The metabolic syndrome (MetS) is the clustering of five inter-related biomedical components including central adiposity, hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), and altered glucose homeostasis 1. It is a significant health issue, with ~25% of the global population being diagnosed with the condition 2. The presence of MetS predicts an increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) 3. Furthermore, the risk of T2DM appears to increase in line with increasing number of MetS components with risk of 11.9, 31.2, and 40.8% in those with zero, three, and four or more MetS components, respectively 4. However, each MetS component is an independent risk factor that clinicians will treat if diagnosed in their patients.
Vitamin D deficiency is a worldwide health issue, and an estimated one billion individuals are classified as having insufficient vitamin D status 5,6. Coupled with this are lower intakes of calcium (Ca)-rich foods, despite increasing production and availability of dairy products 7. 25-Hydroxyvitamin D (25-OHD) has been implicated in the mechanisms underlying a number of the MetS components 8. The majority of studies have found an inverse relationship between 25-OHD and glucose homeostasis, lipids, obesity, and blood pressure (BP) 8,9. However, a few studies have also shown an inverse relationship with Ca intake and MetS 10,11, with limited evidence supporting an association between Ca intake and individual MetS components. Vitamin D and Ca are physiologically tightly interlinked and it is possible that their combination may have a greater potential to interactively influence components of MetS 11,12. We have previously found that, in individuals within low to medium 25-OHD tertiles, increasing Ca intake tertiles had a trend to lower adjusted odds ratio (AOR) of MetS. However, in the high 25-OHD tertile, this trend was no longer present 12. The aim of this study was to explore the potential combined effect of vitamin D status and dietary Ca intake on individual components of MetS.
This cross-sectional study was based on the analysis of the Victorian Health Monitor (VHM) survey, which is a population representative survey of Victorian adults aged 18–75 years. Details about the VHM, and the collection and analysis of the physical, dietary, and biomedical variables, can be found in previous publications 12–14.
In this sample, participants were excluded if there was missing information on HbA1c data (n=31), those with HbA1c of at least 6.5% as they were classified as having T2DM according to the American Diabetes Association cutoffs (n=39) 15, those with diagnosed T2DM (n=140), those with type 1 diabetes mellitus (n=9), those on diabetic medications (n=25), and those with missing data on metabolic components (n=22). Thus, out of 3653 participants recruited in the VHM survey, this study sample consisted of a total of 3387 participants. The three independent variables of interest were serum 25-OHD concentration, dietary Ca intake, and the combination of 25-OHD and dietary Ca.
Venous blood was collected by venepuncture, processed, refrigerated, and transported daily to a single accredited laboratory in Melbourne for storage (at −80°C). All analyses and reporting were completed within two weeks of collection. Blood samples were analyzed for fasting plasma glucose (FPG) using the hexokinase method; HDL-C using elimination/catalase method; and triglycerides (TG) using GPO Trinder reagent set with serum blank. Blood pressure measurements were collected (GE Dinamap 8100 Vital Sign Monitor; Critikon, Tampa, Florida, USA) after a 5-min rest 14.
Serum 25-OHD was measured using the DiaSorin Corporation Liaison 25-OHD total assay, an automated direct competitive chemiluminescent immunoassay that measures D2 and D3 to provide a total value for circulating vitamin D in nmol/l. The detection limit was 10 nmol/l. The precision of the LIAISON assay [(DiaSorin S.p.A. Via Crescentino 13040 Saluggia (VC) – Italy)] was determined by using human serum-based quality controls, spanning a 25-OHD range of 35–180 nmol/l. Each control sample was assayed in 2–4 replicates per run for 3–4 runs; however, within-run and total coefficient of variations were not reported. The laboratory was not part of the vitamin D standardization programs at the time of fieldwork for the study (2009–2010). The all laboratory trimmed mean was not computed by the laboratory, nor were results compared with a target value assigned by the National Institute of Standards and Technology reference measurement procedure.
