Type 2 diabetes mellitus (T2DM) is one of the most common metabolic diseases with 415 million cases estimated globally in 2015; this number is expected to increase dramatically in the next decades reaching 642 million by 2040 [1
]. T2DM represents a leading cause of morbidity and mortality worldwide because of its related microvascular and macrovascular complications. The alarming rise in T2DM prevalence worldwide—including low-income countries and adolescents/young adults—as well as its heavy impact on longevity and quality of life, poses enormous challenges in terms of social, economic, and clinical aspects, urging appropriate preventive strategies [2
]. The progressive diffusion of western dietary habits and low physical activity, and the strictly related global increase in overweight/obesity are the major determinants of the growth of T2DM prevalence observed in the last decades together with the increased longevity connected to the improvements of diabetes care [3
]. In particular, the incidence of T2DM is very high in overweight/obese individuals with visceral adiposity and its linked pathological conditions characterized by interrelated alterations in metabolic and vascular functions such as hyperglycemia, dyslipidemia, insulin resistance, and hypertension [4
Lifestyle interventions aiming at reducing body weight and increasing regular physical activity represent the cornerstone of T2DM prevention and management. Strong evidence from randomized controlled trials (RCTs) in at risk individuals from different populations supports the notion that lifestyle modifications—including a healthy diet, a 7% loss of initial body weight, and a moderate-intensity exercise consisting of at least 150 min/week—represents a very effective strategy for T2DM prevention and treatment [5
Beside physical activity and body weight reduction, a healthy diet represents an additional tool to prevent and treat T2DM over and above its effects on body weight [5
]. In this respect, it is important to underline that body weight reduction and its long-term maintenance are very difficult to be achieved in a large proportion of the at risk population. Therefore, changes in dietary habits, able to reduce the risk of T2DM [5
] independently of calorie restriction, may represent an important resource in the context of a practical and suitable preventive approach at the population level. Along this line, a number of observational studies have highlighted food items that are associated with a reduced risk of T2DM: Fruits, nuts, fish, vegetables, non-tropical vegetable oils, wholegrains, beans, and yogurt [6
]. Recently, a comprehensive meta-analysis has indicated that in addition to foods associated with a lower risk, there are also food items that are associated with an increased risk of T2DM: Red meat, processed meat, eggs, and sugar-sweetened beverages [7
]. A dietary pattern based on the preference of vegetable products and on moderate consumption of animal foods resembles the traditional Mediterranean Diet that has shown to be able to reduce the incidence of T2DM by as much as 30%, despite the fact that body weight did not change [8
Among all food items associated with the incidence of T2DM in observational studies, unambiguous evidence has emerged over the last few decades on the possible role of wholegrain consumption in preventing this disease as well as many other widely chronic non-communicable diseases [9
Several definitions are proposed for “wholegrain” and all give special importance to the intact grain and its three components: Endosperm, germ, and bran [10
], which should be present in the same relative ratio existing in the intact caryopsis. The definition proposed by the European HEALTHGRAIN Consortium also accepts small losses of kernel’s components—2% of the grain or 10% of the bran—that may occur through processing to preserve safety and the quality of the product [11
]. A further distinction should be made to separate intact kernels (i.e., intact, un-milled wholegrains) from milled wholegrains (i.e., wholegrain flours and the products made from them). Wholegrains are represented by cereals (i.e., wheat, rice, maize, rye, oat, millet, barley, sorghum, teff, and triticale), pseudo-cereals (amaranth, buckwheat, and quinoa), and wild rice [12
]. While wholegrains are characterized by the presence of all kernel constituents, great variability in terms of macronutrient/micronutrient composition and content of bioactive compounds has been described for the various cereal classes (Table 1
Wholegrain foods include breads, breakfast cereals, pasta, biscuits, and grain-based snack foods [17
]. In comparison to refined grains, they are rich in dietary fiber, resistant starch, antioxidants, and other important micronutrients such as folic acid and other vitamins [13
]; altogether, these components of wholegrain have relevant functional properties that can at least, in part, justify its health benefits [19
Thus, the aim of the present review is to summarize the available evidence derived not only from epidemiological studies, but also from intervention trials on the possible protective effects of wholegrain foods on T2DM prevention and treatment.
