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Keywords:

  • metabolic syndrome;
  • parathyroid hormone;
  • vitamin D

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Background:  Some reports suggest that concentrations of vitamin D are inversely, whereas concentrations of parathyroid hormone (PTH) are directly, associated with prevalent metabolic syndrome. Because of lingering uncertainty about these associations, we examined the cross-sectional associations between serum concentrations of 25-hydroxyvitamin D3 and PTH with metabolic syndrome in a representative sample of adults in the US.

Methods:  We used data from 1705 participants in the 2005–2006 National Health and Nutrition Examination Survey. Vitamin D was measured by radioimmunoassay, whereas PTH was measured using an electrochemiluminescent process.

Results:  The mean concentration of vitamin D for participants with and without metabolic syndrome was 20.3 and 22.9 ng/mL, respectively (= 0.001). The mean concentration of PTH for participants with and without metabolic syndrome was 44.5 and 41.0 pg/mL, respectively (= 0.002). The age-adjusted mean concentrations of vitamin D (P for linear trend <0.001) decreased linearly, whereas PTH (P for linear trend = 0.002) increased linearly, as the number of components of metabolic syndrome increased. After adjusting for age, gender, physical activity, urinary albumin creatinine ratio, and concentrations of C-reactive protein and calcium, concentrations in the highest quintile of vitamin D [prevalence ratio (PR) = 0.59; 95% confidence interval (CI) 0.44–0.79], but not PTH (PR = 1.18; 95% CI 0.97–1.43), was significantly associated with prevalent metabolic syndrome.

Conclusion:  Concentrations of vitamin D, but not PTH, were significantly associated with prevalent metabolic syndrome among US adults.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Metabolic syndrome is a risk factor for diabetes and cardiovascular disease.1,2 Numerous studies have shown that metabolic syndrome is highly prevalent in many populations around the world, including the US.3,4 However, the syndrome remains a contentious concept. Vitamin D could be an emerging risk factor for diabetes and cardiovascular disease,5–8 and it is possible that some of the increased risk for these conditions attributable to suboptimal vitamin D status may be mediated via metabolic syndrome. The possibility of a link between vitamin D status and metabolic syndrome has been explored previously.9

A growing literature has examined the cross-sectional associations between vitamin D and metabolic syndrome. Although most studies have reported significant inverse associations between vitamin D and metabolic syndrome,10–14 others have failed to do so.15–17 Because of the interplay between vitamin D and parathyroid hormone (PTH) in regulating calcium metabolism, potential associations between PTH and metabolic syndrome were also investigated. Several reports have indicated that PTH could be associated with metabolic syndrome,15,17 whereas others have not corroborated these observations.13,16 A potential inverse association between vitamin D and metabolic syndrome is of considerable interest because supplementation with vitamin D may be an easy and relatively inexpensive way to mitigate cardiometabolic risk. Of note are findings that the vitamin D status of a considerable percentage of the population in the US is inadequate and worsening over time.18 The aim of the present study was to examine the associations between concentrations of vitamin D and PTH with prevalent metabolic syndrome among US adults.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

In the present study, we used data from the National Health and Nutrition Examination Survey (NHANES) 2005–2006.19 The participants were recruited using a multistage, stratified sampling design. The survey was designed to produce results representative of the civilian, non-institutionalized population in the US. The participants were interviewed at home and were invited to attend a mobile examination center, where they were asked to complete additional questionnaires, to undergo various examinations, and to provide a blood sample. The study received human subjects approval, and participants were asked to sign an informed consent form. Details about the survey can be found elsewhere.19

Metabolic syndrome was defined using the 2005 American Heart Association/National Heart, Lung, and Blood Institute definition.20 Waist circumference was measured at the high point of the iliac crest at minimal respiration to the nearest 0.1 cm. Serum triglyceride concentrations were measured enzymatically after hydrolyzation to glycerol21 and high-density lipoprotein–cholesterol (HDL-C) was measured following the precipitation of other lipoproteins with a heparin–manganese chloride mixture.22 Plasma glucose concentrations were determined using an enzymatic reaction.23 Up to four attempts were made to collect three blood pressure readings in the mobile examination center. For participants who had three measurements, the average of the last blood pressure two measurements was used. For participants with only two measurements, the value of the last measurement was used, whereas for participants who had one measurement, that single measurement was used to establish high blood pressure status.