Dietary calcium intake
Dietary data were collected by a five-pass 24-h diet recall using computer-assisted telephone interviews. The FoodWorks nutrition software [(Xyris Software Pvt Ltd., Kenmore Hills, Australia)] were used in conducting the three dietary recalls 13. This provided data on energy, macronutrient, micronutrient, and Ca intake. Dietary Ca intake was included as a continuous variable for every 500 mg/day increment.
The combination of 25-OHD concentration and dietary calcium intake
25-OHD concentration was categorized into tertiles: low 25-OHD tertile (range: 10–44 nmol/l; median: 33 nmol/l), medium 25-OHD tertile (range: 45–65 nmol/l; median: 54 nmol/l), and high 25-OHD tertile (range: 65–204 nmol/l; median: 77 nmol/l). Dietary Ca intake was also classified into tertiles, which were low Ca tertile (range: 72–719 mg/day; median: 579 mg/day), medium Ca tertile (range: 720–1009 mg/day; median: 858 mg/day), and high Ca tertile (range: 1010–3726 mg/day; median: 1233 mg/day).
To assess the combined effect of 25-OHD and Ca tertiles, a nine-level variable was generated based on the combination of these tertiles, which were as follows: (i) low 25-OHD and low Ca; (ii) low 25-OHD and medium Ca; (iii) low 25-OHD and high Ca; (iv) medium 25-OHD and low Ca; (v) medium 25-OHD and medium Ca; (vi) medium 25-OHD and high Ca; (vii) high 25-OHD and low Ca; (viii) high 25-OHD and medium Ca; (ix) and high 25-OHD and high Ca.
Information on the collection of the physical and anthropometric measurements can be found in our previous publications 12,14. MetS components were the dependent variables, and were categorized as per the cutoffs defined by the joint interim statement of key organizations 1. The criteria for the MetS components were as follows: (i) elevated TG of at least 1.7 mmol/l (≥150 mg/dl) (yes/no); (ii) reduced HDL-C of less than 1.0 mmol/l (<40 mg/dl) in males and less than 1.3 mmol/l (<50 mg/dl) in females (yes/no), or on lipid-lowering therapy; (iii) elevated systolic BP (SBP) of at least 130 mmHg or on antihypertensive medications (yes/no); (iv) elevated diastolic BP (DBP) of at least 85 mmHg) or on antihypertensive medications (yes/no); (v) elevated FPG of at least 5.6 mmol/l (≥100 mg/dl) (yes/no); and (vi) elevated waist circumference (WC) of at least 94 cm for males (≥90 cm for Aboriginal and Torres Strait Islander, Asian, and South American males) and at least 80 cm for females (yes/no).
We adjusted for the following confounders in our analysis on the basis of our previous findings 12 and as reported by others 16. The demographic factors included were age (years), sex, country of birth (born in Australia, born overseas), BMI (kg/m2), physical activity level (insufficient physical activity <150 min/week, sufficient physical activity ≥150 min/week), smoking status (current smoker, nonsmoker), income (<$30 000, $30 001–$70 000, ≥$70 001, do not know/refused), and education (high school or less, TAFE/diploma/certificate, tertiary education). Season was categorized as summer, autumn, winter, and spring. The dietary variables were all entered as continuous variables and were energy intake (kJ/day), dietary fiber (g/day), alcohol (g/day), magnesium (mg/day), zinc (mg/day), Ca (25-OHD model only), and 25-OHD (Ca model only).
The analysis targeted the following questions:
- Was there any association between MetS components and increments of 10 nmol/l of 25-OHD?
- Was there any association between MetS components and increments of 500 mg/day of dietary Ca intake?
- Did combinations of 25-OHD and Ca tertiles have a greater influence on any of the MetS components?
The analysis was conducted according to the following steps:
Step 1: Demographic/descriptive statistics by the MetS components were obtained and differences between groups were tested by χ 2 test for categorical variables of interest.