We have reviewed the evidence from observational studies, clinical trials, randomized clinical trials (RCTs), and meta-analyses published in the last fifteen years on Pubmed, which evaluated the relationship between wholegrain consumption and T2DM. We have focused our search on studies performed in humans in which the effect of individual wholegrains/wholegrain foods or wholegrain rich diets were compared with diets or foods based on refined grains with a similar energy intake and macronutrient composition.
We have first considered studies performed in free-living adults who were either healthy or with some known risk factors for T2DM. In observational studies, the incidence of T2DM represented the main outcome. Conversely, due to the absence of long-term RCTs on T2DM incidences, we have included, in our search, shorter term trials—with the exclusion of acute-meal studies—on surrogate endpoints known to be major established T2DM risk factors: Impaired glucose tolerance, plasma glucose, insulin resistance, overweight/obesity, and abdominal obesity. The second part of our search has been performed in patients with T2DM taking into consideration both observational studies and intervention trials. With respect to RCTs on the effects of wholegrain intake in T2DM patients, we have considered studies performed in individuals with clinically established T2DM; changes in fasting and postprandial plasma glucose and glycated hemoglobin (HbA1c) were the main outcomes evaluated in these studies. Finally, we have also evaluated plausible mechanisms by which wholegrain could act on glucose homeostasis and T2DM prevention.
6. Plausible Mechanisms by Which Wholegrains Might Protect against T2DM
Many components of wholegrain can play a role in improving glucose metabolism, thus contributing to T2DM prevention (Figure 1
). Among them, dietary fiber has been extensively investigated since wholegrain foods are a good source of fiber (ranging from 9 to 17 grams for every 100 grams of an edible portion). Fibers from wholegrain cereals are mostly of the insoluble type—i.e., cellulose, hemi-celluloses, and lignin—with the exception of barley and oats that are relevant sources of soluble fiber, i.e., beta-glucan, pentoses, and arabinoxylan [72
]. In particular, the concentration of beta-glucan varies from 0.1% dry weight in corn, to 4.1% in barley, while arabinoxylan ranges from 4.7% in corn to 9.7% in oats; the concentration of cellulose varies from 1.4% dry weight in rye, to 8.2% in oats, while lignin ranges from 1.1% in corn, and up to 6.6% in oats [67
Many plausible mechanisms could be involved in the relationship between wholegrain fiber and improvements of glucose homeostasis. First, it could play a significant role in body weight regulation [37
]. In fact, fiber contributes to lower the energy density of wholegrain foods, as compared to the refined ones [73
]; furthermore, the larger size of starch granules in wholegrain foods and their structural integrity require a higher chewing rate that is strictly related to the oro-sensory stimulation and to satiation, possibly contributing to a reduced food intake [74
]. Second, fiber (particularly the viscous type) is able to increase gastric distension contributing to stimulate satiety signals and to increase hormones involved in body weight regulation and energy homeostasis, as well as in glucose control [76
]. In fact, in a recent study from our group [79
] in which wholegrain pasta was compared with a regular one, the desire to eat and the sensation of hunger were lower after the wholegrain pasta (−16%, p
= 0.04, and −23%, p
= 0.004, respectively); in addition, satiety was higher (+13%; p
= 0.08) compared with the control pasta. Changes in appetite ratings correlated with polypeptide YY (PYY) plasma levels (p
< 0.03). However, wholegrain pasta did not influence the overall energy balance. Similarly, increments of gut hormones and of the insulin sensitivity index were observed following a three-day intervention with a barley kernel-based product [80
The influence of dietary fiber on glucose metabolism has been attributed both to soluble (viscous) and insoluble fibers. Viscous fiber physiologically modulates the postprandial glycaemic response by delaying gastric emptying and small bowel transit time; this can stimulate secretion of intestinal hormones involved in glucose metabolism. In fact, both of them decrease starch accessibility to α-amylase and reduce glucose diffusion through the unstirred layer [81
]. This mechanism is strengthened when the cereal grains are not milled. Unfortunately, few wholegrain cereal foods available for consumers and utilized in intervention studies are based on intact kernels; food structure, besides other features of wholegrain cereal products, has a strong impact on postprandial metabolism by modulating the rate of nutrient digestion (accessibility to digestive enzymes) and absorption in the small intestine. Furthermore, viscous fiber reduces the postprandial glycaemic response by delaying gastric emptying and small bowel transit time; this can stimulate the secretion of intestinal hormones involved in glucose metabolism.
