Increased plasma and tissue levels of vitamin E in
the spontaneously diabetic rat. Life Sci 1984; 35: 199-206.
172. Vatassery GT, Morley JE, Kuskowski MA. Vitamin E in plasma and platelets of human
dia!)etic patients and control subjects. Am J Clin Nutr 1983; 37: 641-4.
1403
173. Krempf M, Ranganathan S, Ritz P, Morin M, Charbonnel B. Plasma vitamin A and E in
Type 1 (insulin-dependent) and Type 2 (insulin-independent) adult diabetic patients, lnternat
J Vit Nutr Res 1991; 61: 38-42.
174. Karpen CW, Pritchard, Jr. KA, Cornwell DG, Panganamala RV. Restoration of
prostacyclin/thromboxane A, balance in the diabetic rat. Influence of dietary vitamin E.
Diabetes 1982; 31: 947-51.
175. Niki E. Interaction of ascorbate and a-tocopherol. Ann NY Acad Sci 1987; 498: 186-99.
176. Asayama K, Kooy NW, Burr IM. Effect of vitamin E deficiency and selenium deficiency
on insulin secretory reserve and free radical scavenging systems in islets: decrease of islet
manganosuperoxide dismutase. J Lab Clin Med 1986; 107: 459-64.
177. Liebovitz B, Hu M-L, Tappel AL. Dietary supplements of vitamin E, p-carotene,
coenzyme Q,, and selenium protect tissues against lipid peroxidation in rat tissue slices. J
Nutr 1990; 120: 97-l 04.
178. Vrano S, Hoshi-Hashizume M, Tochigi N, Matsuo M, Shiraki M, Ito H. Vitamin E and the
susceptibility of erythrocytes and reconstituted liposomes to oxidative stress in aged
diabetics. Lipids 1991; 26: 58-61.
179. Blanchard P, Anton B, Larousse C, Auget D, Mainard F, Charbonnel B, Krempf M.
Plasma vitamin E, non-high-density lipoprotein cholesterol, and apolipoprotein B in diabetic
patients. Clin Chem 1992; 38: 2339-40.
180. Ross WM, Creighton MO, Stewart-De Haan PJ, Sanwal M, Hirst M, Trevithick JR.
Modelling cortical cataractogenesis. 3. In vivo effects of vitamin E on cataractogenesis in
diabetic rats. Can J Ophthalmol 1982; 17: 61-6.
181. Ruf JC, Ciavetti M, Gustafsson T, Renaud S. Effects of PP-56 and vitamin E on platelet
hyperaggregability, fatty acid abnormalities, and clinical manifestations in streptozocin-
induced diabetic rats. Diabetes 1991; 40: 233-9.
182. Gisinger C, Jeremy J, Speiser P, Mikhailidis D, Dandona P, Schernthaner G. Effect of
vitamin E supplementation on platelet thromboxane A2 production in type I diabetic patients,
Diabetes 1988; 37: 1260-4.
183. Collette C, Pares-Herbute N, Monnier L, Cartney E. Platelet function in type I diabetes:
Effects of supplementation with large doses of vitamin E. Am J Clin Nutr 1988; 47: 256-61.
184. Paolisso G, DAmore A, Guigliano D, Ceriello A, Varrichio M, DOnofrio F.
Pharmacological doses of vitamin E improve insulin action in healthy subjects and non-insulin
dependent diabetic patients. Am J Clin Nutr 1993; 57: 650-6.
185. Ceriello A, Guigliano D, Qatraro A, Della Russo P, Lefebvre PJ. Metabolic control may
influence the increased superoxide generation in diabetic serum. Diab Med 1991; 8: 540-2.
186. Chan AC. Partners in defense, vitamin E and vitamin C. Can J Physiol Pharmacol 1993;
71: 725-31.
187. Simonarson 8. Glutathione peroxidase, selenium and vitamin E in defense against
reactive oxygen species. In: Reactive Oxygen Species in Chemistry, Biology and Medicine.
Quintanilha A, ed. Plenum Press: New York. 1985: 15-36.
188. But-k RF. Selenium In man. In:Trace Elements In Human Health And Disease. Prasad
AS, ed. New York: Alan Liss, Inc.1980; 105-33.
189. Bettger WJ, Bray TM. Effect of dietary zinc or copper deficiency on catalase, glutathione
peroxidase, and superoxide dismutase activities in rat heart, Nutr Res 1989; 9: 319-26.