Serum concentrations of 25-hydroxyvitamin D3 were measured using the Diasorin 25-OH-Vitamin D assay (Diasorin, Stillwater, MN, USA), a radioimmunoassay.24 The coefficient of variation of the assay ranged from 9.1% to 10.6%. Serum concentrations of PTH were measured using the ECL/Origen electrochemiluminescent process on an Elecsys 1010 analyzer (Roche Diagnostics, Indianapolis, IN, USA).25 The coefficient of variation of this assay ranged from 2.2% to 5.3%.

Covariates included age, gender, race or ethnicity (White, African American, Mexican American, other Hispanic, mixed race), educational status (<high school, high school graduate, >high school), physical activity, body mass index (BMI), estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio, dietary supplement use during the past month (yes/no), antacid use during the past month (yes/no), dietary calcium intake, and concentrations of cotinine, C-reactive protein (CRP), and calcium. To estimate physical activity, we calculated an average daily MET-hour index that summed transportation, household, and leisure time physical activity,26 where 1 MET is the energy expenditure of approximately 3.5 mL oxygen/kg body weight per min or 1 kcal/kg per h. The BMI (kg/m2) was calculated from measured weight and height. The eGFR was calculated using the Modification of Diet in Renal Disease Study equation.27 Daily intake of dietary calcium was obtained from one or two 24-h dietary recalls. The first recall was obtained during the examination, whereas the second was obtained by telephone 3–10 days later. For participants with a single estimate of intake, that estimate was used. For participants with two estimates, the average intake was used.

The analyses were limited to men and non-pregnant women aged ≥20 years who had fasted for at least 8 h. Differences in means or percentages were calculated using t-tests or Chi-squared tests, respectively. Tests for the linear trend of means were conducted by using orthogonal linear contrasts. Prevalence ratios (PRs) using the log-binomial method were calculated to assess the independent association between the presence of metabolic syndrome (dependent variable) and quintiles of vitamin D and PTH. A test for linear trend was conducted using the median values for the quintiles of vitamin D and PTH. sudaan (Software for the Statistical Analysis of Correlated Data; Research Triangle Institute, Research Triangle Park, NC, USA) was used for the analyses to account for the complex sampling design.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

A total of 1982 participants aged ≥20 years attended the morning examination. Data to establish metabolic syndrome were available for 1859 participants, values for vitamin D were available for 1976 participants, and values for PTH were available for 1968 participants. After excluding pregnant women and participants who had fasted <8 h, 1836 participants were left. After excluding participants with missing data for the study variables, 1705 were finally included in the analyses.

The demographic composition of the sample was as follows: 36.5% of participants were aged 20–39 years, 40.7% were aged 40–59 years, and 22.8% were aged ≥60 years; 49.0% were men and 51.0% were women; 72.4% were White, 10.6% were African American, 7.8% were Mexican American, and the remainder were of other Hispanic origin or of mixed race (Table 1).

Table 1.   Demographic characteristics of 1705 participants aged ≥20 years, National Health and Nutrition Examination Survey 2005–200619
 n%SE
Age (years)
 20–2928117.11.1
 30–3928619.41.3
 40–4932322.51.4
 50–5924718.21.8
 60–6926311.41.2
 ≥7030511.51.4
Gender
 Men89949.01.1
 Women80651.01.1
Percent men by age (years)
 20–2928159.22.1
 30–3928647.72.2
 40–4932349.62.7
 50–5924746.02.8
 60–6926343.83.6
 ≥7030544.52.2
Race or ethnicity
 White87072.42.7
 African American37710.61.6
 Mexican American3277.81.1
 Other Hispanic573.61.0
 Other745.60.9

The age-adjusted prevalence of metabolic syndrome was 33.5% (SE 1.6). Concentrations of vitamin D ranged from 2 to 77 ng/mL (mean 21.9 ng/mL; median 21 ng/mL), whereas concentrations of PTH ranged from 6.36 to 491 pg/mL (mean 42.4 pg/mL; median 38 pg/mL).

