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Nutrition and Disease

Whole-Grain Foods Do Not Affect Insulin Sensitivity or Markers of Lipid Peroxidation and Inflammation in Healthy, Moderately Overweight Subjects^1,2

³ Clinical Nutrition and Metabolism, Department of Public Health and Caring Sciences, Uppsala University, 751 85 Uppsala, Sweden and ⁴ Department of Food Science, the Swedish University of Agriculture Sciences (SLU), 750 07 Uppsala, Sweden

^* To whom correspondence should be addressed. E-mail: agneta.andersson{at}pubcare.uu.se.

	ABSTRACT

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
High intakes of whole grain foods are inversely related to the incidence of coronary heart diseases and type 2 diabetes, but the mechanisms remain unclear. Our study aimed to evaluate the effects of a diet rich in whole grains compared with a diet containing the same amount of refined grains on insulin sensitivity and markers of lipid peroxidation and inflammation. In a randomized crossover study, 22 women and 8 men (BMI 28 ± 2) were given either whole-grain or refined-grain products (3 bread slices, 2 crisp bread slices, 1 portion muesli, and 1 portion pasta) to include in their habitual daily diet for two 6-wk periods. Peripheral insulin sensitivity was determined by euglycemic hyperinsulinemic clamp tests. 8-Iso-prostaglandin F₂ (8-iso PGF₂), an F₂-isoprostane, was measured in the urine as a marker of lipid peroxidation, and highly sensitive C-reactive protein and IL-6 were analyzed in plasma as markers of inflammation. Peripheral insulin sensitivity [mg glucose · kg body wt^–1 · min^–1 per unit plasma insulin (mU/L) x 100] did not improve when subjects consumed whole-grain products (6.8 ± 3.0 at baseline and 6.5 ± 2.7 after 6 wk) or refined products (6.4 ± 2.9 and 6.9 ± 3.2, respectively) and there were no differences between the 2 periods. Whole-grain consumption also did not affect 8-iso-PGF₂ in urine, IL-6 and C-reactive protein in plasma, blood pressure, or serum lipid concentrations. In conclusion, substitution of whole grains (mainly based on milled wheat) for refined-grain products in the habitual daily diet of healthy moderately overweight adults for 6-wk did not affect insulin sensitivity or markers of lipid peroxidation and inflammation.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

Despite indications that whole grain foods may beneficially influence glucose and lipid metabolism, knowledge of how biological mechanisms contribute to the health effects of whole grain remain weak. Several bioactive components, such as dietary fiber, vitamins, minerals, antioxidants, and other phyto-protectants in whole grain may act synergistically to lower the risk of chronic diseases (20,21). Insulin resistance and oxidative stress are both important factors in the pathogenesis of type 2 diabetes and cardiovascular diseases (22–25) and may potentially be affected by whole-grain intake. Induction of lipid peroxidation in humans has been associated with impairment of insulin sensitivity along with a proportional increase in specific markers of lipid peroxidation and inflammation (26). In a study of patients with coronary heart disease, the consumption of whole-grain products, in combination with other plant products, reduced markers of lipid peroxidation (27). A healthy dietary pattern that includes whole grain products lowers serum insulin concentrations (28), and improved glycemic tolerance was found in subjects that consumed a high fiber diet (29–31). Furthermore, a positive effect on insulin sensitivity, measured by clamp test, after a whole grain diet was found in a controlled experiment of overweight or obese hyperinsulinemic adults (32). The quality of carbohydrates in the diet has also been related to inflammation markers (33) as well as to fibrinolytic capacity (34), but the specific effects of whole grains on those variables is still poorly investigated.

The aim of this study was to evaluate the health effects of a diet rich in whole grains, compared with a diet containing the same amount of refined-grain, carbohydrate-rich foods. The primary endpoints examined were the effects on insulin sensitivity, and markers of lipid peroxidation and inflammation in vivo. Secondary aims were to study the effects on serum lipids, blood pressure, and fibrinolytic capacity and to relate the effects, if any, to changes in insulin sensitivity and lipid peroxidation.

