Journal of Nutritional Health & Food Science

Daily diet influences whole body metabolism, and intricately linked to the prevention or progression of metabolic diseases including obesity, diabetes and cardiovascular diseases. Several epidemiological and large scale studies have shown that diets enriched with whole grains improves metabolic function and protect from the development of metabolic diseases. Direct impact of whole grain diet can be mediated on several levels of metabolic functions i.e. reduced glycemic index, improved fat oxidation potential, increased cholesterol clearance or decreased cholesterol biosynthesis and modulation of gut microbiome. In this article we reviewed several studies indicating the beneficial effects of whole grain diets on metabolic functions, as well as discussed the potential active phytochemicals present in these whole grain foods to contribute in modulation of metabolic function in our body.

Keywords: Whole Grain; Diabetes; Obesity; Metabolism; Fat; Phytochemicals; Nutrition; Microbiome; Metabolic Diseases;

The sharp spike in the prevalence and severity of obesity, type 2 diabetes and metabolic syndrome is a chief concern for society as a whole [1]. Obesity is characterized by the accumulation of excess fat in the adipose tissue. At its core, the obesity epidemic stems from an excess of energy intake compared to energy expenditure [1]. Thus, consumption of "healthy" diet is a critical to curtailing the dual epidemics of obesity and type 2 diabetes. Currently, a tremendous amount of research worldwide explores the beneficial health effects and nutritional composition of foods that are part of our diet. Not only vitamins and minerals are explored for their promised beneficial properties, but also bioactive phytochemicals in functional foods are of great interest in research. Growing evidence asserts potent roles of phytoconstituents of various functional foods in the amelioration of chronic diseases, including diabetes, obesity and the resultant metabolic syndrome [2, 3].

Whole grains were brought to public attention as research around the world to uncover their beneficial health effects. The 1995 USDA Dietary Guidelines did not specifically recommend the intake of whole grains; however, the 2005 and 2010 guidelines suggested consuming at least 3 ounces of whole grains per day, and ensuring 50% of daily grain intakes come from whole grains [4, 5]. Further, a markedly greater number of whole grain products are available to consume in the current market. The most recent examination of the principal sources of whole grains in the American diet was done by Bachman et al. in 2001- 2002 [6]. Wheat is the leading grain in the American diet, and oats, corn, barley, rice, rye, millet and spelt are all consumed in varying proportions [6, 7]. These whole grains are present in many types of foods like breads, pastas, baked goods, tortillas, breakfast cereal and several others.

The broad spectrum of foods that constitute whole grains, coupled with varying definitions of a "whole grain" between organizations, studies and databases renders much uncertainty in the estimation of an individual's whole grain intake. Regardless of the variance, however, the overwhelming majority of studies assert that majority of population with western food habits do not consume adequate amounts of whole grains. Despite the positive steps taken by governmental agencies and industry, the average Americans still does not consume the recommended amount of whole grains per day [8-10].

According to the FDA and American Association of Cereal Chemists International, a whole grain is defined as "whole grain consists of the intact, ground, cracked or flaked caryopsis, whose principal anatomical components - the starchy endosperm, germ and bran - are present in the same relative proportions as they exist in the intact caryopsis" [11]. A whole grain may either remain intact, or be reconstituted. A reconstituted whole grain is one in which the components of the whole grain are recombined to match relative proportions that are present in the naturally occurring kernel [12]. The overwhelming majority of whole grain products commercially distributed fall under the category of reconstituted whole grains.

The outermost layer of a whole grain is the bran, which contains mainly non-digestible carbohydrates (cellulose, arabinoxylan and others). Function of bran is to protect the inner layers from external environmental stresses. The inner layers of the grain – the endosperm and the germ consist of soluble fibers, resistant starch, vitamins, minerals, and various other phytonutrients (polyphenols and others) [11]. Refining whole grains removes the bran and germ, leaving the endosperm to be processed into white flour (Figure 1). The majority of nutrients and phytochemicals, however, are concentrated in the bran and germ portions of the whole grain [13, 14]. Therefore, many of the key nutrients and phytochemicals, including over 75% of the fibers, are physically removed through the process of refining [15]. Overall, whole grains have higher phytonutrient content, leading to higher antioxidant activity, and more beneficial modulation of glucose and energy homeostasis. Refining wheat loses 83% of total phenolic acids, 79% of total flavonoids, 93% of ferulic acid, 78% of total zeaxanthin, 51% of total lutein, and 42% of total β-cryptoxanthin [16]. Table 1 described major macronutrient composition of the most common whole grains (Table 1).