Step 2: Logistic regression analysis was used, and the following regression models were developed to examine whether there was any association between MetS components and (i) increments in 25-OHD concentration, (ii) increments in dietary Ca intake, and (iii) the combination of 25-OHD and Ca tertiles, and unadjusted OR, AOR, and 95% CI were reported.
Model 1: An unadjusted logistic regression model was fitted for MetS components, including (1) 25-OHD concentration, (2) Ca intake, and (3) the combination of 25-OHD and Ca tertiles. The combination of ‘low 25-OHD and low Ca’ combination tertile served as the reference group.
Model 2: We adjusted the model 1 for confounders such as age, sex, country of birth, smoking status, physical activity, income, education, BMI, season, energy intake, dietary fiber, alcohol, magnesium, zinc, Ca (25-OHD model only), and 25-OHD (Ca model only).
Model 3: We explored whether any of the associations between the combination of 25-OHD and Ca tertiles and individual MetS components were independent of the other components of MetS. Thus, in model 3, we additionally adjusted model 2 for those MetS components (reduced HDL-C, elevated WC, elevated TG, elevated SBP, elevated DBP, or elevated FPG), which were not the dependent factors.
Analyses were conducted using the IBM SPSS Statistics for Windows, version 23.0 (IBM Corp., Armonk, New York, USA) ‘Complex Samples’ module to eliminate sampling bias arising from the multistage cluster sampling method used in the VHM survey.
The mean age was 49 years, with a higher proportion of subjects with normal levels of HDL-C (86%), TG (79%), SBP (58%), DBP (73%), and FPG (84%) compared with abnormal levels (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/CAEN/A16).
Association between 25-OHD concentration and MetS components
The unadjusted model found a significant association between every 10 nmol/l increment in 25-OHD concentration and a reduced odds of elevated WC (P=0.014), TG (P<0.001), DBP (P=0.006), FPG (P=0.027), and reduced HDL-C (P=0.017). There was no significant association between 25-OHD concentration and elevated SBP (P=0.189). In model 2, after adjustment for all confounders (age, sex, country of birth, smoking, physical activity, income, education, BMI, season, Ca, energy, fiber, alcohol, magnesium, zinc), and model 3, after further adjustment for respective MetS components, every 10 nmol/l increment in 25-OHD reduced the odds of elevated TG by 21%, and elevated FPG by 9% (Table 1). There was no significant association between 25-OHD concentration and elevated WC (P=0.707), elevated SBP (P=0.525), and reduced HDL-C (P=0.433).
Association between dietary calcium intake and MetS components
The unadjusted model found a significant association between every 500 mg/day increment in dietary Ca intake and reduced odds of elevated WC (P=0.008), elevated DBP (P<0.001), and reduced HDL-C (P<0.001). There were no significant associations between dietary Ca intake and elevated TG (P=0.540), elevated SBP (P=0.208), and elevated FPG (P=0.142). After adjustment for confounders in models 2 and 3, every 500 mg/day increment in dietary Ca intake reduced the odds of elevated DBP by 20% (Table 1). There were no significant associations between increments of 500 mg/day in dietary Ca intake and elevated WC (P=0.709), elevated TG (P=0.635), and elevated FPG (P=0.907).
Association between the combination of 25-OHD concentration and dietary calcium intake and MetS components
Models 1 and 2 revealed a significant association between the combination of 25-OHD concentration and Ca intake and reduced HDL-C, elevated TG, and elevated DBP. After further adjustment for respective MetS components in model 3, the significant association remained between the combination of 25-OHD concentration and Ca intake and reduced HDL-C and elevated TG. There was no significant association between combined 25-OHD and Ca intake and elevated DBP, WC, SBP, and FPG (Table 2).
The combined effects of 25-OHD concentration and dietary calcium intake on reduced HDL-C
In all models, the significant association persisted between the combination of 25-OHD concentration and Ca intake and reduced HDL-C. In all models, and all combinations of 25-OHD concentration and Ca intake, there appeared to be a downward trend, with a lower AOR of reduced HDL-C, as Ca intake increased. There appeared to be a dose–response effect of Ca at low 25-OHD on reduced HDL-C, but at higher 25-OHD these effects of Ca were blunted. In model 3, the following four combinations appeared to lower the odds of reduced HDL-C by 47% in low 25-OHD and medium Ca, 68% in medium 25-OHD and high Ca, 57% in medium 25-OHD and low Ca, and 68% in medium 25-OHD and high Ca (Fig. 1 and Table 2).