190. Sunde RA, Hockstra WG. Structure, synthesis and functions of glutathione peroxidase.
Nutr Rev 1980; 38: 265-73.
191. Xia Y, Hill KE, Burk RF. Effect of selenium deficiency on hydroperoxide-induced
glutathione release from the isolated perfused rat heart. J Nutr 1985; 115: 733-42.
192. Chen X, Yang G, Chen J, Chen X, Wen Z, Ge K. Studies on the relations of selenium
and Keshan disease. Biol Trace Elem Res 1980; 2: 91-107.
193. Dohi T, Kawamura K, Morita K, Okamoto H, Txujimoto A. Alterations in the plasma
selenium concentrations and the activities of tissue peroxide metabolism enzymes in
streptozotocin-induced diabetic rats. Horm Metab Res 1988; 20: 671-5.
194. Gebre-Medhin M, Ewald V, Pantin LO, Tuvemo T. Elevated serum selenium in diabetic
children. Acta Paed Stand 1984; 73: 109-14.
195. Sklodowska M, Gromadzinska J, Wasowicz W. Lipid peroxide concentration, selenium
level and glutathione peroxidase activity in blood of type II (non insulin dependent) diabetic
elderly people. J Clin Biochem Nutr 1989; 7: 35-41.
196. Meydani M, Macauley JB, Blumberg JB. Effect of dietary vitamin E and selenium on
susceptibility of brain regions to lipid peroxidation. Lipids 1988; 23: 405-9.
197. Vatassery GT, Smith WE, Quach HT. Ascorbic acid, glutathione and synthetic
antioxidants prevent the oxidation of vitamin E in platelets. Lipids 1989; 24: 1043-7.
198. Hambidge KM. Chromium nutrition in man. Am J Clin Nutr 1974; 27: 505-14.
199. Mertz W, Roginski EE, Schroeder HA. Some aspects of glucose metabolism of
chromium deficient rats raised in strictly controlled environment. J NUtr 1956; 86: 107-l 2.
200. Jeejeebhoy KN, Chu RC, Marliss EB, Greenberg GR, Bruce-Robertson A. Chromium
deficiency, glucose intolerance , and neuropathy reversed by chromium supplementation in
a patient receiving long-term parenteral nutrition. Am J Clin Nutr 1977; 30: 531-8.
201. Rabinowitz MB, Gonick HC, Levin SR, Davidson MB. Effects of chromium and yeast
supplements on carbohydrate and lipid metabolism in diabetic men. Diabetes Care 1983; 6:
319-27.
202. Clausen J. Chromium induced clinical improvement in symptomatic hypoglycemia. Biol
Trace Elem Res 1988; 17: 229-36.
203. Anderson RA. Recent advances in the clinical and biochemical effects of chromium
deficiency. In: Essential and Toxic Trace Elements in Human Health and Disease: an Update,
Wiley-Liss, Inc., 1993; 221-34.
204. Abraham AS, Brooks BA, Eylath U. The effects of chromium supplementation on serum
glucose and lipids in patients with and without non-insulin dependent diabetes. Metabolism
1992; 41: 768-71.
205. Anderson RA, Polansky MM, Bryden NA, Bathena SJ, Canary JJ. Effects of
supplemental chromium on patients with symptoms of reactive hypoglycemia. Metabolism
1987: 36: 351-5.
206. Yoshimoto S, Sakamoto K, Wakabayashi I, Masui H. Effect of chromium administration
on glucose tolerance in stroke-prone spontaneously hypertensive rats with streptozotocin-
induced diabetes. Metabolism 1992; 41: 636-42.
207. Mertz W. Chromium in human nutrition: a review. J Nutr 1993: 123: 626-33
208. Schwarz K, Mertz W. Chromium (III) and the glucose tolerance factor. Arch Biochem
Biophys 1959; 85: 292-5.
209. Offenbacher EG, Pi-Sunyer FX. Beneficial effect of chromium rich yeast on glucose
tolerance and blood lipids in elderly subjects. Diabetes 1980; 29: 919-25.
210. Sherman I, Glennon JA, Brech WJ, Klomberg GH, Gordon ES. Failure of trivalent
chromium to improve hyperglycemia in diabetes mellitus. Metabolism 1968; 17: 439-42.