	Materials and Methods

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
    Subjects. Thirty-four subjects were recruited through advertisements in local newspapers. Thirty subjects (22 postmenopausal women and 8 men) completed the study, whereas 4 subjects dropped out due to personal reasons. Inclusion criteria for study subjects included that they be between 35 and 70 y of age, moderately overweight and/or with abdominal obesity (BMI 26–35), with one or more of the following criteria: elevated plasma insulin levels, elevated fasting glucose concentration, increased serum triglycerides, reduced HDL cholesterol, or borderline hypertension. Of the participating subjects, 28 were nonsmokers, one person smoked daily, and one at special occasions (Table 1).

    Diet intervention. Subjects were encouraged to adhere to their habitual daily diet and to include a fixed amount of either whole-grain products or refined-grain products (Table 2). All food products provided to subjects were based on cereals and available on the Swedish food market, with the exception of 1 type of muesli that was specially produced for the study (Table 3). The whole-grain products used were defined as containing a minimum of 50% whole grain per dry substance, including the starchy endosperm, germ, and bran, in mainly milled form. Whole-grain rice was examined by light microscopy and included as a whole-grain product because the bran was intact and >80% of the germ was present. The total amount of whole grain in the whole-grain food during the whole-grain intervention period was 112 g/d. The daily contributions of energy and dietary fiber from the whole-grain foods were 3180 kJ (28 g protein, 8 g fat, and 143 g carbohydrate) and 18 g, respectively, and, from the refined-grain foods, 3340 kJ (23 g protein, 14 g fat, and 145 g carbohydrate) and 6 g. The dietary fiber content of foods included in the intervention was analyzed according to Theander et al. (35) and compared with values listed in the food database of the Swedish National Food Administration (PC-kost 1/2002) based on the principles of Association of Official Analytic Chemists (36).

Compliance with the dietary intervention was monitored by diaries, including a structured list to tick off the daily portions eaten. Intakes above the daily recommended portions were noted by free text at end of each diary page. All participants received written and oral instructions concerning the diets before the test periods and were supplied with recipes that indicated how the products could be used in the best possible way to ensure good adherence to the diets. Once per week the subjects visited the clinic to collect new food products, turn in their diaries, and record their body weight. At the end of each diet period the participants filled in a form regarding possible concurrent illnesses and other symptoms that may have occurred during the treatment periods. This form also included questions concerning the subject's experience of the food products consumed.

