Dairy/calcium may reduce oxidative stress and inflammation in metabolic syndrome

Metabolic syndrome is characterized by increased oxidative stress and inflammation (Van Guilder, Hoetzer, Greiner, Stauffer, and Desouza, 2006) that may underlie the increased risk for cardiovascular disease (Mottillo et al., 2010). Dietary calcium reduced reactive oxygen species, as well as biomarkers of oxidative stress and inflammation in mouse models (Sun and Zemel, 2006; Zemel and Sun, 2008). A reduction in biomarkers of oxidative stress and inflammation in overweight and obese humans following a high-dairy diet is observed in some (Zemel and Sun, 2008; Zemel, Sun, Sobhani, and Wilson, 2010) but not all (Wennersberg et al., 2009; van Meijl and Mensink, 2010) research. Stancliffe, Thorpe, and Zemel (2011) evaluated whether dairy had an effect in subjects with metabolic syndrome.

The randomized, controlled trial consisted of 40 overweight and obese subjects who were diagnosed with metabolic syndrome according to ATP III guidelines. Each subject was assigned a weight-maintenance diet, individualized by measuring resting metabolic rate (RMR) and estimating maintenance requirements, and randomized into two groups of 20 subjects each; one group consumed a “low dairy diet,” consisting of ≤ 600 mg calcium per day and ≤ 0.5 servings of dairy per day (LD), and the other an “adequate dairy diet,” consisting of ≥ 1000 mg calcium per day and ≥ 3.5 servings of dairy per day (AD). Three daily servings of food items were provided to each group to better control calcium intake: LD received prepackaged nondairy items, and AD received dairy. Diet and physical activity diaries were maintained throughout the 12 weeks of the study and individual counseling and assessment ensured similar macronutrient percentages between the groups. The following measurements were assessed at baseline and on a weekly basis: body weight, waist circumference, height (once for BMI calculation), blood pressure (mm Hg), and heart rate (beats/min). On days 28 and 84, total fat mass, trunk fat mass, and percentage lean and fat mass measurements were taken. On days 7, 28, and 84, plasma concentrations of the following were measured: malondialdehyde (MDA; nmol/L), oxidized LDL (oxLDL; ng/mL), interleukin-6 (IL-6; pg/mL), monocyte chemoattractant protein 1 (MCP-1; pg/mL), adiponectin (ng/mL), tumor necrosis factor-alpha (TNF-alpha; nmol/L), C-reactive protein (CRP; ng/mL), glucose (mmol/L), insulin (µU/mL), cholesterol (mg/dL), LDL cholesterol (LDL-C; mg/dL), HDL cholesterol (HDL-C; mg/dL), and triglycerides (mg/dL). Insulin resistance was calculated from fasting insulin and glucose using the HOMA-IR. Statistical analysis measured changes from baseline values, differences between treatments, and possible effects from subjects characteristics. Subjects were also subgrouped and analyzed according to BMI (overweight = 25-29.9 kg/m2; obese = ≥ 30 kg/m2).

Of the 40 subjects, 28 met criteria for compliance of at least 9 of the 12 weeks. The AD group significantly decreased waist circumference (-2.8 ± 0.8 cm) and fat mass (-1.3 ± 0.9 kg) after 84 days compared to baseline, with the majority of fat loss coming from trunk fat (-1.4 ± 0.7 kg). Plasma insulin (-3.38 ± 1.27), insulin resistance (-0.59 ± 0.34), and systolic blood pressure (-7.1 ± 3.1) were significantly lower compared to baseline in the AD group. Diastolic blood pressure at the final measurement only (-5.2 ± 2.4), and plasma cholesterol, and triglycerides (values not reported) were significantly lower compared to baseline in the obese AD subgroup. The plasma concentrations of MDA and oxLDL were significantly reduced in the AD group both overall (-1.39 ± 0.89 and -88 ± 36, respectively) and in the obese AD sub-groups (-1.96 ± 0.89 and -95 ± 22, respectively) compared to baseline, suggesting a reduction in oxidative stress. All biomarkers of inflammation were significantly improved in the AD group compared to baseline: TNF-alpha (-5.99 ± 2.07), MCP-1 (-45.3 ± 29.9), IL-6 (-13.7 ± 3.8), CRP (-9.1 ± 5.3), and adiponectin (9.01 ± 5.64). Additionally in the AD obese subgroup, TNF-alpha (-7.41 ± 0.71), IL-6 (-18.1 ± 3.3), CRP (-11.7 ± 6.6), and adiponectin (11.82 ± 3.06) were significantly improved at the last measurement compared to baseline. The reductions in markers of oxidative stress and inflammation were significant beginning at day 7, which may represent an effect independent of changes in fat mass, but because fat mass was not assessed at that time point it is unknown if significant changes in fat mass had occurred.