The epidemiology demonstrating that consumption of whole grains ameliorates obesity, type II diabetes and their resultant complications is fairly consistent. Over the past decade, many large scale studies have reached the conclusion that there exists a significant inverse association between the intake of whole grains and the incidence of type II diabetes [14] and cardiovascular disease in both sexes [17-19]. Kastorini and Panagiotakos reviewed several broad studies exploring whole grains and diabetes [20] and Priebe et al. compiled numerous cohort studies [21, 22]. Phytochemicals present in whole grains may confer

potent anti-diabetic/obesity properties. The succeeding sections of this article will review the important phytochemicals part of whole grains, and their role in amelioration of type 2 diabetes and metabolic derangements. However, as the research exploring the specific effects of phytochemicals isolated from whole grains is relatively young, it is important to keep the findings in context until stronger and more mechanistic studies demonstrate their definite role against metabolic diseases. Furthermore, as it has been shown with phytochemicals from fruits, vegetables and other food groups have synergistic effect of whole grain's phytochemicals that may be responsible for the significant health benefits derived from whole grains.

Pioneering studies conducted in 1980's uncovered the role of whole grains in the regulation of glucose homeostasis. Compared to a high glycemic index diet (GI = 90) of potatoes and white bread, a low glycemic index diet (GI = 67) containing bread with whole grains, parboiled wheat, pasta and legumes demonstrated a significantly decreased blood glucose and circulating insulin levels in both normal and diabetic subjects [23]. And compared with a diet using refined grain flour, one using whole grain flour demonstrated a significantly lowered circulating glucose and insulin levels [24]. In 2004, Slavin thoroughly reviews the subsequent studies that substantiated the evidence of association between whole grain intake and beneficial regulation of glucose homeostasis, and in some cases, amelioration of diabetes mellitus [25]. Overall, they reports that consumption of whole grains is inversely correlated with circulating insulin and glucose levels. Interestingly in 2002, Periera et al. showed that there may be enhancement of insulin sensitivity due to whole grain intake [26].

The research is young, and relatively few phytochemicals about whole grains and metabolic diseases have been shown to beneficially from modulate glucose metabolism. Many antinutrients, including phytic acid, amylase inhibitors, saponins, phenolics and lectins have been shown to decrease circulating glucose and insulin [25]. Cyanidin, an anthocyanidin with a characteristic reddish-orange color, has previously been shown to reduce blood glucose levels and improve insulin sensitivity due to the reduction of retinol binding protein 4 expression in type 2 diabetic mice [27]. In addition,

Takanori et al discovered that cyanidin glucoside from purple corn extract has a potential to ameliorate diabetic complications [28]. Members of the carotenoids, flavonoids, hydroxycinnamic acids, vitamin E, and other phytochemicals that are part of whole grains have also been shown to play roles in diabetes. β-Cryptoxanthin is an antioxidant, which beneficial may help prevent free radical damage to cells and DNA, as well as stimulate the repair of oxidative damage to DNA. An increased to intake of total β-Cryptoxanthin along with other phytochemicals was associated with a reduced risk to type 2 diabetes [29, 30]. Lutein, an antioxidant that is an essential chemical in ocular function, is also found in whole grains [31]. Arnal et al found that a combined treatment with lutein and insulin prevented the development of cataracts in streptozotocin-induced diabetic rats by inhibiting

lipid peroxidation in the diabetic rats [31]. Furthermore, Muriach et al discovered eye lenses of that lutein may reduce susceptibility to infections in diabetic patients [32], as diabetic subjects have higher risk of common infections [33, 34]. Another phytonutrient present in whole grains, zeaxanthin, also has the potential to inhibit the development of retinopathy in diabetic patients [35].

Acute consumption of barley β-glucan, but not resistant starch, in muffins was effective in reducing glucose and insulin responses in men who were mildly insulin-resistant [36-38].