The combined effects of 25-OHD concentration and dietary calcium intake on elevated TG
In all models the significant association persisted between the combination of 25-OHD concentration and Ca intake and elevated TG. The combination of medium 25-OHD and low and medium Ca significantly reduced the odds of having elevated TG by 43 and 41%, respectively (P<0.001). The combination of high 25-OHD and low, medium, and high Ca significantly reduced the odds of having elevated TG by 83, 62, and 67%, respectively (P<0.001) (Fig. 2 and Table 2).
In this study, we investigated the associations between the individual MetS components and (i) 25-OHD concentration, (ii) dietary Ca intake, and (iii) the combination of 25-OHD concentration and dietary Ca intake, as they are commonly recommended together for optimal bone health. After adjustment for demographic, physical, dietary factors, and MetS components, every 10 nmol/l increment in 25-OHD reduced the odds of elevated TG and elevated FPG. Every 500 mg/day increment in dietary Ca intake reduced the odds of elevated DBP. The combination of 25-OHD concentration and Ca intake lowered the odds of having low HDL-C and elevated TG.
Previous studies of 25-OHD and MetS components
We found that increments of 10 nmol/l in 25-OHD lowered the odds of having elevated TG, and having elevated FPG (Table 1). However, there appears to be inconsistent evidence between 25-OHD concentration and MetS components. A large British study (n=7198) of middle-aged (45 years) Caucasian adults found an inverse association between 25-OHD concentration and high WC, high BP, high HbA1c, and high TG but not with low HDL-C 17. We too found an association between 25-OHD and elevated TG and FPG; however, there were no associations with other MetS components. An American study (n=8421) found an inverse association between 25-OHD and high WC, TG, and FPG 18; however, we found no association with WC. In an older cohort, 25-OHD concentration was inversely associated with high WC, TG, FPG, and reduced HDL-C; however, no association was seen with BP 16. A large prospective study from Australia (n=4164) found an inverse association between 25-OHD and the incidence of WC, TG, FPG, but not with HDL-C and BP 19. The variation in results among previous studies and our findings may be owing to a few reasons, such as the use of different MetS criteria and cutoff points for 25-OHD concentration. The majority of these associations were found in middle-aged or older population; however, our study covered adults aged 18–75 years 16,20,21. Older populations may be at higher risk of vitamin D deficiency, owing to certain physiological impairments that occur with age; thus, the results from older adults may not be applicable to the general population 22. Evidence drawn from specific cultural groups 17,20,21, sex 20, and the use of differing confounders may also partially explain the variation in results.
Previous studies of dietary calcium intake and MetS components
There are limited studies examining the association between Ca and MetS components. In a large cohort study (n=6375) of adults aged older than or equal to 40 years, the highest quartile of Ca intake (median: 530.8 mg/day) was inversely associated with high WC and high blood glucose in women and hypertriglyceridemia in men 23. A second large study (n=10 066) in women found a lower prevalence of lower WC, high BP, and high HDL-C in the highest quintile of dietary Ca intake 11. However, we found an association between 500 mg/day increments in dietary Ca intake and reduced odds of elevated DBP. We found no significant association between Ca intake and any other MetS components, after controlling for demographic, physical, dietary factors, and MetS components. Results may vary owing to the investigation of one sex 11, older age group (≥40 vs. ≥45 vs. 30–65 years) 11,23,24 versus a broad age range of 18–75 years in our study, and the adjustment for different confounders. In addition, these studies did not mutually adjust for MetS components in their analysis, and thus the associations between MetS components and dietary Ca intake may be confounded by the presence of other MetS components. The association between dietary Ca intake and MetS components has not been well investigated, and requires further research.