The age-adjusted mean concentration of vitamin D for participants with and without metabolic syndrome was 20.3 and 22.9 ng/mL, respectively (= 0.001). The mean concentration of PTH for participants with and without metabolic syndrome was 44.5 and 41.0 pg/mL, respectively (= 0.002). The age-adjusted mean concentrations of vitamin D decreased linearly (P for linear trend <0.001), whereas the age-adjusted mean concentrations of PTH increased linearly (P for linear trend = 0.002), as the number of components of the metabolic syndrome increased (Fig. 1).

image

Figure 1.  Age-adjusted concentrations of (a) vitamin D and (b) parathyroid hormone (PTH) by number of components of metabolic syndrome among 1705 US adults aged ≥20 years in the National Health and Nutrition Examination Survey 2005–2006.19

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After adjusting for age, gender, race or ethnicity, educational status, physical activity, eGFR, urinary albumin creatinine ratio, and the concentrations of cotinine, CRP, calcium, and vitamin D or PTH, concentrations of vitamin D, but not PTH, were found to be significantly associated with prevalent metabolic syndrome. To improve model stability and parsimony, we sequentially eliminated race or ethnicity, educational status, concentrations of cotinine, and eGFR from the models (Fig. 2). This had a minimal effect on the PRs. Specifically, the PRs for quintiles 2–5 of concentrations of vitamin D were 0.89 [95% confidence interval (CI): 0.71, 1.12], 0.74 (95% CI: 0.57, 0.95), 0.76 (95% CI: 0.56, 1.03), and 0.59 (95% CI: 0.44, 0.79), respectively (adjusted Wald F-test = 0.016; P for linear trend = 0.005). After additional adjustment for the use of dietary supplements during the past month (yes/no), the use of antacids (yes/no), and dietary intake of calcium (= 1659), the PRs for quintiles 2–5 were 0.90 (95% CI: 0.73, 1.12), 0.71 (95% CI: 0.55, 0.92), 0.76 (95% CI: 0.57, 1.01), and 0.59 (95% CI: 0.44, 0.78), respectively (P for linear trend = 0.003).

image

Figure 2.  Adjusted prevalence ratios for metabolic syndrome by quintiles of concentrations of (a) vitamin D and (b) parathyroid hormone (PTH) among 1705 US adults aged ≥20 years in the National Health and Nutrition Examination Survey 2005–2006.19 Prevalence ratios were adjusted for age, gender (except gender-specific models), physical activity, albumin:creatinine ratio, and concentrations of C-reactive protein, calcium, and vitamin D or PTH.

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The analyses stratified by gender show a significant inverse association between concentrations of vitamin D and prevalent metabolic syndrome in women, but not in men. However, there was no statistical evidence for effect modification by gender (= 0.541).

The PRs for quintiles 2–5 of PTH were 1.08 (95% CI: 0.82, 1.42), 1.09 (95% CI: 0.85, 1.42), 1.13 (95% CI: 0.89, 1.44), and 1.18 (95% CI: 0.97, 1.43), respectively (adjusted Wald F-test = 0.535; P for linear trend = 0.077). There were no significant linear trends in men or women. Furthermore, there was no significant effect modification by gender (= 0.746).

The adjusted (including PTH) regression coefficient per ng/mL vitamin D was −0.02306 (SE = 0.00627; = 0.002) and the adjusted (including vitamin D) regression coefficient per pg/mL PTH was 0.00066 (SE = 0.00098; = 0.513).

When we introduced BMI into the model, the PRs for quintiles of concentrations of vitamin D were no longer significant (adjusted Wald F-test = 0.354). In addition, PTH was not significantly associated with prevalent metabolic syndrome (adjusted Wald F-test = 0.329; Fig. 3). A significant inverse linear trend was observed among women, but not men.

image

Figure 3.  Adjusted prevalence ratios for metabolic syndrome by quintiles of concentrations of (a) vitamin D and (b) parathyroid hormone (PTH) among 1705 US adults aged ≥20 years in the National Health and Nutrition Examination Survey 2005–2006.19 Prevalence ratios were adjusted for age, gender (except gender-specific models), physical activity, albumin:creatinine ratio, and concentrations of C-reactive protein, calcium, vitamin D or PTH, and body mass index.