Dietary intake of β-glucans has been shown to help with control of blood glucose level and lipids; and reduction of hypertension [39]. Kobori et al asserted that quercetin (a flavonol found in many fruits, vegetables, leaves and grains) reduced blood glucose level and improved plasma insulin levels in streptozotocin-induced diabetic rats [40]. Another study concluded that quercetin may have a pharmacological application in treating cardiovascular disease in diabetic patients via its antioxidant and anti-inflammatory potential [41, 42]. Yang et al showed that quercetin combined with resveratrol can inhibit fat cell differentiation and development [43].

Ohnishi et al found that dietary ferulic acid can alleviate oxidative stress and attenuated hyperglycemic associated response in diabetes [44]. Balasubashini et al showed that ferulic acid enhances antioxidant capacity thus alleviating diabetes [45].

In another study, it has been shown that saponin (a common phytochemical found in grains) from Tribulue terrestris could significantly reduce the level of serum glucose [46], but it was not clear that saponin from whole grain sources has the same effects on blood glucose levels. Lower β-tocopherol (vitamin E) concentration is known to be associated with impaired insulin sensitivity[47, 48], and treatment of vitamin E exerts a protective role against diabetes-induced peripheral muscle dysfunction and renal function [49-51], as well as reduced risk of type 2 diabetes [30]. Kushad et al showed that tocotrienol can prevent diabetes associated cognitive deficits [52], and reduced risk of type 2 diabetes have been associated with increased tocotrienol [30]. Mice on diets with greater phytic acid (a common anti-nutrient in grains) intake displayed lower blood glucose levels after glucose tolerance tests [53, 54], and also known to lower blood glucose response by reducing the rate of starch digestion and slowing the gastric emptying [55]. Gamma-oryzanol or rice bran oil (an oil extracted from the hard outer brown layer of rice after chaff / rice husk) increased insulin sensitivity in diabetic mice [56]. Despite the current research efforts, there is a dearth of studies that explore the molecular mechanisms and the role of specific whole grain phytochemicals to regulate glucose homeostasis. Although many hypotheses (e.g. the fiber hypothesis) float around, it is critical that future research explores the beneficial effects of whole grains in blood sugar metabolism at a mechanistic level. Further, as many believe that the mechanism by which whole grains regulate glucose metabolism is largely based on the botanical structure of the grain and its phytochemicals detailed analyses of structural interactions are warranted. Overall, it is critical to further elucidate the role of whole grain phytochemicals in ameliorating the pathogenesis of type 2 diabetes.

Antioxidant activity is a potent mechanism by which whole grains deliver their beneficial health effects against several human diseases including obesity and diabetes. At core, the function of antioxidants is to react with free radicals to protect against free radical or Reactive Oxygen Species (ROS) attack on self-lipids, protein and DNA [57]. Free radical attack is established to be a critical initiator of several chronic diseases, including type 2 diabetes [58]. Whole grains contain a mass of antioxidant compounds, which have been shown to possess potent antioxidant activity [59]. Many soluble antioxidant compounds, including phenolic acids, tocopherols and flavonoids, are present in whole grains [60]. The highest phenolic acid content is present in corn (265 mg gallic acid equivalents/ 100 g), followed by wheat (135 mg), oats (111 mg) and rice (95 mg) [61]. Ferulic acid, one of the most well studied phenolic acids, is shown to be a strong antioxidant by donating hydrogen atoms to free radicals [61, 62]. Carotenoids in whole grains include lutein, alpha-carotene, beta-carotene and beta-cyproxanthin, are found in the bran and germ layers of whole grains, can also serve as antioxidants [63]. Further, antioxidant capacity is inherent in insoluble grain fibers [64, 65]. Phytic acid is common phytochemical in many whole grains, and is well known as an antioxidant that represses ironcatalyzed redox reactions [66, 67].

