The potential role of phytochemicals in
wholegrain cereals for the prevention of
Damien P Belobrajdic1,2*and Anthony R Bird1,2
Diets high in wholegrains are associated with a 20-30% reduction in risk of developing type-2 diabetes (T2D), which
is attributed to a variety of wholegrain components, notably dietary fibre, vitamins, minerals and phytochemicals.
Most phytochemicals function as antioxidants in vitro and have the potential to mitigate oxidative stress and
inflammation which are implicated in the pathogenesis of T2D. In this review we compare the content and
bioavailability of phytochemicals in wheat, barley, rice, rye and oat varieties and critically evaluate the evidence for
wholegrain cereals and cereal fractions increasing plasma phytochemical concentrations and reducing oxidative
stress and inflammation in humans. Phytochemical content varies considerably within and among the major cereal
varieties. Differences in genetics and agro-climatic conditions explain much of the variation. For a number of the
major phytochemicals, such as phenolics and flavanoids, their content in grains may be high but because these
compounds are tightly bound to the cell wall matrix, their bioavailability is often limited. Clinical trials show that
postprandial plasma phenolic concentrations are increased after consumption of wholegrain wheat or wheat bran
however the magnitude of the response is usually modest and transient. Whether this is sufficient to bolster
antioxidant defences and translates into improved health outcomes is still uncertain. Increased phytochemical
bioavailability may be achieved through bio-processing of grains but the improvements so far are small and have
not yet led to changes in clinical or physiological markers associated with reduced risk of T2D. Furthermore, the
effect of wholegrain cereals and cereal fractions on biomarkers of oxidative stress or strengthening antioxidant
defence in healthy individuals is generally small or nonexistent, whereas biomarkers of systemic inflammation tend
to be reduced in people consuming high intakes of wholegrains. Future dietary intervention studies seeking to
establish a direct role of phytochemicals in mediating the metabolic health benefits of wholegrains, and their
potential for mitigating disease progression, should consider using varieties that deliver the highest possible levels
of bioavailable phytochemicals in the context of whole foods and diets. Both postprandial and prolonged
responses in systemic phytochemical concentrations and markers of inflammation and oxidative stress should be
assessed along with changes related to health outcomes in healthy individuals as well as those with metabolic
Keywords: Wholegrain, Phytochemical, Type-2 diabetes, Oxidative stress, Inflammation
* Correspondence: firstname.lastname@example.org
1Commonwealth Scientific & Industrial Research Organisation (CSIRO) Food
Futures National Flagship, GPO BOX 10041, Adelaide, SA 5000, Australia
2CSIRO Animal Food & Health Sciences, Adelaide, SA 5000, Australia
© 2013 Belobrajdic and Bird; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Belobrajdic and Bird Nutrition Journal 2013, 12:62
Metabolic disease and protective role
Type-2 diabetes (T2D) is a major health problem world-
wide. Rates are increasing alarmingly in many countries
and the global incidence is predicted to rise from 366
million people to about 552 million in the next two de-
cades [1,2]. It is a leading cause of death and disability
globally and carries a considerable socioeconomic bur-
den, especially in low and middle income settings [2-5].
Cost-effective mitigation strategies rather than contain-
ment are therefore of paramount importance. The initi-
ation and progression of T2D and related chronic
metabolic disorders is governed by a complex interplay
of genetic and multiple lifestyle influences of which diet
is a major and modifiable high exposure risk factor.
Dietary change has proven successful in both preventing
and managing diabetes and, when combined with other
lifestyle modifications, such as regular exercise and
weight loss, is more effective than pharmacological inter-
Dietary patterns featuring wholegrain cereals are asso-
ciated with reduced risk of T2D [7-10]. Systematic re-
views and meta-analyses of large, prospective studies
consistently demonstrate that frequent consumption of
wholegrain foods improves metabolic homeostasis and
delays or prevents the development of T2D and its com-
plications in a variety of cohorts, albeit mostly of European
ancestry [11-18]. Two to three serves daily of wholegrain
foods reduced the risk of T2D by 20-30% compared to
about 1 serve a week [12,13,15,18]. Randomised, con-
trolled dietary studies in humans and other experimental
research provides evidence of a causal relationship be-
tween wholegrain consumption and diabetes prevention
[15,18]. Furthermore, wholegrain foods improve indices of
diabetes risk, including glycemic control, fasting plasma
insulin and glucose, and insulin sensitivity and also aid in
the management of those individuals with or at high risk
of developing T2D [13,16,19-21].