Interestingly, the effects on the postprandial glycemic response and on satiety of isolated cereal fibers have been compared with those obtained with intact kernel wholegrain products in acute meal studies [82
]. The outcomes of these studies indicates that both a wheat bread enriched with oat beta glucan (highly viscous) and an intact kernel rye bread similarly reduce the postprandial blood glucose response, as compared with a refined wheat bread. Conversely, a wheat bread enriched with wheat arabinoxylan (less viscous) had no major impact on the postprandial blood glucose response. However, both beta glucan and arabinoxylan increased satiety feelings in comparison with refined wheat bread; the magnitude of their effects is similar to that of intact rye kernel.
Wholegrain fiber—as well as dietary fibers from other sources—can be fermented by the intestinal microbiota with several beneficial metabolic effects. In fact, short chain fatty acids (acetate, propionate and butyrate) represent the main products of fiber fermentation and they have been shown to influence glucose metabolism by reducing plasma levels of non-esterified fatty acids, that impair insulin sensitivity, and by increasing hepatic glycolysis and decreasing hepatic glucose production, thus lowering plasma glucose levels [37
]. Indeed, in a study from our group in subjects with the metabolic syndrome, higher plasma propionate levels were associated with a better insulin sensitivity after a 12-week of a wholegrain-based dietary intervention [85
In addition, wholegrain consumption has been shown to influence the composition of the gut microbiota; this is now recognized as a major determinant of the interplay between diet and metabolic health. In particular, in some studies, the chronic intake of wholegrain wheat [86
], rye [65
], and barley [87
] induced a decrease of colonic bacterial species that produce molecules able to trigger endotoxemia (i.e., lipopolysaccharides and peptidoglycans) and to promote chronic low-grade inflammation (by tumor necrosis factor-α) and insulin resistance.
Wholegrain can influence glucose control and T2DM risk by multiple mechanisms of action. The lower energy density of wholegrain foods could play a significant role in reducing the energy intake; this is, furthermore, enabled by the larger size of starch granules in wholegrain foods and by their structural integrity, which requires a higher chewing rate, thus increasing satiation. Fiber from wholegrain is able to increase gastric distension and to delay intestinal transit time contributing to stimulate satiety signals and to increase hormones (Ghrelin, PYY, CCK, GIP, GLP-1) involved in energy homeostasis and plasma glucose control. A lower energy intake leads to a decrease of body fat with an improvement of insulin sensitivity. Furthermore, fiber from wholegrain delays nutrient absorption (glucose, FFA) at the intestinal level, and this reduces the insulin demand and stimulates fat oxidation, thus contributing to reduce fat storage. In the colon, wholegrain modulates the composition of gut microbiota and promotes fiber fermentation with production of SCFA. This improves insulin sensitivity at the liver site and reduces subclinical inflammation. A long term improvement of plasma glucose level can be the consequence of lower fat storage, improved insulin sensitivity at the liver site together with a reduced subclinical inflammation and a reduced energy and nutrient intake. Finally, bioactive compounds present in wholegrains (i.e., phenolic compounds, phytosterols, betaine, and carotenoids) may contribute to improve insulin sensitivity and reduce the development and progression of T2DM by acting on the oxidative stress, the transcription of inflammatory cytokines, and subclinical inflammation.