Clinical and laboratory tests were conducted before and after both the 6-wk test periods, in the morning after an overnight fast. Blood samples were drawn from an antecubital vein. Body weights were measured, with the subject dressed in light clothes and without shoes, to the nearest 0.1 kg with a digital scale. BMI was calculated as body weight (kg) divided by squared height (m²). Blood pressure was measured in the supine position in a standardized way after 5–10 min rest with an automatic analyzer (OMRON 711, GmbH). Peripheral insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique (37). The insulin (Actrapid R Human; Novo) infusion rate during the clamp was 389 pmol (=56 mU)/(m body surface² · min), with a target mean plasma insulin concentration of 694.5 pmol/L (100 mU/L). The glucose disposal rate (M-value, mg · kg body wt ^–1 · min^–1) was measured during the last 60 min of the clamp. The insulin sensitivity index [M/I,⁵ (mg glucose · kg body wt^–1 · min^–1 per unit plasma insulin (mU/L) x 100] was measured by dividing the mean glucose disposable by the mean plasma insulin concentration during the last 60 min of the total 120-min clamp test. The plasma insulin concentration was measured with an enzymatic immunological assay (Mercodia) in a Coda Automated EIA Analyzer (Bio-Rad Laboratories). Blood glucose concentrations were measured by the glucose oxidase assay (HemoCue). The concentration of free 8-iso-prostaglandin F₂ (8-iso PGF₂), an F₂-isoprostane, in urine was analyzed as a marker of in vivo lipid peroxidation using a radioimmunoassay with a specific antibody against free 8-iso-PGF₂ (38). The urinary 8-iso-PGF₂ concentrations were corrected for creatinine and measured in a Konelab 20 Clinical Chemistry (Thermo Electron) by a commercial kit (Konelab Creatinine 981811, Thermo Clinical Labsystems). The concentrations of - and -tocopherols in plasma, as indicators of antioxidative status, were measured using HPLC with fluorescence detection (39). Adjusted tocopherol concentrations relative to serum lipid levels (sum of serum triglycerides and cholesterol) were also calculated (40). Triacylglycerol and cholesterol concentrations in serum were analyzed by enzymatic colorimetric methods (Thermo Electron) in a Konelab 20 Clinical Chemistry Analyzer (Thermo Electron). HDL was isolated by precipitation and centrifugation (2900 x g for 20 min) with a sodium phosphotungstate and magnesium chloride solution and HDL cholesterol measured by enzymatic colorimetric methods as described above for the cholesterol analysis. The LDL cholesterol concentration was calculated according to the formula of Friedwald (41). Free fatty acids in serum were analyzed by an enzymatic colorimetric method (Wako Chemical) in Konelab 20, described above. The fatty acid composition of whole serum lipid esters was evaluated by GC of fatty acid methyl esters (Hewlett Packard system GLC 5890) (42). Standards from Nu Chek (Nu Chek Prep) were used to identify individual fatty acids. IL-6 and highly sensitive C-reactive protein (CRP) in plasma were analyzed as markers of inflammation. Measurement of CRP was performed by latex-enhanced reagent with the use of a Behring BN ProSpec analyzer (Dade Behring). IL-6 was analyzed by an ELISA kit (IL-6 HS, R&D Systems).

PAI-1 activity (plasminogen acticator inhibitor, an inhibitor of the fibrinolysis in the blood) was analyzed in plasma with commercial 2-step indirect enzymatic assay (Spectrolyse/pL PAI, Biopool AB) described in Eriksson et al. (43). The activity is given in kU/L, where 1 U is the amount of PAI-1 that inhibits 1 U of human single-chain tissue-type plasminogen activator.

    Statistics. The number of subjects included was estimated to allow a 80% power for detecting a 10% difference in M/I between the 2 test groups at significance of P < 0.05. The analysis was performed with SAS, version 9.1 (SAS institute). Values were presented as means ± SD. For variables with skewed distribution, data were log transformed before statistical analysis. Analyses were performed using ANCOVA appropriate for crossover design. Treatment sequence, patient-nested-within-sequence, period, and treatment were included as factors in the model and BMI was included as a covariate. Carryover effects were evaluated by comparing the treatment sequences with "patient nested within treatment" as the error term. These tests were 2-sided and performed at the 10% significance level. If the carryover effect was significant, the treatment effect was analyzed only at the 1st dietary period using ANCOVA for parallel groups design, including the baseline value as a covariate. This was the case for dietary protein (E %, energy percentage), calcium, and systolic blood pressure. The tests for the treatment effect were 2-sided and performed at the 5% signficance level.

	Results

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
    Dietary intake and compliance to dietary instructions. The reported intakes of dietary fiber, -tocopherol, phosphorus, iron, magnesium, and zinc were, as expected, higher during the whole-grain diet period than during the refined-grain diet period (Table 4). Otherwise, nutrient intakes did not differ between the 2 test diet periods, with the exception of a slightly higher intake of calcium during the refined-grain diet period. Furthermore, dietary fiber intake was clearly higher during the whole-grain diet period than when the subjects consumed their habitual diets before the study (P < 0.001), and the fiber intake during the refined-grain diet period was less than the reported habitual intake (P < 0.001). There was a strong correlation between analyzed dietary fiber content of test foods and values reported in the database, which were used for nutrient calculations (r = 0.90, P < 0.001), although the analytical methods used were different. The analyzed and calculated fiber contents in the products are presented in Table 3 and the daily portions of the products in Table 2.