Mechanisms by which wholegrains might protect against
Understanding the mechanisms by which wholegrains
prevent or delay the onset and progression of T2D is
pivotal to developing effective diabetes prevention op-
tions. The components of wholegrains which are respon-
sible for protecting against diabetes have not been
clearly identified but the high nutrient and fibre contents
in general, as well as the physical structure of wholegrains
are considered leading contenders [15,22,23]. Prospective
studies show that T2D risk is inversely related to cereal
fibre intake  and that cereal fibre accounts for much of
the reduction in diabetes risk associated with wholegrain
intake . Dietary fibre is concentrated primarily in the
bran layer of grains and it is this fraction which is more
strongly associated with reduction in risk of T2D .
Most but not all wholegrains are high in fibre  and in-
dividual wholegrains differ markedly in the types and
hence physiological properties of fibres they contain. Vis-
cous soluble fibres, such as those in oats and barley, slow
available carbohydrate assimilation and dampen postpran-
dial glycemic and insulinemic responses . However
most observational studies provide evidence of a protect-
ive role for insoluble rather than soluble fibres . The
likely explanation is that insoluble fibre is simply serving
as a marker of an intact (grain) food structure. Foods and
diets rich in carbohydrates that are rapidly digested and
absorbed have adverse consequences for metabolic health
[28-33]. Refinement of cereal grains removes the protect-
ive bran layer and greatly increases starch availability.
However, not all wholegrain foods elicit a moderate gly-
cemic response . Although wholegrain foods may
contain intact, cracked, broken or flaked kernels, most
commercially processed cereal foods consist of ground
and reconstituted wholegrain products .
Wholegrains contain a plethora of minerals, vitamins
and phytochemicals  and it is often difficult to
ascribe protective effects on metabolic health to any one
particular constituent, such as fibre. One of the primary
pathogenic factors leading to insulin resistance, β-cell
dysfunction, impaired glucose tolerance and ultimately
T2D is oxidative stress [36-38]. This mechanism has
been implicated as the underlying cause of both the
macrovascular and microvascular complications associ-
ated with T2D . Furthermore, the cells and tissues of
people with metabolic syndrome and T2D have an im-
paired ability to cope with the burden of increased oxi-
dative stress [40-42]. Therefore, dietary components
including phytochemicals (non-nutritive, plant bio ac-
tives that reduce risk of chronic diseases ), and a
limited number of micronutrients that function as anti-
oxidants, may prevent the development and progression
of metabolic syndrome and T2D by reducing oxidative
stress . Furthermore, systemic, low grade inflamma-
tion, especially in adipose tissue, is a hallmark of many
chronic diseases, including T2D . In addition to their
antioxidant properties, some cereal phytochemicals have
thereby modulate diabetes risk by this mechanism as
Phytochemicals in whole grains
Wholegrains generally contain diverse combinations of
phytochemicals depending on the type of cereal, location
within the grain and how the grain has been processed.
The outer structures of grains, in particular the pericarp
seed coat and aleurone layers, contain much higher
levels of phytochemicals such as phenolic compounds,
phytosterols, tocols, betaine and folate, than the germ
Belobrajdic and Bird Nutrition Journal 2013, 12:62
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and endosperm . Phenolic compounds are the most
diverse and complex class of phytochemicals in cereal
grains [35,49]. They include numerous derivatives of
benzoic and cinnamic acids as well as flavonoids, fla-
vones and flavanols, anthocyanidins, avenanthramides,
lignans and alkylresorcinols. In most grains phenolic
acids are concentrated in the bran and embryo cell walls
and exist mostly in an insoluble bound form, free and
soluble-conjugated forms being minor entities [25,48].
The phenolic acid content of wholegrains is considered
a major contributor to total antioxidant capacity .
Other major phytochemicals that occur in wholegrains
which may have a role in protecting against diabetes in-
clude various carotenoids, notably α- and β-carotene, lu-
tein, β-cryptoxanthin and zeaxanthin, all of which are
located mainly in the bran and germ fractions .
Aside from some having pro-vitamin A activity, they all
function as antioxidants. Other phytochemicals with
strong antioxidant capacities include phytate (which che-
lates prooxidant minerals) and various terpenes and ter-
penoids (phytosterols and tocols).
To render them palatable, grains are processed by
various means including milling, grinding and flaking.
Although these treatments may reduce content of phyto-
chemicals, their bioavailability is often increased [45,50,51].
Thermal and bioprocessing too can improve phytochem-
ical bioavailability, especially the latter method, although
the results are not always consistent.