Subjects returned empty food item packages and maintained diet and physical activity diaries for weekly assessment to better control for these variables. Even though 30% of subjects did not meet compliance criteria for 9 of 12 weeks (75%) compliance, all were included in the analyses, and it is not reported if this significantly altered average calcium and dairy intakes for each group. The authors noted that trans fatty acids from peanut butter crackers given to the LD group may have influenced results. A recent study by Smit, Katan, Wanders, Basu, and Brouwer (2011) found that a high dose of trans-fat (7% of energy) did not increase biomarkers for inflammation, but did increase a marker of oxidative stress. It is unknown if the amount consumed by the LD group would be sufficient to increase oxidative stress, and details about this and other dietary differences are not reported.

Two previous studies (Wennersberg et al., 2009; van Meijl and Mensink, 2010) found no effect of dairy on oxidative stress or inflammation, the former also in subjects diagnosed with metabolic syndrome. The baseline calcium intake in the subjects of Wennersberg et al. (2009) who were instructed to increase dairy intake was 815 ± 364 mg per day as determined from 3-day food records, which may be too high to see benefit from additional consumption. Similarly, Meijl and Mensink (2010) used a food frequency questionnaire and estimated the average intake of calcium in the control group at 931 mg per day. Because neither Stancliffe et al. (2011) nor Zemel et al. (2010) reported actual calcium intakes, it is difficult to compare to these results, but previous research by their lab used archived control group samples from two separate trials with calcium intakes of 495 ± 28 mg, 458 ± 96 mg, and 468 ± 23 mg per day (Zemel and Sun, 2008) and found a reduction on biomarkers of inflammation when placed high-dairy diets. Future research is needed to study the possible threshold effect. In addition, servings and types of dairy should be strictly controlled, as constituents in dairy other than calcium may have an additive effect on outcomes (Zemel and Sun, 2008). The fat mass loss in Stancliffe et al. (2011) of 1.3 ± 0.9 kg in the AD group without a statistically significant reduction in body weight, with a calcium intake of ≥ 1000 mg per day over 12 weeks on a weight maintenance diet is notable. A meta-analysis of seven randomized controlled trials of calcium supplementation of at least 24 weeks with intakes of ≥ 1600 mg calcium found a fat mass loss of .93 kg and body weight loss of .74 kg compared to placebo (Onakpoya, Perry, Zhang, and Ernst, 2011). Another meta-analysis of 13 trials on the use of calcium or dairy products on weight loss found no effect on body weight (Trowman, Dumville, Hahn, and Torgerson, 2007), but fat mass loss was not analyzed. The reduction in systolic blood pressure (-7.1 ± 3.1) in the AD group and diastolic blood pressure (-5.2 ± 2.4) in the AD obese group in Stancliffe et al. (2011) is comparable to other research. As reviewed by Kris-Etherton, Grieger, Hilpert, and West (2009), randomized controlled trials using dairy products in normotensive and hypertensive subjects tend to reduce systolic and diastolic blood pressure.

A dairy-rich diet reduced biomarkers of oxidative stress, inflammation, plasma insulin, insulin resistance, and blood pressure compared to a low-dairy diet in subjects with metabolic syndrome. Ameliorating these conditions may reduce the risk of developing cardiovascular and other associated diseases. Further research is warranted, and in particular should examine these relationships compared to moderate dairy intakes, and elucidate the influence of fat loss.

The principal investigator, Michael Zemel, has previously been admonished in another journal for failing to report potential conflicts of interest from his patents and patent applications (Atkinson, 2005). In Stancliffe et al. (2011), he again reports no conflicts of interest for his patents, which is against The American Journal of Clinical Nutrition’s guidelines (www.nutrition.org/publications/guidelines-and-policies/conflict-of-interest/#authors) and should be noted. It should also be noted that Zemel received a grant from the National Dairy Council of $422,220 for this research (obesity.tennessee.edu/pdf/Faculty/MichaelZemel-Bio.pdf).

*Note: Thanks to Yoni Freedhoff for pointing out the patent issue in his review here. He also points out that there seems to be an issue with how waist circumference was measured, something I am not an expert in. Although there are certainly limitations to this paper, I think compared to other research there is merit to a possible threshold effect for calcium and oxidative stress. As i’ve noted, there are several things not reported or not considered in the design, so subsequent research will be needed (as always!). It also should be noted that at these calcium doses there are concerns for increased risk of some cancers (mainly prostate), so one must wonder if other dietary interventions are more appropriate.

References

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Smit, L. A., Katan, M. B., Wanders, A. J., Basu, S., & Brouwer, I. A. (2011). A high intake of trans fatty acids has little effect on markers of inflammation and oxidative stress in humans. The Journal of Nutrition, 141(9), 1673-8. doi:10.3945/jn.110.134668

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