In the last few decades, interest in vitamin D (VitD) has grown significantly since
numerous studies have suggested that besides its well-established roles in bone metabolism
(1), it could have other important roles in organism, including roles in immunity,
endocrine, cardiovascular, and reproductive system (2–7). Many studies indicated that
VitD status is inversely associated with the incidence of several metabolic diseases
and conditions, including obesity (8, 9), insulin resistance (10–14), metabolic syndrome
(15–17), dyslipidemia (13, 18, 19), diabetes (10, 11, 20–22), non-alcoholic fatty
liver disease (NAFLD) (23–25), and cardiovascular diseases (7, 26–28). However, the
findings were often inconsistent, and the cause/effect relationships particularly
remained to be confirmed, as well as the molecular pathways of these associations.
Moreover, the relationship of VitD with metabolic and cardiovascular disorders seems
to be bidirectional: e.g., obesity could worsen VitD deficiency (8), and vice versa,
VitD deficiency could aggravate obesity and related metabolic and cardiovascular complications
(insulin resistance, defects in insulin secretion, disordered metabolism of lipids,
hepatic steatosis, and gut dysbiosis) (7, 9) by multiple mechanisms, many of which
are still undiscovered and unclarified. Additionally, since in the above-mentioned
disorders and diseases there is also chronic inflammation and increased oxidative
stress, the role of VitD as immunomodulator and anti-oxidative agent has been proposed
as one of the mechanisms by which VitD can influence these conditions (29–34).
This Frontiers Research Topic “The role of vitamin D in metabolic and cardiovascular
health” focused on epidemiological research on associations of VitD with metabolic
and cardiovascular health, particularly in specific population groups, and pathophysiological
pathways of these associations, as well as possible confounding factors which modulate
these associations. The Research Topic welcomed also articles on the role of VitD
as one of supporting therapeutics in cardiovascular and metabolic diseases, as well
as immunomodulator.
In this Research Topic there are 13 papers covering the above-mentioned aspects.
Chen Y. C. et al. compared the risk for VitD deficiency across different categories
of metabolically healthy normal weight (MHNW) to metabolically unhealthy overweight/obese
insulin resistant (MUO) subjects, by studding 6,655 Chinese adults. The study confirmed
the highest risk for VitD deficiency among the MUO subjects, but also indicated some
gender and age- related differences: among men, the increased risk was noted particularly
in MUO men >50 years old, while in younger men, the risk was highest among metabolically
healthy obese (MHO) men. In contrast, among women, in both age subgroups the highest
risk was represented among MUO women, but the stronger association was noted among
younger women. This study indicated possible gender-influenced associations of VitD
status with obesity and adverse cardiometabolic and inflammatory profiles.
Similarly, Yin X. et al. analyzed the associations of VitD status with HOMA-IR (Homeostatic
Model Assessment of Insulin Resistance), as a robust measure of insulin resistance,
in 6,079 American adults without diabetes and other chronic diseases, by using the
data from the National Health and Nutrition Examination Surveys (NHANES). The study
also confirmed the negative associations between serum VitD concentrations and HOMA-IR,
which remained significant after multiple adjustments for many possible confounders,
including age, gender, race/ethnicity, and body mass index (BMI). Nevertheless, the
further stratification analyses showed some racial/ethical differences: in people
with Non-Hispanic Black origin this inverse association between VitD and HOMA-IR was
not observed, which indicates the need for further studies focused on ethnic/racial
disparities.
Song et al. examined the possible additive effects of obesity and VitD status on the
all-cause, cardiovascular and cancer-related mortality, by using the data from the
NHANES surveys. In the models adjusted for multiple confounders (including age, gender,
race/ethnicity, smoking, and BMI), an independent effect of VitD both insufficiency
and deficiency on all mortality rates was confirmed, with deficiency having stronger
effect. Interestingly, the effect of VitD deficiency overcame the effect of obesity
on all mortality rates. The highest risk for overall and cardiovascular mortality
was observed among VitD deficient obese subjects, while for cancer mortality among
VitD deficient normal weight subjects, indicating different mechanisms of associations
of VitD with mortality in different conditions.
Similarly, Chen X. et al. examined the possible effects of VitD status on the all-cause,
cardiovascular and cancer-related mortality among subjects with hyperlipidemia, by
using the data from the NHANES surveys. In the models adjusted for multiple confounders
(including age, gender, race/ethnicity, smoking, and BMI), serum VitD level was identified
as an independent factor for all-cause and cardiovascular mortality, but no association
was found with malignancy-specific mortality among these subjects. Particularly serum
VitD levels <25 ng/ml were associated with a higher risk for all-cause and cardiovascular
mortality, indicating the need for monitoring of VitD levels and correcting VitD insufficiency/deficiency
among hyperlipidemic subjects.
