The most important finding of the present study is that both 25(OH)D and PTH were strongly associated with adiposity but not with MetS or most of its components. Several other studies have suggested that low 25(OH)D status is associated with the development of the MetS and its individual components. However, our data do not support an independent contribution of 25(OH)D or PTH to the pathogenesis of the MetS in a population with a wide range of adiposity. Our data are also consistent with previous reports on the high prevalence of alterations in calcium metabolism[5, 24] in obese subjects.
Traditionally, vitamin D has been the key regulator of serum calcium metabolism either directly or indirectly through PTH. However, vitamin D receptors are found in a wide variety of tissue, including gut, adipose tissue, cardiac and skeletal muscles, and β-cells. Therefore, it is not surprising that numerous studies have investigated the potential key role of vitamin D in the pathogenesis of MetS and its individual components. As stated in the introduction section, some but not all epidemiologic studies conducted in general populations have demonstrated a relationship between low plasma 25(OH)D concentrations and the presence of MetS or its individual components[15–17]. Although these epidemiological observations are supported by mechanistic studies, experimental data are limited, especially in obese populations.
In this regard, a recent cross-sectional study conducted on 380 individuals, more than 80% of whom were overweight or obese, showed a strong association between plasma 25(OH)D concentrations and BMI. Individuals with 25(OH)D deficiency had higher odds of MetS than those who had normal 25(OH)D status, probably because the authors failed to account for the confounding effect of BMI on the association between MetS and 25(OH)D. In this study, no associations between plasma 25(OH)D concentrations and the individual components of MetS were shown.
Similar data were obtained by Botella-Carretero et al. in a Spanish study conducted in a reduced sample of severely obese subjects. In this study, 25(OH)D deficiency was more prevalent in patients with the MetS than in those without. In contrast, Hjelmesaeth et al., and Roislien et al. 2011, failed to find any association between 25(OH)D and MetS, but reported a positive relationship between PTH plasma levels and MetS in individuals with morbid obesity. Neither was an association found between PTH or 25(OH)D and MetS in overweight or obese individuals from New Zealand or Spanish morbidly obese patients.
There is also some controversy about the effect of low 25(OH)D status on the pathogenesis of obesity-related metabolic comorbidities and individual components of the MetS. As far as glucose metabolism is concerned, Forouhi et al. used data from the Medical Research Council Ely Prospective Study to show that 25(OH)D concentrations at baseline were inversely related with a 10-fold risk of hyperglycemia and insulin resistance. Recent studies also suggest that increased levels of PTH are independently associated with insulin resistance in individuals with abdominal obesity suggesting a direct link between PTH and MetS.
Similar results have been found in many observational studies[33, 34]. In contrast, the results of intervention studies are inconclusive, often because they involve the joint administration of vitamin D3 (cholecalciferol) and Ca. This makes it difficult to interpret the results, because it is not clear whether the response observed is due to vitamin D and/or Ca. In some randomized clinical trials (RCTs) in which cholecalciferol was used as a single treatment, insulin response to glucose improved[35, 36], but in others it did not. Similar findings were observed in relation to blood pressure and hypertension. Despite strong mechanistic evidence, the results of epidemiologic studies evaluating the association between 25(OH)D status and blood pressure are contradictory and inconclusive. The odds of having high blood pressure were lower in Australian individuals with higher 25(OH)D concentrations than in those with lower concentrations. In contrast, 25(OH)D did not predict future risk of hypertension or increases in blood pressure in the Tromso Study. Only one RCT using cholecalciferol has been conducted to determine the relationship between 25(OH)D and blood pressure. Scragg et al. randomized 189 elderly subjects who received a single dose (2.5 mg) of cholecalciferol or placebo during the winter. There was no effect on blood pressure. Likewise, our study, conducted in a large sample of individuals with different degrees of obesity, did not show any independent relationship between 25(OH)D concentrations and the odds of having diabetes and/or hypertension.
Vitamin D status has also been inversely related to atherogenic dyslipidemia in some studies[13, 40] but not others[31, 34, 41]. For example, plasma triglyceride concentrations were lower in US adult individuals in the top quartile of 25(OH)D than in those in the reference quartile. A positive association has also been observed between 25(OH)D and plasma HDL-cholesterol concentrations. No RCTs have been conducted to directly analyze the effect of vitamin D supplementation alone on lipid profile. However, a significant decrease in LDL-cholesterol and a non-significant increase in HDL-cholesterol concentrations have recently been observed after an 18-month period of oral vitamin D3 supplementation in Saudi T2DM individuals. Treatment with cholecalciferol associated with energy restriction resulted in a more pronounced decrease in plasma triglyceride concentrations than energy restriction alone. However, long term supplementation with low doses of cholecalciferol (5 to 20 μg) in healthy individuals had no effect on lipid profile, probably because the doses administered were not sufficient to achieve a clinically meaningful effect on lipids. Other RCTs that administered vitamin D supplements and focused on insulin sensitivity/release and blood pressure as the main variables reported no significant effects on lipids[35, 36].