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The age-adjusted prevalence of metabolic syndrome ranged from 21.6% (SE 3.3) among participants in the lowest tertile of PTH and the highest tertile of vitamin D to 43.1% (SE 3.9) among participants in the highest tertile of PTH and the lowest tertile of vitamin D (Fig. 4).

image

Figure 4.  Age-adjusted prevalence of metabolic syndrome by tertiles of concentrations of vitamin D and parathyroid hormone (PTH) among 1705 US adults aged ≥20 years in the National Health and Nutrition Examination Survey 2005–2006.19 Tertiles for vitamin D concentrations are as follows: T1, ≤17 ng/mL; T2, 18–24 ng/mL; T3, ≥45 ng/mL. Tertiles for PTH are as follows: T1, ≤31 pg/mL; T2, 32–44 pg/mL; T3, ≥45 pg/mL.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

In this sample of adults in the US, concentrations of vitamin D were significantly and inversely associated with prevalent metabolic syndrome when BMI was not included as a potential confounder. Concentrations of PTH were not significantly associated with prevalent metabolic syndrome.

At least six reports (including the present study) have found significant inverse associations between concentrations of vitamin D and metabolic syndrome,10–14 whereas three have not.15–17 Among 8421 participants aged ≥20 years in NHANES III, the odds ratio (OR) among participants with the highest quintile of concentrations of vitamin D compared with those in the lowest quintile was 0.49 (95% CI: 0.37, 0.66).10 These results were adjusted for age, gender, race or ethnicity, education, smoking status, alcohol use, physical activity, intake of fruits and vegetables, vitamin or supplement use, season of study participation, and concentrations of cotinine, total cholesterol, and CRP. An analysis of data from 1070 participants aged 44–96 years of the Rancho Bernardo Study failed to find a significant association between quintiles of concentrations of vitamin D and metabolic syndrome after adjusting for age, current smoking, alcohol use, exercise, season, and hormone use in women.15 The adjusted OR was 0.57 (95% CI: 0.26, 1.25) for men in the highest quintile of concentrations of vitamin D and 0.88 (95% CI: 0.43, 1.80) for women. A study of 73 morbidly obese participants found that the prevalence of metabolic syndrome decreased with increasing tertiles of vitamin D.11 A subsequent study of 298 severely obese participants with a mean age of 42.9 years failed to find an association between concentrations of vitamin D and metabolic syndrome.16 After adjusting for age, gender, percent fat mass, and season, the OR for metabolic syndrome among participants in the highest quartile of concentrations of vitamin D was 0.63 (95% CI: 0.26, 1.52). Among 6810 men and women of the 1958 British birth cohort, the OR for metabolic syndrome in the highest tertile of concentrations of vitamin D was 0.31 (95% CI: 0.24, 0.39) after adjusting for gender, month, and hour of measurement.12 Data from 1654 participants aged ≥20 years from NHANES 2003–2004 yielded an OR of 0.26 (95% CI: 0.15, 0.44) for the metabolic syndrome in the highest quintile of concentrations of vitamin D after adjusting for age, gender, race or ethnicity, income, smoking status, alcohol use, physical activity, intake of total calcium and energy, and concentration of PTH.13 Another analysis of 1017 Norwegian patients who were morbidly obese with a mean age of 42 years failed to report a significant association between concentrations of vitamin D and prevalent metabolic syndrome.17 After adjusting for age, gender, season, BMI, current smoking, albuminuria, homeostasis model assessment–insulin resistance (HOMA-IR), diabetes, and concentrations of CRP, magnesium, calcium, phosphate, and creatinine, the OR was 1.06 (95% CI: 0.69, 1.63) per unit of log-transformed 25-hydroxy vitamin D. Finally, among 3262 participants aged 50–70 years of the Nutrition and Health of Aging Population in China study, the OR for the metabolic syndrome in the lowest quintile of concentrations of vitamin D was 1.52 (95% CI: 1.17, 1.98) after adjusting for age, gender, location, rural status, date of visit, education, physical activity, smoking, alcohol use, family history cardiovascular disease or diabetes, coronary heart disease, stroke, and concentrations of CRP and interleukin-6.14