During the whole-grain period, subjects consumed 98% of the recommended intake of whole-grain bread, 97% of the whole-grain crisp bread and muesli, and 90% of the whole-grain pasta, according to items they checked on a list. In addition, 21 subjects reported (as free text added in the diaries) an intake above this daily portion on some days, which on average corresponded to 1 portion pasta, <1 portion muesli, 2 slices bread, and 6 slices of crisp bread during the total whole-grain period. During the refined-grain period, subjects consumed 99% of the recommended intake of bread, 97% of crisp bread, 95% of the muesli, and 92% of the pasta. Additional consumption during the total refined period was reported by 22 subjects and corresponded on average to <1 portion of pasta, 3 slices of bread, 4 slices of crisp bread, and 1 portion of muesli. As much as 1 wk of data were lacking from the diaries of 3 subjects, otherwise all diaries were complete.

    Effects on metabolic endpoints. Subjects' BMI was slightly but signficantly greater during the whole-grain period compared with the refined-grain period (Table 5). Therefore, all tests for treatment effects presented were adjusted for BMI. The diet treatments did not affect peripheral insulin sensitivity (M-value or M/I), blood glucose, serum insulin, lipids, free fatty acids, systolic or diastolic blood pressure, or markers of lipid peroxidation, antioxidative activity, biomarkers of inflammation, or fibrinolytic activity (Table 5).

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Epidemiological data consistently suggest an inverse relation between the consumption of whole-grain food and the risk of coronary heart diseases (2–6) and possibly also for type 2 diabetes (11,14–16). Insulin resistance, lipid peroxidation, and inflammation are presumed to be central factors involved in the etiology of coronary heart disease and type 2 diabetes (22–25) and are suggested to contribute to the beneficial effects by whole grain. However, we did not find a significant effect of whole-grain intake on insulin sensitivity, lipid peroxidation, inflammatory markers, or on any of the metabolic variables studied.

In the present study, 30 participants were included to allow an 80% power to detect a 10% change in insulin sensitivity. This permitted the possibility of detecting a clinically important effect of whole grain on insulin sensitivity and gave a low risk for type 2 error. However, there were no indications of any improvement after subjects consumed a diet enriched with whole-grain foods, suggesting that an effect on insulin sensitivity would be small, if any. An intervention of 6 wk might be too short to achieve significant effects on insulin sensitivity. However, one earlier dietary intervention study with a similar fiber intake and including 11 subjects with similar BMI as in the present study, indicated improved insulin sensitivity after 6-wk of consuming a whole-grain diet. Their fasting insulin concentrations were lowered by 10% during the whole-grain diet period and the glucose infusion rate increased during the final 30 min of a clamp test (32). Those subjects were hyperinsulinemic, with fasting insulin levels 3 times that of the present study. Dietary effects are more likely to occur in individuals with a poor habitual diet and more pronounced metabolic abnormalities.

The whole-grain products in the present study were mostly based on milled flour with small particle size in the form of bread and pasta. Wheat, rye, oats, and rice were all included, but wheat clearly dominated. Improved blood glucose and insulin metabolism following a higher fiber intake was particularly evident for soluble fiber (29–31). The domination of wheat indicated in the present study may reduce the effects on glucose and insulin because wheat contains less soluble and more insoluble fiber than rye, oats, or barley. However, two other intervention studies showed no effect of high-fiber cereals (even when high in soluble fiber; rye and oats) on insulin sensitivity measured indirectly by intravenous-glucose tolerance test (44,45). Paradoxically, a stronger inverse relationship with the intake of insoluble fiber than soluble fiber on the risk of diabetes is suggested (16).