Differences among the most economically important
cereals in their contents of various micronutrients and
phytochemicals are shown in Table 1. Note that the
phytochemical values refer to uncooked wholegrains.
Wholegrains are normally cooked and are rarely con-
sumed in their unprocessed or raw form. Cooking re-
sults in considerable reductions in their phytochemical
levels. For instance, quick-cooking wild rice had a much
lower total phenolic content (2076 mg ferulic acid
equivalent (FAE)/kg) than uncooked wild rice varieties
(2472 to 4072 mg FAE/kg) .
Variation in grain phytochemical content
Wheat, barley, rice, rye and oats vary markedly in the
types and amounts of phytochemicals they contain.
The antioxidant properties of wheat have been
attributed primarily to the high phenolic content,
principally alkylresorcinols and hydroxycinnamic
acids (ferulic, sinapic, and ρ-coumaric acids) that are
concentrated in the bran fraction [49,75-77]. The
flavonoid concentration in the bound fraction of
wheat cultivars has been shown to vary from 97 ±
4 μmol catechin equivalents/100 g (Roane) to 139 ±
17 μmol catechin equivalents/100 g (Superior) .
However, there is less variation in total flavonoid
content (122 ± 10 μmol catechin equivalents/g
(Roane) to 149 ± 17 μmol catechin equivalents/100 g
(Superior) ) whereas tocopherols and tocotrienols
levels vary more than 2-fold (28 to 80 μg/g) among
175 different wheat genotypes from all over the world
grown at the same site in Europe . Even greater
variation (up to 10-fold variation) was seen in
Table 1 The type and concentration of phytohcemicals in a range of wholegrain cereals
PhytochemicalWheatBarley Rice RyeOat
Methionine (g/100g) [48,53-56]0.17 – 0.240.03 – 0.080.18 – 0.210.180.18
Cystine (g/100g) [48,53-56]0.19 – 0.400.06 – 0.2 0.11 – 0.160.180.18
Selenium (mg/100g) [48,57-60]0.0003 – 3 0.002 – 0.030 0.0002 – 1.370.00014< 0.10 – 3.3
Folate (mg/100g) [60,61]0.01 – 0.090.5 – 0.8 0.0160.55 – 0.800.05 – 0.06
Choline (mg/100g) [48,62]27 – 195 6.9 – 11UnknownUnknown2.0 – 2.6
Tocopherols + tocotrienols [48,63-67]2.3 – 8.0 4.7 – 6.8 0.4 – 0.9 0.4 – 0.7 0.05 – 4.8
Carotenoids (total) (mg gallic acid eq./100g) [48,60]0.04 – 0.630.015 – 0.105 0.014 – 0.077 Unknown0.031
Polyphenols (mg/100g) 70 – 145950 – 19654 – 313 125 – 255 9 – 34
Phenolic acids (total) (μg/g) [61,64,68]200 – 900 100 – 550 Unknown200 – 1080350 – 874
Phenolic acid (free) (ug/g) [61,64,68] 5 – 395 – 23Unknown10 – 3550 – 110
Ferulic acid (total, mg/100g) [48,69]16 – 213110 – 12030 3.9 – 5.02.1 – 2.4
Flavanoids (total, mg/100g) [48,69]30 – 4312 – 18Unknown6.7 – 7.55.6 – 8.2
Alkylresorcinols μg/g [61,70]200 – 7500 – 150Not present570 – 3220Not present
Avenanthramides (mg/100g [71,72]Not presentNot presentNot present Not present4.9 – 27.5
Betaine (mg/100g) [48,60,62,73]22 – 29140 – 760.5 (brown) Unknown11.3 – 100
Phytosterols (mg/100g) [48,74]
57 – 9890 – 115UnknownUnknownUnknown
Belobrajdic and Bird Nutrition Journal 2013, 12:62
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α-tocopherol levels measured in several hundred
wheat cultivars grown in the United States .
The major phytochemicals in barley are phenolics,
tocols and folate. Analysis of a selection of 10 barley
lines showed a large variation in the concentration
of total phenolics (100 to 550 ug/g) but only
minimal variation in folate (500 to 800 ug/g) and
total tocols (45 to 70 ug/g) . Our group has
recently developed a new variety of barley,
BARLEYmax®  that has a range of substantiated
nutritional and health benefits [82,83]. It has a
phenolic content (5 mg/g) which is 40% greater than
that of standard cultivars such as Golden Promise
(2.9 mg/g) and Torrens (3 mg/g). It also contains
levels of tocopherol and tocotrienols (125 μg/g)
which are nearly 5 times those of other barley grain
varieties (McInerney, JK, Morell, MK and Bird, AR
Brown rice generally is a good source of lipid-soluble
antioxidants including ferulated phytosterols (i.e.