In two of the three reports that failed to find a significant association between concentrations of vitamin D and prevalent metabolic syndrome, adjustments for percent fat mass or BMI were performed.16,17 In contrast, the studies that found significant associations did not adjust for an anthropometric parameter in most instances.10–14 One study that reported no significant association between concentrations of vitamin D and the metabolic syndrome and that did not adjust for BMI found a borderline significant inverse trend among men but not women.15 To some degree, the interpretation of the available results may revolve around the issue of whether the analyses should adjust for BMI or another anthropometric index. Given that abdominal obesity drives much of the metabolic syndrome and that waist circumference is highly correlated with BMI, a case can be made that adjusting for an anthropometric measure may not be warranted, especially when it is also part of the dependent variable. None of the published studies adjusted for other components of metabolic syndrome, namely blood pressure and concentrations of triglycerides, HDL-C, and glucose.

Several studies have found that lower concentrations of vitamin D are significantly associated with surrogate measures of insulin resistance.7,9,28–33 Furthermore, administration of vitamin D has been shown to improve insulin secretion.34–36 Thus, these studies provide a potential explanation for the observed associations between vitamin D and metabolic syndrome. In addition, concentrations of vitamin D are inversely related to several components of the metabolic syndrome, including excess weight, blood pressure, and concentrations of glucose,15 providing another explanation for the observed association between concentrations of vitamin D and metabolic syndrome.

The literature on the cross-sectional associations between concentrations of PTH and metabolic syndrome remains contentious.13,15–17 Among 1070 participants aged 44–96 years in the Rancho Bernardo Study, the OR was 2.02 (95% CI: 0.96–4.24) for men in the highest quintile of concentrations of PTH and 1.13 (95% CI: 0.57, 2.26) for women after adjusting for age, current smoking, alcohol use, exercise, season, and hormone use in women.15 In a study of 298 severely obese Spanish participants with a mean age of 42.9 years, concentrations of PTH were not significantly associated with metabolic syndrome.16 After adjusting for age, gender, percent fat mass, and season, the OR for participants in the highest quartile of concentrations of PTH was 0.84 (95% CI: 0.33, 2.12). An analysis of data from participants aged ≥20 years from NHANES 2003–2004 did not find a significant association between concentrations of PTH and metabolic syndrome among women and young men, but did find an association among older men after adjusting for age, gender, race or ethnicity, income, lifestyle factors, total calcium, and energy intake.13 Finally, among 1017 Norwegian patients who were morbidly obese, concentrations of PTH were significantly associated with metabolic syndrome.17 After adjusting for age, gender, season, BMI, current smoking, albuminuria, HOMA-IR, diabetes, and concentrations of CRP, magnesium, calcium, phosphate, and creatinine, ORs ranged from approximately 1.5 to approximately 2.3 for the 2nd–4th quartiles of PTH. Although we found a significant positive association between quintiles of concentrations of PTH and prevalent metabolic syndrome after only adjusting for age, this association turned non-significant after more extensive adjustment.

There are several limitations to the present study. The cross-sectional nature of the study precludes establishing causality. Furthermore, the sample size limited our ability to conduct more detailed stratified analyses. Finally, we were unable to adjust for seasonality and location, variables known to correlate with concentrations of vitamin D.

With several prospective studies suggesting that concentrations of vitamin D could be inversely related to incident diabetes5–7 and metabolic syndrome being a potent risk factor for diabetes, the potential public health ramifications dictate that the existing uncertainty about vitamin D and metabolic syndrome be resolved. Certainly, prospective studies are needed. However, randomized clinical trials may have to eventually provide conclusive evidence about whether boosting concentrations of vitamin D, likely through supplementation, can lower the incidence of metabolic syndrome, and by extension diabetes and cardiovascular disease. In light of the growing burden of metabolic syndrome,37 diabetes,38 and possibly insulin resistance39 in the US, a favorable effect of vitamin D on these conditions would be a welcome ray of hope in helping to reduce the public health burden.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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