The potential role of phytochemicals in wholegrain cereals for the prevention of type-2 diabetes
© Belobrajdic and Bird; licensee BioMed Central Ltd. 2013
Received: 27 February 2013
Accepted: 24 April 2013
Published: 16 May 2013
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 disease.
KeywordsWholegrain Phytochemical Type-2 diabetes Oxidative stress Inflammation
Metabolic disease and protective role for wholegrains
Type-2 diabetes (T2D) is a major health problem worldwide. 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 decades [1, 2]. It is a leading cause of death and disability globally and carries a considerable socioeconomic burden, especially in low and middle income settings [2–5]. Cost-effective mitigation strategies rather than containment are therefore of paramount importance. The initiation 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 interventions .
Dietary patterns featuring wholegrain cereals are associated with reduced risk of T2D [7–10]. Systematic reviews 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 complications 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, controlled dietary studies in humans and other experimental research provides evidence of a causal relationship between 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 type-2 diabetes
Understanding the mechanisms by which wholegrains prevent or delay the onset and progression of T2D is pivotal to developing effective diabetes prevention options. The components of wholegrains which are responsible 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 individual wholegrains differ markedly in the types and hence physiological properties of fibres they contain. Viscous soluble fibres, such as those in oats and barley, slow available carbohydrate assimilation and dampen postprandial glycemic and insulinemic responses . However most observational studies provide evidence of a protective 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 protective bran layer and greatly increases starch availability. However, not all wholegrain foods elicit a moderate glycemic 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 associated with T2D . Furthermore, the cells and tissues of people with metabolic syndrome and T2D have an impaired ability to cope with the burden of increased oxidative stress [40–42]. Therefore, dietary components including phytochemicals (non-nutritive, plant bio actives that reduce risk of chronic diseases ), and a limited number of micronutrients that function as antioxidants, may prevent the development and progression of metabolic syndrome and T2D by reducing oxidative stress . Furthermore, systemic, low grade inflammation, especially in adipose tissue, is a hallmark of many chronic diseases, including T2D . In addition to their antioxidant properties, some cereal phytochemicals have potent anti-inflammatory actions [44, 45] and may thereby modulate diabetes risk by this mechanism as well [43, 46, 47].
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 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, flavones 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 include various carotenoids, notably α- and β-carotene, lutein, 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 chelates prooxidant minerals) and various terpenes and terpenoids (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 phytochemicals, their bioavailability is often increased [45, 50, 51]. Thermal and bioprocessing too can improve phytochemical bioavailability, especially the latter method, although the results are not always consistent.
The type and concentration of phytohcemicals in a range of wholegrain cereals
0.17 – 0.24
0.03 – 0.08
0.18 – 0.21
0.19 – 0.40
0.06 – 0.2
0.11 – 0.16
0.0003 – 3
0.002 – 0.030
0.0002 – 1.37
< 0.10 – 3.3
0.01 – 0.09
0.5 – 0.8
0.55 – 0.80
0.05 – 0.06
27 – 195
6.9 – 11
2.0 – 2.6
2.3 – 8.0
4.7 – 6.8
0.4 – 0.9
0.4 – 0.7
0.05 – 4.8
0.04 – 0.63
0.015 – 0.105
0.014 – 0.077
Polyphenols (mg/100g) 
70 – 1459
50 – 196
54 – 313
125 – 255
9 – 34
200 – 900
100 – 550
200 – 1080
350 – 874
5 – 39
5 – 23
10 – 35
50 – 110
16 – 213
110 – 120
3.9 – 5.0
2.1 – 2.4
30 – 43
12 – 18
6.7 – 7.5
5.6 – 8.2
200 – 750
0 – 150
570 – 3220
4.9 – 27.5
22 – 291
40 – 76
11.3 – 100
57 – 98
90 – 115
Variation in grain phytochemical content
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 winter wheat genotypes were grown under controlled conditions α-tocopherol levels varied by as much as 3-fold, highlighting the significant contribution of genetic variation . However, studies in Europe show that tocopherol 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 genotypes for free and conjugated phenolic levels . However, 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) .
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 capacity.
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 .
Cereal bioprocessing for improving phytochemical bioavailability
Phytochemical bioavailability in the large intestine: role of the microbiota
Major wholegrain phytochemicals, factors affecting their bioavailability and suggested mechanisms for promoting health
Major grain sources
Food & dietary factors affecting bioavailability
Other factors that enhance bioavailability
Potential mechanisms of action
Increase plasma total antioxidant capacity to directly mitigate oxidative stress
Indirect through cell signalling
Wheat, barley, oats, rye
Bio-processing of grain
Increase plasma total antioxidant capacity to directly mitigate oxidative stress
Colonic fermentation (limited evidence)
Indirect through cell signalling
Increase plasma uric acid levels which has reducing and free radical scavenging activities
Improve glutathione radical scavenging system
Wheat, barley, oats, rye
Not relevant as readily available
Not relevant as readily available
A cofactor for glutathione peroxidase, an enzyme that quenches reactive oxygen species
Impact of wholegrain phytochemicals on metabolic health
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 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.
Antioxidant capacity of blood
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 fraction .
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 cereals provides limited benefit for preventing oxidative stress and development of T2D. Wholegrain consumption 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. Although there is growing interest in the colonic microbiota and bio-processing for increasing phytochemical bioavailability the improvements so far are small and have not improved markers of clinical relevance for reducing 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 context of whole foods and diets. Both postprandial and prolonged responses in systemic phytochemical concentrations and markers of inflammation and oxidative stress should be monitored and along with changes related to health outcomes in healthy individuals as well as those with metabolic disease.
Ferulic acid equivalent
Ferric reducing antioxidant potential
Oxygen Radical Absorbance Capacity
Short chain fatty acid
Total antioxidant capacity
Thiobarbituric acid reactive substance
Trolox Equivalent Antioxidant Capacity
Type-2 diabetes Mellitus.
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