γ-oryzanol), tocopherols and tocotrienols, although
the levels of these phytochemicals vary widely
among rice varieties . For instance, tocol
concentration ranged from 90 to 220 nmol/g in six
varieties of rice . Brown rice may also be a good
source of phenolic acids as suggested by the levels
reported for the botanically related wild rice
(Zizaniae palustris and Zizaniae aquatica; 2472 to
4072 mg of ferulic acid equivalent (FAE)/kg). These
values are substantially higher than that of the
mixed sample of white rice, basmati rice and wild
rice (1460 mg of FAE/kg) . The total phenolics
content of these rices was directly related to their
in vitro antioxidant capacity, which was 30 times
higher for wild rice than the control (white) rice .
Rye contains more alkylresorcinols (568 to 3220 μg/g)
than the other major cereal varieties (0 to 750 μg/g).
The concentration of alkylresorcinol in rye [70,84] is
related to the high level of folate in the grain (0.55 to
0.80 mg/100 g) . Select varieties of rye also contain
very high levels of total phenolics (up to 1080 μg/g)
but the content of free phenolics is quite low
(between 10 to 35 μg/g) . Other phytochemicals,
including tocols, polyphenols and ferulic acid are
found at low levels in rye .
The major phytochemicals present in oats include
tocopherols and tocotrienols, phenolic acids, sterols,
selenium and avenanthramides (a group of
N-cinnamoylanthranilate alkaloids, unique to oats)
[85,86]. Tocol levels differ greatly (5 to 48 μg/g)
[61,65,66] among oat varieties but generally are
comparable to those found in rice and rye (4 to
9 μg/g) and also to the higher levels found in wheat
and barley (23 to 80 μg/g) . The range in the
total phenolic levels of oats are also similar to those
in wheat and rye, however oats contains up to
10-fold higher levels of free and conjugated
phenolics. Other phytochemicals, including folate,
polyphenols, ferulic acid and flavonoids are present
at low levels in oats.
Major regulators of phytochemical content of cereals:
genetics and agro-climatic conditions
The phytochemical content of cereal grains is influenced
considerably by genetics and a variety of agro-climatic
factors. In rice, the growing environment had a greater
effect on tocol and/or sterol esters of ferulic acid levels
than did genotype [87,88]. In wheat, genetic variation
and agro-climatic conditions are both important but the
extent of their influence depends on the phytochemical
concerned. In an assessment of over 200 lines of wheat,
α-tocopherol levels were influenced by not only varietal
differences but also crop year and production site .
Fertilization practices, soil type and wheat variety had
no influence . Additionally, when eight selected win-
ter wheat genotypes were grown under controlled condi-
tions α-tocopherol levels varied by as much as 3-fold,
highlighting the significant contribution of genetic vari-
ation . However, studies in Europe show that toc-
opherol and tocotrienol levels in some wheat varieties
are more susceptible to seasonal variation than others
. This greater susceptibility to seasonal variation and
growing location is also evident in some wheat geno-
types for free and conjugated phenolic levels . How-
ever, bound phenolics which comprise the greatest
proportion of total phenolic acids in wheat, are mostly
stable across different growing conditions. Thus, the
total phenolic acid content of wheat is mostly influenced
by genotype, for instance winter varieties contain up to
2-fold more total phenolic acids (1171 μg/g) than the
average level of 175 wheat genotypes (658 μg/g) .
Bioavailability refers to the fraction of ingested phyto-
chemical (or other dietary constituent) which reaches
the systemic circulation. More commonly it is defined as
the fraction which is absorbed in the gastrointestinal
tract. Tracer methods, in which atoms or molecules of
the phytochemical within the grain are labelled with an
intrinsic radioactive or stable marker, provide the only
means for accurately determining bioavailability. Given
the challenges of labelling cereal phytochemicals intrin-
sically, this technique has not been used to measure bio-
availability of phytochemicals in cereals. Simpler indirect
Belobrajdic and Bird Nutrition Journal 2013, 12:62
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measures are more commonly used, such as the balance
method (intake minus fecal output), incremental area
under the postprandial serum concentration curve and
incremental urinary excretion. Numerous in vitro methods
have also been published however they, understandably,
have many limitations  aside from questionable valid-
ity, and so provide at best only a guide to the bioacces-
sibility of a phytochemical.