211. Evans GW, Bowman TD. Chromium picolinate increases membrane fluidity and rate of
insulin internalization. J lnorg Biochem 1992; 46: 243-50.
212. Polansky MM, Bryden NA, Canary JJ, Anderson F!A. Beneficial effects of supplemental
chromium (0) on glucose, insulin and glucagon of subjects consuming controlled low
chromium diets. FASEB J 1990; 4: A777.
213. Korc M. Manganese homeostasis in humans and its role in disease states. In: Essential
and Toxic Trace Elements in Human Health and Disease, Prasad, AS, ed. New York: Alan
Liss, Inc. 1988; 253-73.
214. Paynter DI. Changes in activity of manganese superoxide dismutase enzyme in tissues
of the rat with changes in dietary manganese. J Nutr 1980; 110: 437-47.
215. de Rosa G, Keen CL, Leach RM, Hurley LS. Regulation of superoxide dismutase activity
by dietary manganese. J Nutr 1980; 110: 795804.
216. Paynter DI. The role of dietary copper, manganese, selenium and vitamin E in lipid
peroxidation in the rat. Biol Trace Elem Res 1980; 2: 121-35.
217. Burch RE, Williams RV, Hahn HKJ, Jetton MM, Sullivan JF. Tissue trace element and
enzyme content in pigs fed a low manganese diet. A relationship between manganese and
selenium. J Lab Clin Med 1975; 86: 132-9.
218. Hurley LS, Theriault L, Dreosti IE. Liver mitochondria from manganese deficient and
pallid mice: Function and ultrastructure. Science 1970; 170: 1316-8.
219. Shani J, Ahronson Z, Sulman FG, Mertz W, Frenkel A, Kraicer PF. Insulin-potentiating
effect of salt bush (Atriplex halimus) ashes. Isr J Med Sci 1972; 8: 7578.
220. Everson GJ, Shrader RE. Abnormal glucose tolerance in manganese-deficient guinea
pigs. J Nutr 1968; 94: 89-94.
221. Nishida M, Sakurai H, Kawada J. Alteration of manganese distribution in organs of rats
treated with streptozotocin. Naturwissenschatten 1989; 76: 220-2.
222. Keen Cl, Baly DL, Lonnerdal B. Metabolic effects of high doses of manganese in rats.
Biol Trace Elem Res 1984; 6: 309-I 5.
223. Davis ML, Jarrett CR, Adeleye BO, Stoecker BJ. Chromium and manganese interaction
in streptozocin-diabetic rats. FASEB J 1991; 5: Al 310.
224. Welsh JJ, Narbaitz R, Begin-Heick N. Metabolic effects of dietary manganese
supplementation in ob/ob mice. J Nutr 1985; 115: 919-28.
225. El-Yazigi A, Hannan N, Raines DA. Urinary excretion of chromium, copper and
manganese in diabetes mellitus and associated disorders. Diab Res 1991; 18: 129-34.
1407
226. Oster MH, Uriu-Hare JY, Trapp CL, Stern JS, Keen CL. Dietary macronutrient
composition influences tissue trace elements accumulation in diabetic Sprague-Dawley rats.
Proc Sot Biol Med 1994; 207: 67-75.
227. Korc M, Schoni MH. Quin 2 and manganese define multiple alterations in cellular
calcium homeostasis in diabetic rat pancreas. Diabetes 1988; 37: 13-20.
228. Zidenberg-Cherr S, Keen CL. Enhanced tissue lipid peroxidation. Mechanism
underlying pathologies associated with dietary manganese deficiency. In: Nutritional
Bioavailability of Manganese, Kies, C. ed., Am. Chem Sot.: New York 1987: 56-66.
229. Coassin M, Ursini F, Bindoli A. Antioxidant effect of manganese. Arch Biochem Biophys
1992: 299: 330-3.
230. Tampo Y, Yonaha M. Antioxidant mechanism of Mn(ll) in phospholipid peroxidation.
Free Rad Biol Med 1992; 13: 115-20.
231. Bhuyan KC, Bhuyan DK, Chiu W, Malik S, Fridovich I. Desferal-Mn(lll) in the therapy
of diquat -induced cataract in rabbit. Arch Biochem Biophys 1991; 288: 525-32.
232. Walter RM, Aoki TT, Keen CL. Acute oral manganese administration does not
consistently affect glucose tolerance in non-diabetic and type II diabetic humans. J Trace
Elem in Exptl Med 1991; 4: 73-9.