Processing affects the biological activities of food and their ingredients, and most of grains and their food products go through very exhaustive food processing route [66, 68-70]. Vitamin E, is another common ingredient of whole grains is a potent antioxidant that protects cell membranes and inhibits the formation of nitrosamines [72, 73]. but it is almost wholly removed during the refining process of whole grains [71]. In addition, the toasting process that many whole grains undergo (e.g. toasting whole wheat bread) increases the antioxidant activity compared to the raw materials, and actually develops a similar activity as that of many fruits and vegetables [74]. However, it is important to note that although many potent antioxidant compounds have been identified in whole grains, and their individual effects have been reported, but studies elucidating which compounds provide the most potent and specific effects in the context of whole grains is not done very comprehensively.

Epidemiologically, whole grains have been shown to beneficially alter critical measures of obesity, such as weight, Body Mass Index (BMI) and waist circumference [75]. Jonnalagadda et al. review the prospective studies that utilize diverse patient databases to conclude that consumption of whole grains is inversely correlated with weight, BMI and waist circumference [14]. Further, visceral adipose tissue volume is negatively correlated with intake of whole grains (3 ounceequivalent servings per day) in both men and women [76]. Overall, reduction in weight gain has been the central benchmark for many of the clinical studies conducted on whole grains and obesity [14], with the trend heading towards examining the role of whole grains in decreasing visceral adiposity. The recent evidences also suggest that in addition to the marked decreases in body weight are associated with whole grain intake and suggested that, whole grains may contribute to the redistribution of fats within the body [76]. Intervention studies, however, report the inconsistent results of the beneficial effects of whole gains in reducing overweight and obesity [14]. Therefore, it is more critical to place the emphasis on placing refined grains versus whole grains as a central tenant in many of these studies, as therein lies the challenge for society as a whole.

Overall, however, the vast majority of clinical studies – both epidemiological and mechanistic – are conducted in the Caucasian population. Studies exploring similar benefits in other populations both within the United States and around the world are warranted in more comprehensive manner and considering parallel comparison to existing studies designs.

The mechanisms by which phytochemicals present in whole grains directly affect various conditions of obesity have been minimally explored. One mechanism suggests that whole grains act to increase satiety, and consequently render those who consume whole grains to desire less food intake [77, 78]. Indeed, several studies have reported an increased feeling of fullness with the addition of whole grain to the diet [77, 78]. These reductions in hunger caused by intake of whole grains may be due to a differential profile of gut hormones, as whole grains have been shown to influence ghrelin, peptide YY, glucagon-like peptide 1, cholecystokinin [14]. Although variability in changes in hunger versus satiety feelings levels in several studies have been reported, and acknowledged the subjects do not demonstrate a decrease in energy intake [14]. However, in some studies, whole grains have been clearly observed to reduce energy intake [79]. This calls for further research elucidating the mechanisms by which whole grains may alter satiety and food intake signals, a critical player in the delicate balance between energy intake and expenditure.

Imbalance in cholesterol metabolism and elevated cholesterol levels are common conditions in obese and diabetic subjects, and tightly correlated with increased incidence of cardiovascular diseases [80, 81]. Phytosterols from whole grains have been shown to displace cholesterol from micelles, in turn reducing cholesterol absorption, increasing excretion, and ultimately decrease serum cholesterol in hyper cholesterolemic men and women [82-84]. Linoleic acid and palmitate, both part of the unsaturated fatty acids that are highly present in whole grain fats, and whole grain derived these fatty acids have been demonstrated to reduce serum cholesterol and increase Low

Density Lipoprotein (LDL) [85-87]. Anti-nutrients discussed by Slavin et al, strongly suggested that beneficial effects of whole grain derived anti-nutrients modulated blood sugar levels along with lowering plasma cholesterol and triglycerides [25]. Maki et al showed that whole grain Ready To Eat (RTE) oat cereal consumption as part of a dietary program for weight loss had favorable beneficial impacts on fasting lipid levels and waist circumference in selected population [88]. Durrazo et al, described in a very well designed randomized clinical trial investigating the effect of intake of whole grain foods rich in lignans as part of an habitual diet showed a modest hypocholesterolemic effects [89]. Still, several studies have inconclusive results to show beneficial effects of whole grain foods on cholesterol metabolism, but the limitation in these studies are that many studies used processed whole grain foods and that food processing might have great impact on biological activities of whole grain as is. Further studies are needed to conclude, effects of whole grain foods, their ingredients and types of processing have impact of health beneficial effects.