a. Absorption from the small intestine
Bioavailability varies markedly among the different
types of phytochemicals. Folate and α-tocopherol are
readily absorbed from the small intestine and their
bioavailability is independent of dietary fibre content
(Table 2) [94,95]. The majority of polyphenols
however, are tightly bound to cell walls within the
grain matrix thereby greatly limiting their
bioavailability in the upper gut . Even if
polyphenols are released from the grain matrix
during digestion it is unlikely that they will be
absorbed in the small intestine as they are too
hydrophilic to cross the epithelium by passive
diffusion . It is possible that there are apical
membrane carriers that facilitate polyphenol
absorption however the intestinal transport
processes remain largely unknown . Oats
contain the highest levels of free, or unbound,
phenolics (up to 30% of total phenolics) whereas
wheat, barley and rye contain only very low levels
(as little as 1.6%) . Thus specific varieties of oats
have the greatest potential to raise postprandial
plasma phenolic concentration and antioxidant
Wholegrain consumption elicits only minimal
increases in systemic levels of phytochemicals in
humans. Consumption of 100 g of boiled wheat bran
increased postprandial plasma phenolic
concentration by 5 μmol (60 min post ingestion)
which represented <2% increase over baseline levels
. As these changes in circulating phenolic levels
are minimal and of short duration it is unlikely that
high intakes of wholegrains such as wheat can
modulate systemic levels. Alternatively,
alkylresorcinols, a class of phenolic lipids found at
high levels in wheat and rye are relatively well
absorbed within the small intestine (about 58%) ,
and as they are primarily transported in the serum
in lipoproteins  they have a half life in serum of
5 h . However, alkylresorcinols are rather weak
antioxidants per se  and do not affect the
susceptibility of LDL to oxidation ex vivo .
Wholegrains wheat, oats and barley are good dietary
sources of betaine which can also contribute to
improving antioxidant status as well as acting possibly
as a methyl donor (transmethylation) and lipotrope
[48,104,105]. The bran and aleurone layers of wheat
are concentrated sources of betaine (~1% w/w)
[104,106] and there is evidence in humans that the
latter source is readily bioavailable .
It is important to consider how components of the
diet may affect phytochemical bioavailability because
cereal products are rarely consumed alone. Non-
heme iron when consumed with cereals reduced the
absorption of phenolics . Milk may also reduce
the absorption of phenolics , however other
studies have also shown no impairment [109-111].
Flavonol absorption (in particular quercetin and its
metabolites) may also be affected by a variety of
dietary constituents such as ethanol, fat, and
emulsifiers , but this observation is based on
evidence from in vitro and animal studies and
further research in humans is required.
Table 2 Major wholegrain phytochemicals, factors affecting their bioavailability and suggested mechanisms for
Phytochemical Major grain
sourcesaffecting bioavailabilityenhance bioavailability
Food & dietary factorsOther factors thatPotential mechanisms of action
freeOatsMilkUnknownIncrease plasma total antioxidant capacity to directly mitigate
Heme ironUnknownIndirect through cell signalling
Grain structureBio-processing of grainIncrease plasma total antioxidant capacity to directly mitigate
Indirect through cell signalling
Flavanoids Wheat, barleyGrain structureUnknown Increase plasma uric acid levels which has reducing and free
radical scavenging activities
Improve glutathione radical scavenging system
Not relevant as
Not relevant as
A cofactor for glutathione peroxidase, an enzyme that
quenches reactive oxygen species
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b. Cereal bioprocessing for improving phytochemical
Cereal bioprocessing is receiving increasing attention
as a technique for purportedly improving the
bioavailability of bound phytochemicals in grains.
This technique utilises hydrolytic enzymes or
enzyme cocktails to selectively release
phytochemicals from the bran layer. However, there
is very little evidence that cereal bioprocessing
actually improves phytochemical bioavailability in
humans. Recently Anson and colleagues 
developed a bioprocessing technique whereby wheat
bran undergoes a yeast fermentation and enzyme
treatment procedure. When this wheat bran was
incorporated into a wholemeal bread and consumed
by volunteers the plasma concentrations of ferulic,
vanillic and sinapic acids, and 3,4-dimethoxybenzoic
acid were 2- to 3-fold higher than in the control
bread . Ferulic acid in particular increased in
plasma to a maximal level of 2.5 μmol/L, which is
considerably higher than baseline levels reported
previously (5 to 30 nmol) . The relevance of
these changes in circulating phytochemical levels to
metabolic health impact has yet to be demonstrated.
c. Phytochemical bioavailability in the large intestine:
role of the microbiota
Microbial fermentation of cereal grains has the
potential to increase the bioavailability of
phytochemicals bound to the fibre matrix [114-117].