Zheng et al. using the NHANES data found a significant negative correlation between
serum VitD levels and the risk of frailty in older people.
Shree et al. performed a meta-analysis on the association of serum VitD levels and
polymorphism in the VitD receptor (VDR) gene with celiac disease, showing that reduced
serum level of 25(OH)D and rs2228570-T polymorphism of Fok1 T-allele of VDR gene could
be implicated in pathophysiology of this autoimmune disease. Zhou et al. examined
the association between serum VitD levels and plasma myeloperoxidase (MPO) levels,
as a marker of oxidative stress, in 6,414 Chinese women and men. After adjusting for
multiple confounders, the study found that circulating 25(OH)D was negatively associated
with MPO levels.
Yin W. J. et al. examined 3,713 pregnant Chinese women in the second trimester of
pregnancy, their serum VitD levels, biochemical and clinical indicators of cardiovascular
risk and inflammation, and the inflammatory potential of their diet, using the empirical
dietary inflammatory pattern (EDIP) score. The study revealed that serum VitD levels
mediated significant proportion of the association between the dietary inflammatory
potential (i.e., EDIP score) and cardiovascular risk in pregnant women. At the same
time, the circulating marker of inflammation, high-sensitivity C-reactive protein
(hs-CRP), mediated significant proportion of the association between serum VitD levels
and cardiovascular risk, indicating significance of anti-inflammatory effect of VitD
in the prevention of cardiometabolic disturbances related to pro-inflammatory diets.
Yang et al. performed a meta-analysis on the effects of VitD supplementation on the
circulating lipid levels in subjects with prediabetes, and found that VitD supplementation
might beneficially affect triglyceride levels in these subjects, while no significant
effects on total cholesterol, HDL-cholesterol and LDL-cholesterol were found. The
study revealed that particularly longer duration of treatment (more than 1 year),
with doses which correct VitD deficiency/insufficiency, are required to improve triglyceride
levels. However, just a few studies were included, and more research on that topic
is necessary.
An interesting article by Lee et al. focused on the effect of VitD supplementation
on hypercalciuria/urolithiasis prevention in 140 children with epilepsy undergoing
ketogenic dietary therapy (KDT). It is known that ketogenic diets relate to increased
risk for hypercalciuria/urolithiasis, while the role of VitD on this risk is less
clear. Interestingly, the study showed an inverse association of serum VitD levels
with the urinary calcium/urinary creatinine ratio, a marker of hypercalciuria. The
study also pointed-out that the serum VitD levels >40 ng/mL and the vitamin D3 supplementation
doses >50 IU/kg are probably needed for preventing hypercalciuria related to KDT.
Bernardo et al. studied the combined effect of obesity (induced by a high-fat diet)
and VitD dietary depletion on metabolic profile and progression of kidney damage in
an experimental model of ischemia/reperfusion kidney injury in rats. The study pointed
out both independent and additive effects of obesity and VitD depletion on exacerbation
of multiple metabolic and inflammatory changes, and progression of functional, hemodynamic,
and morphological kidney alterations.
Gázquez et al. studied the effect of VitD supplementation during pregnancy in rats
by using different VitD metabolites. The study showed that the monohydroxylated form
of VitD, 25(OH)D3, given orally provided better VitD availability compared to vitamin
D3: it doubled 25(OH)D3 concentrations in maternal and fetal blood. No adverse effects
on pregnancy and fetus were shown. Moreover, 25(OH)D3 had an additional effect on
the expression of VDR, fatty acid translocase (FAT), and scavenger-receptor class
B type-1 (SR-B1) in maternal liver; and VDR and glutamate decarboxylase GAD67 in fetal
brain, which requires further investigation.
Finally, Hanel et al. compared the gene-regulatory potential of three different VitD
metabolites: 25(OH)D3, 25(OH)D2, and 1,25(OH)2D3 in human peripheral blood mononuclear
cells (PBMCs), and found that although monohydroxylated metabolites can have similar
effect on expression of 206 common target genes, their effective concentrations were
in the range of supra-physiological concentrations and were 600-fold higher than effective
concentrations for 1,25(OH)2D3, indicating 600-fold lower effectiveness.
In summary, the articles in this Research Topic confirm the independent and additive
role of VitD in pathophysiology of cardiometabolic and autoimmune diseases, and emphasizes
the need for further research in this field. Particularly studies in different population
groups, studies on pathophysiological mechanisms, and well-controlled randomized trials
with VitD as preventive and therapeutic agent, are needed.
Author contributions
IŠ wrote the manuscript. MD-I and JD-M revised, co-wrote, and edited the manuscript.
All authors listed have made a substantial, direct, and intellectual contribution
to the work and approved it for publication.