Now It's very obvious that microbiome have major impact on human health and contribute in pathology of several human diseases including cancer, metabolic and immune disorders [90]. Initial original studies from Jeffery Gordon and others concluded that gut microbiome have major impact on obesity and type 2 diabetes development and contribute in regulation of whole body metabolic function of host [91]. Although, recent study couldn't find the direct correlation of gut microbiome with obesity from pooled data of more than 10 studies [92], but several independent studies have concluded not only correlation, rather direct impact of microbiome on several metabolic features i.e. body weight gain, fat mass, blood glucose and lipid levels [93]. Diet has major impact on gut microbiome and its derived metabolites to influence host metabolism by several mechanisms [94]. Dietary fibers are major source of gut microbiome derived metabolites i.e. short chain fatty acids that can influence several metabolic pathways i.e. gut hormone release, AMP activated kinases, and mitochondrial functions [95-97]. Effect of gut microbiome is not limited only into the gut but signal from microbiome sense by several other metabolic organs i.e. liver, adipose tissue, skeletal muscles, pancreas, and brain to regulate major energy homeostasis mechanisms [96-98]. Modulation of gut microbiome has been proposed one of the prominent strategies to counter metabolic diseases. Probiotics and prebiotics are major natural modulators of gut microbiome and have been known for several health beneficial effects to the host, including improvement in metabolic functions [99, 100]. Whole grains have also been suggested to possess prebiotic effects, as fecal samples of humans fed with whole grain cereals contain significantly increased numbers of fecal bifidobacteria and lactobacilli [101]. Prebiotics and probiotics are increasingly being explored by many research groups worldwide, and are being established to play critical roles in the pathogenesis of obesity [99]. Connolly et al showed the impact of oat grain on the microbial ecology of the human gut and its potential to beneficially modulate the gut microbiota through increasing Bifidobacterium population by changing fermentation activity to produce short chain fatty acids i.e. propionate and butyrate [102]. Whole grains showed significant decreasing obesity parameters that correlated with changes in gut microbiome [103]. Whole grain feeding impacted energy intake that was associated with changes in metabolomics profile of gut microbiome derived metabolites and gut hormone changes [104]. Zhou et al clearly described that feeding of whole grains dominantly changes gut microbiome and improve insulin sensitivity and other metabolic measures in mice models [105].

Whole-grain barley feeding known to decrease the high fat dietinduced inflammation that is possibly related to formation of short chain fatty acids i.e. propionate, butyrate and changes in microbiota composition [106]. In addition, in this study authors found that high β-glucan content in the diet reduced plasma cholesterol levels [106]. Food processing is always a factor in whole grain induced changes in gut microbiome, as recent study showed that processing of whole-grain barley to barley malt have significant impact on gut microbiota and metabolites in rats fed high-fat diets [107]. As the mechanisms by which whole grains improve characteristics of overweight and obesity are for the most part obscure, it is critical for research to specifically explore the roles of phytochemicals and other constituents.

Whole grains contain a host of bioactive phyto-constituents i.e. fibers, alkaloids, flavonoids, saponins and other phytochemicals, vitamins, antioxidants and immune modulators, with known health benefits, including amelioration of chronic diseases (such as obesity and diabetes). These bioactive phytochemicals, both in isolation and in combination, appear to be key players in the improvement of glucose metabolism in different metabolic organs i.e. liver, pancreas, skeletal muscles, adipose tissue, gastrointestinal tract, immune cells and brain directly or indirectly via influencing gut microbiome, gut hormones, gutbrain axis and inflammatory response as well as oxidative stress and cholesterol profiles (Figure 2). However, the phytochemicals reviewed here warrant further in depth research. In current literature rarely any phytochemicals from whole grains are reported and discussed directly to influence metabolic function with Comprehensive and defined mechanism(s) of action.. In summary, whole grains possess evident anti-diabetic and antiobese properties, but research must seek to further elucidate the role of both specific phytochemicals and establish mechanistic explanations for these effects. Further, there are unique subsets of phytochemicals in whole grains that are poorly characterized and purified. Therefore, chemical research is also essential to discover all of the bioactive components in whole grains, as each may have potent abilities to improve the pathophysiology of diabetes, obesity, and the resultant metabolic complications.

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