For instance, microbial esterases hydrolyse
conjugated phenolic acids, such as those from wheat
bran [118,119], potentially improving their
absorption.. In addition, ferulic acid from wheat
bran has been shown to increase plasma antioxidant
activity more effectively than pure ferulic acid in rats
. This highlights the important function cereals
may have in delivering ferulic acid to the large bowel
whereby enzymes from the microbiota cause the
slow release of ferulic acid up to 24 h after its
consumption. However, in humans there is limited
evidence that large bowel fermentation contributes
significantly to plasma phytochemical levels in the
systemic circulation. A study by Kern et al. 
showed that the absorption of wheat bran phenolics
was limited essentially to the postprandial period.
Plasma phenolics and metabolites of ferulic acid
(hydroxycinnamic and diferulic acids) were at
baseline levels 6 to 24 h after wheat bran
consumption, suggesting that the microbial
fermentation of the ingested wheat bran did not
contribute to the systemic phenolic level. In
addition, the authors also showed that diferulic acids
(formed by microbial esterase digestion of ferulic
acid) or their reduced dimers (formed by colonic
microbiota hydrogenation reactions of diferulic
acids) could not be detected in plasma or urine
samples. In a study by Anson et al.  whole wheat
bread increased plasma concentrations of two
metabolites of ferulic acid (3-hydroxyphenylpropionic
acid and phenylpropionic acid) 9 to 24 h after
consumption by healthy volunteers. It is unlikely that
these metabolites exert any biological affects
systemically as the maximal plasma concentrations
reached were only in the nanomolar range (100 nmol/L
and 350 nmol/L respectively). The evidence suggests
that the colonic microbiota contribute little to
systemic levels of phenolic metabolites.
Impact of wholegrain phytochemicals on metabolic health
Various blood and urine biomarkers are routinely used
to determine the metabolic health benefits of wholegrain
phytochemicals. For instance, plasma and urine levels of
oxidised lipids provide an indirect measure of the capacity
of cereal phytochemicals to protect circulating lipids from
damage by reactive oxygen species. In addition, circulating
levels of C-reactive protein and pro-inflammatory cyto-
kines are indicative of low grade systemic inflammation, a
hallmark of many metabolic diseases.
a. Oxidised lipids
There is some evidence supporting a role for
wholegrain consumption in reducing oxidised lipids
in plasma or urine. Kim et al.  showed that a
mixture of brown and black rice when consumed for
6 wk by healthy adults reduced plasma
thiobarbituric acid reactive substance (TBARS)
levels. Jang et al.  also showed a reduction in
oxidised plasma malondialdehyde (MDA) and urine
8-epi-prostaglandin F2α when subjects with
coronary heart disease consumed a wholegrain
powder mix (70 g/d) for 4 mo. Two other studies of
shorter duration (2 and 6 wk) in which refined grain
foods were replaced with wholegrain foods (7 to
8 servings/d) did not show any improvements in
urinary levels of oxidised lipids.[123,124] LDL
susceptibility to oxidation was also similar when
healthy subjects consumed 250 g of rye or wheat
bran bakery products for 6 weeks . It is not
clear from these later studies [103,123,124] whether
the lack of an effect was due to the shorter duration
of the interventions, differences in wholegrain type
or differences in the type of biological fluid analysed
(urine was analysed rather than plasma).
b. Antioxidant defence
The most promising evidence for wholegrain-rich
diets improving blood-based antioxidant defence is
through modulation of the glutathione radical
scavenging system. This system utilises glutathione
Belobrajdic and Bird Nutrition Journal 2013, 12:62
Page 6 of 12
peroxidase to metabolise hydrogen peroxide to water
by using reduced glutathione as a hydrogen donor
. The capacity for reduced glutathione to
quench free radicals can be impaired if oxidised
glutathione is not recycled back to glutathione by
glutathione reductase, or if glutathione peroxidase
activity is reduced . An increase in reduced
glutathione (21%) occurred 15 min after healthy
subjects consumed an oat extract containing 1 g
avenanthramide-enriched mixture and remained
elevated (by up to 14%) for 10 h , a dose which
far exceeds a level that could be achieved by
consumption of wholegrain oats.. Alternatively,
wholegrain dietary intervention studies showed that
plasma glutathione peroxidase activity increased by
15% when subjects consumed brown and black rice
for 6 wk  but decreased by 35% when subjects
consumed a phytochemical-rich diet containing
wholegrains for 4 wk . These studies suggest
that the type of wholegrain and duration of
consumption is important in regulating glutathione
enzyme status or redox state. A possible mechanism
explaining the effect of wholegrains on glutathione
balance comes from in vitro evidence that flavonoids
alter the expression of genes responsible for the
synthesis and regulation of glutathione (Table 2)
[128,129]. There is further evidence from a dietary
intervention study in humans that selenium
improves glutathione peroxidase activity .