The combined effect of 25-OHD concentration and dietary calcium intake on MetS components
Calcium intake and vitamin D play an interdependent role in bone metabolism and skeletal health. It was therefore appropriate to examine their combined role in extraskeletal health. The combined effect of 25-OHD concentration and Ca intake tertiles lowered the odds of having reduced HDL-C and elevated TG, and the reduction in AOR of having these components was greater than that obtained from the independent effects of 25-OHD concentration or dietary Ca intake.
Independently, every 10 nmol/l increment in 25-OHD reduced the odds of elevated TG by 21%. However, the combination of medium 25-OHD tertile and low and medium Ca intake appeared to reduce the odds of elevated TG further by 43 and 41%, respectively (Fig. 2). There also appeared to be a dose–response effect of Ca intake at low 25-OHD concentration, although the combinations were not significant. The odds of having elevated TG were approximately halved between medium 25-OHD and high 25-OHD.
Increments in 25-OHD and Ca intake did not significantly reduce the odds of elevated HDL-C. However, in combination, there appeared to be a strong effect of Ca at low 25-OHD on reduced HDL-C. The combination of low 25-OHD and medium and high Ca intake lowered the odds of having reduced HDL-C by 47 and 64%, respectively (Fig. 1). The combination of 25-OHD concentration and Ca intake appeared to further reduce the odds of having reduced HDL-C than when 25-OHD concentration was taken into account alone. However, at high 25-OHD concentration, the effects of Ca appear to be blunted.
Independently, 500 mg/day increment in dietary Ca intake appeared to reduce the odds of elevated DBP by 22%, with a marginal association between 25-OHD concentration and elevated DBP. The combined effect of high 25-OHD and medium Ca tertiles revealed 43% lower odds of having elevated DBP, which was marginally significant (P=0.080) (Table 2).
We are unaware of other studies that have investigated the combined effect of 25-OHD concentration and Ca intake on MetS components. From our results it appears that there may be a combined effect of Ca to 25-OHD in reducing the odds of having reduced HDL-C and elevated TG. There appeared to be a strong effect of Ca at low 25-OHD on reduced HDL-C, whereas there appeared to be a stronger effect of Ca at high 25-OHD on elevated TG. The potential mechanisms are explored below.
25-OHD concentration and MetS components
The pathophysiological mechanisms linking vitamin D to the MetS components are not yet confirmed. One potential mechanism may be through the renin–angiotensin system (RAS). The RAS is the key regulatory system of cardiovascular function, particularly for BP 25; however, it has regained attention for its potential action in aspects of MetS 26. Vitamin D may play a role in modulating BP through regulating the RAS, and renin production (the enzyme involved in maintaining BP) 27. Vitamin D deficiency has been found to increase RAS activity 28,29 and stimulate renin synthesis. Increased RAS and renin activity can result in hypertension and insulin resistance (IR), which are characteristics of MetS 27,30. Second, IR may also be related to RAS whereby vitamin D deficiency may increase renin–angiotensin II expression, which may induce IR 31–33. In addition, the vitamin D pathway is involved in insulin secretion through the regulation of intracellular Ca2+ concentration 34, and lower levels of vitamin D are linked with increased IR 35,36. Third, 25-OHD modulates enzyme activity directly related to lipoprotein lipase 37. Vitamin D and its metabolites may upregulate lipoprotein lipase and in turn increase HDL-C and reduce TG 37. Fourth, vitamin D may reduce inflammation and as a result reduce IR, leading to improved lipid metabolism 38,39. Overall, vitamin D deficiency may increase RAS activity, which is linked with the pathogenesis of hypertension, reduced insulin secretion, and IR 40.