Our study demonstrated that there was an association between 25(OH) concentrations and the hypertriglyceridemia component of the MetS, even after adjusting for several confounders. It also showed an association between plasma 25(OH)D concentrations and atherogenic dyslipidemia after adjusting for such potential confounding variables as BMI, which suggests that 25(OH)D status may play a role in lipid profile. This association could be mediated by inflammation, because it disappeared when uCRP was introduced as a covariable in the analysis.
Our results confirm the results of other studies that show that obese individuals with higher BMI have a higher risk of vitamin D deficiency and elevated PTH serum concentrations. When 25(OH)D deficiency and insufficiency were merged, only 38% of individuals with a BMI <30 kg/m2 had 25(OH)D insufficiency or deficiency, compared to 88-95% of those with a BMI>35 kg/m2. The prevalence of hyperparathyroidism increased from 12% in non-obese individuals to 47.5% in those with a BMI>50 kg/m2. Consistent with our results, several other studies have demonstrated an inverse relationship between BMI and 25(OH)D deficiency for both sexes, and for BMIs ranging from normal to severe obesity. In cases of severe obesity, the vitamin D abnormalities were usually more prominent. Prevalence of 25(OH)D deficiency or hyperparathyroidism has been observed to be as high as >50% or 40%, respectively, in individuals with a BMI>50 kg/m2. In overweight or obese women, an increase of 1 kg/m2 in BMI has been associated with a decrease of 1.21 nmol/L in 25(OH)D levels. Weight loss has been associated with an increase in peripheral 25(OH)D concentrations[24, 46]. Therefore, our data confirm previous reports, and show that the presence of obesity is a strong predictor of hypovitaminosis D and hyperparathyroidism.
One reason for the increase in the prevalence of vitamin D deficiency with increasing adiposity may be the higher prevalence of non alcoholic steatohepatitis (NASH) in obesity and insulin resistance states. Vitamin D3 is converted into 25-OH-vitamin D in the liver, and vitamin D deficiency is common in patients with advanced liver disease. In our study we did not include those patients with advanced liver disease in order to discount the effect of this condition on vitamin D concentrations. In fact, only 1.6% of our population had ALAT values that were twice as high as the normal cut-off values (data not shown).
Some of the strengths of our study are the significant amount of clinical data that were collected in a large population of people with different degrees of obesity, and the adjustment for potential confounders such as age, gender, season of blood sampling, current smoking and BMI. However, our study also has its limitations. First, cross-sectional studies are inherently limited in that they cannot establish cause and effect relationships, and our results may not necessarily be valid in non-obese or non-white populations. Second, we acknowledge that major biases with retrospective cohort studies can impact the recall of former exposure to risk variables. Among the biases that can negatively impact the veracity of this type of study are selection bias and misclassification or information bias as a result of the retrospective aspect. Third, in our study we assumed that all individuals with a BMI higher than 35 kg/m2 met the abdominal MetS criterion. This could lead to an overestimation of MetS prevalence in individuals between 35 and 40 kg/m2. This overestimation is probably minor, as only 0.5% of the PREDIMED individuals with a BMI between 30 and 35 kg/m2 had a waist circumference lower than the criterion established for abdominal obesity (data not shown). However, abdominal obesity may have been underestimated specially in individuals between 25 and 30 kg/m2. Finally, considering the diversity of results obtained in previous reports on the relationship between 25(OH)D and MetS, and the strong association found between obesity and MetS in this study, we cannot discount that the effect of BMI may have overwhelmed any marginal effect on MetS that could have been attributed to 25(OH)D.
In conclusion, in our study BMI was the variable that was most strongly associated with plasma 25(OH)D and PTH concentrations. Low plasma 25(OH)D and high PTH concentrations were also associated with an increased risk of MetS, but these associations disappeared after adjustment for BMI. On the other hand, our data support a possible contribution of plasma 25(OH)D to the pathogenesis of hypertriglyceridemia, and atherogenic dyslipidemia through inflammation. New prospective studies will be needed to confirm these findings.