Subjects consuming brown or wholemeal bread
made from wheat containing high levels of selenium
increased whole blood glutathione peroxidase levels
by 10% . As most people in European countries
have plasma selenium levels below the
recommended level , wholegrain cereals with
high selenium concentrations may offer an
opportunity to improve glutathione status.
Alternatively, Fardet  recently proposed that
wholegrain wheat may increase glutathione levels
through the supply of the sulfur amino acids
methionine and cystine, which are precursors of
glutathione. However, these amino acids are present
in wholegrain wheat at low levels (0.5% of protein)
, thus other dietary sources of sulphur amino
acids such as egg and meat would presumably have
a greater influence on circulating selenium levels.
There is limited evidence for whole grain-rich diets
affecting copper-zinc superoxide dismutase (SOD),
uric acid and tocopherol levels in the blood. Plasma
SOD levels were unaffected in a study where
subjects consumed black rice for 6 mo . In
contrast, another study showed that erythrocyte
SOD levels were reduced when healthy adults
consumed a phytochemical-rich diet containing
wholegrains for 4 wk . Plasma uric acid levels
were increased (by 9%) in subjects who had
consumed bread (200 g/d) made from inulin, linseed
and soya fibre for 5 wk . These findings are
biologically significant in that uric acid accounts for
up to 90% of plasma total antioxidant capacity .
Furthermore, high levels of flavanoids in some
wholegrains are responsible for increasing plasma
total antioxidant capacity as a result of stimulating
uric acid levels rather than through the direct
actions of flavonoids . However, further
research is required that investigates the impact of
flavanoid-rich cereal consumption on uric acid levels
and antioxidant status in healthy people as well as
those with metabolic syndrome and T2D. Plasma
α-tocopherol concentrations barely increase after
consumption of wholegrains suggesting that this
compound is of limited importance for the
prevention of T2D , In addition, α-tocopherol
contributes less than 2% of the antioxidant capacity
of plasma , and a wholegrain-rich diet cannot
provide the level of Vitamin E necessary to reduce
oxidative stress in people with T2D (> 200 mg/d)
 Furthermore, a review of human clinical trials
concluded that vitamin E, and other common
antioxidants, were not useful for managing diabetic
c. Antioxidant capacity of blood
Most dietary intervention studies on wholegrains
have used the ferric reducing antioxidant potential
(FRAP) assay to determine plasma total antioxidant
capacity. In two studies by the same group, meals
consisting of approximately 100 g of wheat bran
were fed to subjects and the postprandial change in
plasma antioxidant status measured [98,140]. Both
studies showed an increase but in the study by
Beattie et al.  the magnitude of the response
was only 4% (an increase of approximately 50 μmol
of FRAP/L from a baseline of 1,204 ± 57.5 μmol of
FRAP/L). It is not known whether this change is
sufficient to protect against oxidative stress, a
hallmark of metabolic syndrome and T2DM, and
many other chronic diseases. In a study of longer
duration (5 wk) fasted plasma FRAP levels did not
change when subjects consumed bread (200 g/d)
made with inulin, linseed and soya fibre, which had
a 50% higher α-tocopherol content than the control
German wheat-rye bread . Although these
studies show a somewhat promising result for wheat
bran in improving plasma antioxidant capacity, the
FRAP assay has some limitations. For instance, it
does not account for the antioxidant capacity
provided by blood proteins (as they too are
extracted in sample preparation) and the assay is
Belobrajdic and Bird Nutrition Journal 2013, 12:62
Page 7 of 12
based on the reduction of iron which is considered
too slow a measure of antioxidant potential
[137,141]. Alternative antioxidant capacity assays,
such as the one for plasma total antioxidant capacity
(TAC), have been used to show an increase in
plasma antioxidant capacity in subjects with
coronary heart disease who consumed black rice for
6 mo . Other total antioxidant capacity assays,
such as the Oxygen Radical Absorbance Capacity
(ORAC) and Trolox Equivalent Antioxidant
Capacity (TEAC), may be useful for evaluating
radical scavenging, however they are not suitable for
assessing lipid peroxidation inhibition . Thus
future studies should deploy a combination of
different antioxidant capacity assays and the results
interpreted in the context of changes in plasma lipid
and protein oxidative stress biomarkers and clinical
d. Anti-inflammatory actions
There is growing evidence supporting a reduction in
pro-inflammatory markers in people consuming
higher levels of wholegrains and/or cereal fibre. For
instance, cereal fibre intakes (> 8.8 g/d), but not
total fibre, were associated with significantly lower
plasma cytokine levels in healthy adults .