Dietary calcium intake and MetS components
The positive effect of Ca on the MetS components may occur through different pathways. Those with lower Ca intakes (<600 mg/day) tend to have higher body weight, BMI, % fat mass, fat mass, WC, and abdominal adiposity 41. Dietary Ca intake may increase fat oxidation, which may in turn lower lipid levels 42,43. Zemel 44 suggested that low Ca intake may affect hormones associated with bone growth. An increase in parathyroid hormone (PTH) and 1,25-OH2D may result in a rise in intracellular Ca2+ concentrations influencing lipogenesis 44,45. Higher intakes of Ca of ∼1200 mg/day from dairy sources may increase fecal fat excretion by ∼5 g/day 46. A meta-analysis of randomized controlled trials found that Ca supplementation of ∼1000 mg/day reduced SBP and DBP; however, those with lower Ca intake had a greater decrease in BP 47. Interestingly, those who were Ca deficient and receiving Ca supplements tended to have a stronger effect on BP compared with those with higher habitual intakes.
From our results, it appears that the additive effect of 25-OHD and Ca is more beneficial than 25-OHD alone, in reducing the odds of having reduced HDL-C and elevated TG. There appears to be a dose–response effect of Ca at low 25-OHD on reduced HDL-C, but at higher 25-OHD the effects of Ca were blunted (Fig. 1). However, high 25-OHD appeared to lower the odds of elevated TG, irrespective of Ca intake (Fig. 2). This indicates that there are a multitude of mechanisms at play for each component constituting a complex relationship between 25-OHD, Ca intake, and MetS components.
There are several strengths to our study. We draw our findings from a large population-based sample of adults aged 18–75 years. We adjusted for a range of demographic and dietary variables as compared with other studies 11,16,17,20,21,23,24. In our study, 25-OHD concentration was measured at one laboratory rather than multiple laboratories, which may limit variability in 25-OHD results 48. In contrast to other studies 23,24,49, we adjusted for the effect of other MetS components in the final model. This allowed us to see whether the association between 25-OHD and Ca tertiles and MetS components was independent from the rest of the components.
The cross-sectional study design is good to show an association between two variables; however, causality and National Health and Medical Research Council level 2 evidence can be obtained from longitudinal cohort studies 50. Supplement usage was not collected in the VHM survey, thus teasing out the role of Ca from food versus a pharmacological source would be important to public health recommendations. Furthermore, Ca consumed as part of a food or food matrix has varying absorbability and hence metabolic effects. Future studies may wish to explore the differences between dietary Ca versus Ca as part of a food matrix for any metabolic differences 51. The database lacked information on sun exposure and vitamin D supplement use; thus, the contribution of each could not be investigated. The lack of data on markers of IR, such as HOMA-IR, limits our understanding of the effects of 25-OHD and Ca intake on glucose homeostasis IR 52. However, unlike some studies, we have controlled for other individual components of MetS, which would be strongly related to IR. PTH is crucial for 25-OHD concentration and Ca metabolism; however, this was not measured in our participants. A raised PTH can increase MetS components 53,54 and controlling for such a confounder would be important.
Our findings have indicated that increments of 10 nmol/l of 25-OHD concentration may lower the likelihood of having elevated TG and FPG, and 500 mg/day increments in dietary Ca intake may reduce the odds of elevated DBP. The combination of 25-OHD and Ca tertiles appears to further reduce the odds of reduced HDL-C and elevated TG. This warrants further investigation of the optimal level of the combination of 25-OHD and dietary Ca intake in reducing the risk of MetS components. Future prospective longitudinal studies and high-quality randomized controlled trials of vitamin D and/or calcium supplementation are needed to evaluate whether there is a causal relationship between 25-OHD concentration, dietary Ca intake, and individual MetS components.
P.K.P. analyzed the data and wrote the first draft. M.J.S. generated the idea, planned the analysis, and co-wrote the manuscript. Y.Z. cross-checked the analysis and co-wrote the manuscript. L.S.P. and Z.A. critically reviewed all aspects of the manuscript.
M.J.S. acknowledges the Victorian Department of Health and Human Services for use of the Victorian Health Monitor survey dataset. P.K.P. is the recipient of an Australian Postgraduate Award.
Conflicts of interest
There are no conflicts of interest.
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