233. Rubenstein AH, Leven NW and Elliott GA. Manganese-induced hypoglycemia. Lancet
1962; 1348-51.
234. Failla ML, Kiser RA. Hepatic and renal metabolism of copper and zinc in the diabetic rat.
Am J Physiol 1983; 244: El 15-21.
235. Gassman CA, Failla ML, Osborne SP, Alexander AR. Copper accumulation in the
soluble and particulate fractions of renal cortex in the streptozotocin-diabetic rat. Biol Trace
Elem Res 1983; 5:475-87.
236. Noto R, Alicata R, Sfogliano L, Neri S, Bifarella M A study of cupremia in a group of
elderly diabetics. Acta Diabetol Latina 1983; 20: 81-5.
237. Salonen JT, Salonen R, Seppanen K, Kantola M, Suntionen S, Korpela H. Interactions
of serum copper, selenium, and low density lipoprotein cholesterol in atherogenesis. Brit Med
J 1991: 302: 765-70.
238. Chen Y, Saari JT, Kang YJ. Weak antioxidant defenses make the heart a target for
damage in copper-deficient rats. Free Rad Biol Med 1994; 17: 529-36.
1408
239. Saari JT. Implication of nonenzymatic glycosylation as a mode of damage in dietary
copper deficiency. Nutr Res 1994; 14: 1689-99.
240. Paynter DI, Moir RJ, Underwood EJ. Changes in activity of the Cu-Zn superoxide
dismutase enzyme in tissues of the rat with changes in dietary copper. J Nutr 1979; 109:
15706.
241. DiSilvestro RA, Marten JT. Effects of inflammation and copper intake on rat liver and
erythrocyte Cu-Zn superoxide dismutase levels. J Nutr 1990; 120: 1223-7.
242. Carville DGM, Strain JJ. The effect of a low copper diet on blood cholesterol and
enzymic antioxidant defence mechanisms in male and female rats. Int J Vitamin Nutr Res
1988; 58: 456-62.
243. Nelson SK, Huang CJ, Mathias MM, Allen KGD. Copper-marginal and copperdeficient
diets decrease aortic prostacyclin production and copper-dependent superoxide dismutase
activity, and increase aortic lipid peroxidation in rats. J Nutr 1992; 121: 2101-8.
244. Olin KL, Walter RM, Keen CL. Copper deficiency affects selenoglutathione peroxidase
and selenodeiodinase activities and antioxidant defense in weanling rats. 1994; 59: 6548.
245. McLaren GD, Muir WA, Kellermeyer RW. Iron overload disorders: natural history,
pathogenesis, diagnosis and therapy. CRC Crit Rev Clin Lab Sci 1983; 19: 20566.
246. Phelps G, Chapman I, Hall P, Braund W, Mackinnon M. Prevalence of genetic
haemochromatosis among diabetic patients. Lancet 1989; ii: 233-34.
247. Cutler P. Deferoxamine therapy in high-ferritin diabetes. Diabetes 1989; 38: 1207-10.
248. Kuzuyama M, Naito M, Yamada K, Funaki C, Hayashi T, Asai K, Kuzuya F. Involvement
of intracellular iron in the toxicity of oxidized low density lipoprotein to cultured endothelial
cells. Biochem Int 1990; 22: 567-70.
249. Gannon DE, Varani J, Phan SH, Ward JH, Kaplan J, Till GO, Simon RH, Ryan US,
Ward PA. Source of iron in neutrophil-mediated killing of endothelial cells. Lab Invest 1987;
57: 37-42.
250. Kvietys PR, lnauen W, Bacon BR, Grisham MB. Xanthine oxidase-induced injury to
endothelium: role of intracellular iron and hydroxyl radical. Am J Physiol 1989; 257: Hl640-7.
251. Nielson FH. Ultratrace elements. In: Modern Nutrition in Health and Disease, Vol 1.
Shils ME, Olsen JA, Shike M, eds. Lea and Fibiger: Philadelphia 1994: 269-86.
252. Heyliger CE, Tahiliani AG, McNeil1 JH. Effects of vanadate on elevated blood glucose
and depressed cardiac performance of diabetic rats. Science 1985; 227: 1474-7.
1409
253. Shechter Y. Insulin-mimetic effects of vanadate. Possible implications for future
treatment of diabetes. Diabetes 1990; 39: l-5.