Intervention trials provide evidence that plasma
cytokines or C-reactive protein were reduced after
consumption of bakery products containing rye bran
, bread made from whole wheat with
bioprocessed bran  or a black rice pigment
The fibre component of wholegrains is often
associated with having favourable effects on pro-
inflammatory markers including C-reactive protein
and interleukin-6 [145,146]. In particular, the
fermentation of cereal fibre in the large bowel
produces short chain fatty acids (SCFA) that bind to
G-protein coupled receptors, inhibiting transcription
factor Nfκβ and thereby increasing the threshold for
an inflammatory response in the colonic mucosa
. The anti-inflammatory actions of SCFA may
extend beyond the large bowel as these bacterial
metabolites are readily absorbed by colonocytes
. However, SCFA concentrations in the
systemic circulation are low (<0.2 mM) as most
SCFA absorbed from the lumen of the gut are
metabolised extensively by the gut mucosa and the
liver. Furthermore, consumption of fermentable
dietary fibres produces only a modest rise in plasma
SCFA levels . Whether these modest levels of
circulating SCFA are sufficient to prevent or
attenuate the elevated inflammatory status of
individuals with diabetes and related disorders is yet
to be established and deserves further investigation.
Dietary fibre may help prevent chronic inflammation
by also reducing circulating levels of
lipoplysaccharides (LPS), which are known to
contribute to the development of obesity-related
inflammatory liver diseases [150-152]. The
consumption of prebiotics has been shown to
restrict the translocation of LPS from the large
bowel of mice fed a high fat diet, resulting in
reduced markers of inflammation in adipose tissue
. However, the relevance of these findings for
humans is not yet clear.
Evidence from postprandial and medium-term intake
studies suggest that the phytochemical component of ce-
reals provides limited benefit for preventing oxidative
stress and development of T2D. Wholegrain consump-
tion may increase postprandial plasma phenolic levels
but the response is modest and transient. Whether this
effect is sufficient to bolster antioxidant defences and
improve health outcomes has not been established. Al-
though there is growing interest in the colonic micro-
biota and bio-processing for increasing phytochemical
bioavailability the improvements so far are small and
have not improved markers of clinical relevance for re-
ducing risk of T2D. Future dietary intervention studies
seeking to establish a direct role of phytochemicals in
mediating the metabolic health benefits of wholegrains,
and their potential for mitigating disease progression,
should consider using varieties that deliver the highest
possible levels of bioavailable phytochemicals in the con-
text of whole foods and diets. Both postprandial and
prolonged responses in systemic phytochemical concen-
trations and markers of inflammation and oxidative
stress should be monitored and along with changes re-
lated to health outcomes in healthy individuals as well as
those with metabolic disease.
FAE: Ferulic acid equivalent; FRAP: Ferric reducing antioxidant potential;
LPS: Lipopolysaccharide; MDA: Malondialdehyde; ORAC: Oxygen Radical
Absorbance Capacity; SCFA: Short chain fatty acid; SOD: Superoxide
dismutase; TAC: Total antioxidant capacity; TBARS: Thiobarbituric acid reactive
substance; TEAC: Trolox Equivalent Antioxidant Capacity; T2D: Type-2
There are no conflicts of interest.
DPB and ARB participated in the acquisition, analysis and interpretation of
data, and drafting of the manuscript. Both authors read and approved the
Received: 27 February 2013 Accepted: 24 April 2013
Published: 16 May 2013
Belobrajdic and Bird Nutrition Journal 2013, 12:62
Page 8 of 12
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Cite this article as: Belobrajdic and Bird: The potential role of
phytochemicals in wholegrain cereals for the prevention of type-2
diabetes. Nutrition Journal 2013 12:62.
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