Other aspects of the cereal products may be of importance. The postprandial insulin response to grain products has been determined more by the form of food and botanic structure than by the amount of fiber or type of cereal (31,46). Whole-grain bread with a more intact structure has been shown to improve postprandial glycemic and insulinemic responses than whole-wheat bread made from milled flour (47).

Based on epidemiological studies, positive health effects can be expected at a level of 3 servings of whole-grain foods per day (48). Our study included 7 servings per day, which is comparable to the dietary intervention by Pereira et al. (32). In that study, all of the food consumed was provided to the subjects on a 6 d menu rotation. In our study, only cereal products were provided as a part of each individual's habitual diet. The products eaten were carefully noted in the diaries. The reported nutrient intakes during both diet periods were similar, except for a higher intake of several minerals, fiber, -tocopherol, and linoleic acid, 18:2 (n-6) during the whole-grain period, as expected. Diet adherence was therefore considered good in the present study.

Another study suggested that whole-grain intake, in combination with other plant products, reduced markers of lipid peroxidation (27). The intervention period in that study was 16 wk. The whole grain was supplied in the form of coarse powder, and the study was performed on patients with coronary heart disease. The lack of effect on lipid peroxidation markers in our study was compatible to the simultaneous lack of effect on insulin sensitivity. Insulin sensitivity has been shown to be inversely related to lipid peroxidation and inflammation (26). Consistent with this, we did not observe an effect on either CRP or IL-6, two frequently used markers of inflammation. In an earlier study, inverse associations of whole grain intake and markers of inflammation were shown in diabetic women (33) but could not be confirmed in a healthy population (49). However, other aspects of carbohydrate-rich foods, such as glycemic index and dietary fiber, have been associated with lower inflammatory status (50,51). An inverse association between dietary fiber consumption and PAI-1 has also been suggested (34). In our study PAI-1 was not affected after consuming whole-grain products.

Subjects' health characteristics, age, and gender, as well as the type of food, its structure, amount, and preparation, are all important factors when interpreting metabolic responses, or lack of response, to whole-grain foods as in present study (31). Despite a lack of observed effects on the metabolic variables, the majority of the subjects did tolerate the whole-grain products well and without any apparent side effects. A general positive experience with feelings of well being was reported after the whole-grain period.

In conclusion, the substitution of whole-grain (mainly based on milled wheat) for refined-grain products in the habitual diet of healthy, moderately overweight adults did not demonstrate a beneficial effect on the insulin sensitivity or on markers of lipid peroxidation and inflammation. To explain the mechanisms behind the positive health effects of whole-grain products, as suggested in epidemiological studies, more extensive and controlled dietary studies on different groups of subjects, utilizing different forms of whole grain foods with varying structure, is needed. Ascribing an equal health value to all types of whole-grain products, without regard to the physical structure and type of cereal, may be misleading.

	ACKNOWLEDGMENTS

 
We thank Sylvia Olofsson and Lars Berglund at the Biostatistician Uppsala Clinical Research Centre for statistical help, Agneta Hedman, dietitian, for assistance with nutrient calculations, and Eva Sejby and Barbro Simu for laboratory assistance.

	FOOTNOTES

 
¹ Supported by grants from the Swedish Governmental Agency for Innovation Systems (VINNOVA), the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS), the Swedish Research Council, and the Swedish Diabetes Association. Supported by food products from Lantmännen Food R&D AB, Wasa Bröd AB and ICA AB.

² Author disclosures: A. Andersson, S. Tengblad, B. Karlström, A. Kamal-Eldin, R. Landberg, S. Basu, P. Åman, and B. Vessby, no conflicts of interest.

⁵ Abbreviations used: CRP, C-reactive protein; M/I, insulin sensitivity index; PAI-1, plasminogen activator inhibitor-1; PGF, prostaglandin F.

Manuscript received 31 January 2007. Initial review completed 8 February 2007. Revision accepted 10 March 2007.

	LITERATURE CITED

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 

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