254. Thompson KH, McNeil1 JH. Effect of vanadyl sulfate feeding on susceptibility to
peroxidative change in diabetic rats. Res Comm Chem Pathol 8 Pharmacol. 1993; 80: 187-
200.
255. Tolman EL, Barris E, Burns M, Pansini A, Partridge R. Effect of vanadium on glucose
metabolism in vitro. Life Sci 1979; 25: 1159-64.
256. Meyerovitch J, Farfel Z, Sack J, Shechter Y. Oral administration of vanadate normalizes
blood glucose levels in streptozocin-treated rats. Characterization and mode of action. J Biol
Chem 1987; 262: 6658-62.
257. Thompson KH, Leichter J, McNeil1 JH. Studies of vanadyl sulfate as a glucose-lowering
agent in STZ-diabetic rats. Biochem Biophys Res Comm 1993; 197: 1549-55.
258. Orvig C, Thompson KH, Battell M, McNeil1 JH. Vanadium compounds as insulin mimics.
Metal Ions Biol Syst 1995; 31: 575-94.
259. Henquin JC, Carton F, Ongemba LN, Becker DJ. Improvement of mild hypoinsulinaemic
diabetes in the rat by low non-toxic doses of vanadate. J Endocrinol 1994; 142: 555-61.
260. Elfant M, Keen CL. Sodium vanadate toxicity in adult and developing rats. Biol Trace
Elem Res 1987; 14: 193-208.
261. Ugazio G, Bosia S, Burdino E, Grignolo F. Amelioration of diabetes and cataract by
Na,VO, plus U83836E in streptozotocin treated rats. Res Comm Mol Pathol and Pharmacol
1994; 85: 313-28.
262. Saxena AK, Srivastava P, Kale RK, Baquer NZ. Effect of vanadate administration on
polyol pathway in diabetic rat kidney. Biochem Int 1992; 26: 59-68.
263. Breuch M, Quintanilla ME, Legrum W, Koch H, Netter KJ, Fuhrmann GF. Effects of
vanadate on intracellular reduction equivalents in mouse liver and the fate of vanadium in
plasma, erythrocytes and liver. Toxicol 1984; 31: 283-95.
264. Haider SS, El-Fakhri M. Action of alpha-tocopherol on vanadium-stimulated lipid
peroxidation in rat brain. Neurotoxicol 1991; 12: 79-86.
265. Fillat C, Rodriguez-Gil JE, Guinovart JJ. Molybdate and tungstate act like vanadate on
glucose metabolism in isolated hepatocytes. Biochem J 1992; 282: 659-63.
266. Barbera A, Rodriguez-Gil JE, Guinovart JJ. Insulin-like actions of tungstate in diabetic
rats - normalization of hepatic glucose metabolism. J Biol Chem 1994; 269: 2004753.
267. Srivastava P, Saxena AK, Kale RK, Baquer NZ. Insulin like effects of lithium and
vanadate on the altered antioxidant status of diabetic rats. Res Comm Chem Pathol
Pharmacol 1993; 80: 283-93.
268. American Diabetes Association Task Force on Nutrition and Exchange Lists. Nutritional
recommendations and principles for individuals with diabetes mellitus: 1986. Diab Care 1987;
10: 126-32.
269. Mertz W. A balanced approach to nutrition for health: the need for biologically essential
minerals and vitamins. J Am Dietetic Assoc 1994; 94: 125962.
270. Pryor WA. The antioxidant nutrients and disease prevention - what do we know and
what do we need to find out? Am J Clin Nutr 1991; 53: 391535.
271. Mooradian AD, Failla M, Hoogwerf B, Maryniuk M, Wylie-Rosett J. Selected vitamins
and minerals in diabetes. Diab Care 1994: 17: 464-79.
272. Herbert V. The antioxidant supplement myth. Am J Clin Nutr 1994; 60: 157-8.
273. Turnlund JR. Future directions for establishing mineral/trace element requirements. J
Nutr 1994; 124: 1765S7OS.
Accepted for publication January 30, 1995.

Diabetes and Antioxidants

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Diabetes and Antioxidants

Uploaded by

Copyright:

Available Formats

Nutrition Research, Vol. 15, No. 9, 1377-1410, 1995 pp.

Copyright 0 1995 Elsevier Science Ltd

You might also like