A possible beneficial role has been ascribed to some bioactive compounds present in wholegrain [72
]. In particular, phenolic compounds, phytosterols, betaine, and carotenoids, for their antioxidant and anti-inflammatory properties, may contribute to reduce the development and progression of T2DM by hampering the oxidative stress, the transcription of inflammatory cytokines and chronic low-grade inflammation [14
], thus improving insulin sensitivity [90
]. Our group has recently shown that a diet based on natural products rich in polyphenols improves glucose tolerance and insulin sensitivity in non-diabetic people and lowers the postprandial triglyceride response [91
Finally, wholegrain is a good source of vitamins and minerals that may also play a role in glucose metabolism. The most representative vitamins in wholegrain are the B complex vitamins, ranging from one mg (for thiamin) to 11 mg (for nicotinic acid) in every 100 g of wholegrain; vitamin E is also present in a good quantity (two-to-seven mg/100 g wholegrain). Vitamin B complex may contribute to the regulation of hepatic glucose uptake [92
], while vitamin E may be beneficial in reducing the oxidative stress and chronic low-grade inflammation associated with obesity, metabolic syndrome, and insulin resistance [93
]. With respect to minerals, wholegrain is a good source of iron, magnesium, zinc, manganese, and selenium [72
]. Magnesium, in particular, has been suggested in some studies to contribute to the regulation of insulin-mediated glucose uptake, and more generally, to the improvement of insulin sensitivity [96
]. Zinc may support the signal transduction of insulin and could improve glucose homeostasis by reducing the production of some cytokines and oxidative stress involved in β-cell death [97
]. Obviously, many of these mechanisms are operative in people with severe deficits of these micronutrients. Further studies in humans are needed to highlight their metabolic relevance in general populations, or at least in people with less severe deficits like elderly people.
Findings from large observational-prospective or cross-sectional studies reviewed in this paper have consistently demonstrated that a higher intake of wholegrain is associated with a lower risk of T2DM, as well as an improvement of its major risk factors, i.e., overweight/obesity, plasma glucose regulation, postprandial hyperinsulinemia, and insulin resistance. Moreover, habitual wholegrain consumption is also associated with a reduced risk of other chronic diseases and with a better nutritional quality of the diet, due to greater intakes of micronutrients [17
]. With respect to T2DM, epidemiological evidence indicates that individuals who consume an average of two-to-three daily servings (60–90 g/day) of wholegrain have a 21–32% reduction in the incidence of T2DM compared with those who rarely or never consume wholegrain. This amount can be easily achieved by substituting at least half of the refined cereal foods in the habitual diet with the wholegrain ones.
Many intervention trials have been undertaken in order to investigate whether wholegrain consumption is able to improve major risk factors for T2DM; however, findings from these studies have not been as impressive as those from the observational ones. So far, the evidence from these trials do not allow us to draw definite conclusions about the preventive efficacy of wholegrain foods on the development of T2DM or its major risk factors. This represents a remarkable research gap that needs to be filled by well-designed, adequately powered, and randomized clinical trials with sufficient duration to be able to ascertain the long-term effects of wholegrains on T2DM prevention and treatment.
However, given the strength and the reproducibility of the evidence related to the possible benefits of wholegrain for prevention of T2DM achieved in epidemiological studies—as well as the consistency of the observational data showing other better health outcomes associated with habitual wholegrain consumption—it seems wise to include wholegrain foods in the dietary recommendations for T2DM prevention and treatment. This also seems appropriate in view of the lack of relevant adverse effects associated with wholegrain intake. Special emphasis should be given to specific types of wholegrain cereals, like oats and barley, for which a beneficial impact on glucose metabolism has been more clearly demonstrated in intervention studies. Regular consumption of wholegrain is now recommended by nutritional guidelines in many countries [17
] and by statements from major scientific societies in the field of diabetes [5
]. For the time being, on the basis of the evidence reviewed in this paper, two-to-three servings per day of wholegrain (60–90 g/day), as indicated by dietary recommendations for T2DM prevention and treatment [5
], represents an appropriate and achievable goal for the general population, and even more for individuals at increased risk of T2DM.