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Title: INTERPLAY OF VITAMIN D AND METABOLIC

SYNDROME: A REVIEW
Author: Priyanka Prasad Anita Kochhar
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DOI:
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http://dx.doi.org/doi:10.1016/j.dsx.2015.02.014
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Diabetes & Metabolic Syndrome: Clinical Research & Reviews

Please cite this article as: Prasad P, Kochhar A, INTERPLAY OF VITAMIN D AND
METABOLIC SYNDROME: A REVIEW, Diabetes and Metabolic Syndrome: Clinical
Research and Reviews (2015), http://dx.doi.org/10.1016/j.dsx.2015.02.014
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Review
Title of the manuscript: INTERPLAY OF VITAMIN D AND METABOLIC SYNDROME: A
REVIEW
Author names: Priyanka Prasad* (Corresponding Author) and Anita Kochhar**
Author affiliations: *Research Scholar, Department of Food and Nutrition
Punjab Agricultural University, Ludhiana, Punjab. Postal Code: 141004
email id: priyankadwivedi16@gmail.com

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Mobile No. +918437411773

** Professor, Department of Food and Nutrition

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Punjab Agricultural University, Ludhiana, Punjab. Postal Code: 141004

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Mobile No. +919988880346 email id: dranitakochhar@yahoo.com

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,
Priyanka Prasad (Corresponding Author)

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Department of Food and Nutrition

College of Home Science
Punjab Agricultural University
Ludhiana 141004
Punjab
India
Telephone number: +918437411773, +919988880346
E-mail address:
priyankadwivedi16@gmail.com

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ABSTRACT
Vitamin D deficiency is a worldwide public health problem. Vitamin D deficiency plays key role
in the pathophysiology of risk factors of metabolic syndrome which affect cardiovascular

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system, increase insulin resistance and obesity, stimulate rennin-angiotensin-aldosterone system

that cause hypertension. The discovery of vitamin D receptor expressed ubiquitously in almost

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all body cells such as immune, vascular and myocardial cells, pancreatic beta cells, neurons and

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osteoblasts suggests an involvement of vitamin D mediated effects on metabolic syndrome.

Moreover vitamin D deficiency as well as cardiovascular diseases and related risk factors

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frequently co-occur. This underlines the importance of understanding the role of vitamin D in the
context of metabolic syndrome. The paper provides an insight into the physiology of vitamin D

observational and supplementation studies.

and relationship of vitamin D deficiency with risk factors of metabolic syndrome through

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KEY WORDS: Cardiovascular disease, Cholecalciferol, Metabolic syndrome, Vitamin D.

1. INTRODUCTION
Vitamin D is a fat-soluble vitamin. Vitamin D along with parathyroid hormone and its major
circulating form 1,25-dihydroxyvitamin D (1,25(OH)2D or calcitriol) is largely responsible for
the regulation of calcium and phosphorus homeostasis.1 The well known pathologic condition
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associated with vitamin D deficiency is malformed bones. However many recent research
advances provoked enormous public health interest in vitamin D. The identification of vitamin D
receptor (VDR) in almost all human cells2 has proved the association of vitamin D deficiency
with various chronic diseases. Moreover, vitamin D deficiency is shown to be highly prevalent

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among general populations in the world.3

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Metabolic syndrome is a cluster of risk factors that include abdominal obesity, atherogenic
dyslipidemia, hypertension and insulin resistance. It increases the risk of cardiovascular disease

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and type 2 diabetes.4 The third expert panel in Detection, Evaluation and Treatment of High
Blood Cholesterol in Adults established diagnostic criteria for this syndrome when three or more

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of the following factors are present: abdominal obesity, blood triglycerides 150 mg/dl, HDL
cholesterol < 50 mg/dl, systolic BP 130 or diastolic BP 85 mm Hg, and a basal glycemia

110 mg/dl.5 Dietary habits, levels of physical activity, age and sex structure of population,

heredity influence the prevalence of metabolic syndrome and its components.6 This could be due

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to increasing obesity and sedentary lifestyles and require necessity for therapeutic intervention.7
In this review, current knowledge on the association of vitamin D with risk factors of metabolic
syndrome is discussed.

There are three routes to maintain adequate stores of this essential micro nutrient i.e. sunlight
exposure, dietary intake and pharmaceutical supplementation. In the skin, vitamin D is present as
7-dehydrocholesterol (previtamin D). It is converted to vitamin D3 or cholecalciferol on exposure
to solar ultraviolet B radiation. Dietary and pharmaceutical sources of vitamin D are available
either in the form of vitamin D2 (ergocalciferol) mainly derived from plant sources, or vitamin
D3 (cholecalciferol) derived from animal sources. Vitamin D3 and D2 obtained from sunlight
exposure, dietary and medicinal preparation undergoes first hydroxylation predominantly in liver
to form 25 hydroxyvitamin D (25[OH] D). With relatively low biologic activity, 25(OH) D is the
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major circulating form of vitamin D in the body and is representative of total vitamin D stores.
The final activating step is the second hydroxylation of 25(OH) D primarily in the kidney to
produce 1,25 dihydroxy vitamin D (1,25[OH]2 D), biologically the most active form of vitamin
D and is responsible for physiologic functions of vitamin D.8 The 25(OH) D is converted to

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1,25(OH)2 D by renal 1 hydroxylase which is tightly regulated by calcium and phosphorus

metabolism by parathyroid hormone. Hence, circulating levels of 1,25(OH)2 D regulates calcium

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absorption and bone homeostasis. However, Correlations of serum level of 25(OH)D and

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1,25(OH)2D are usually not very strong and patients with low 25(OH)D levels frequently have
relatively high 1,25(OH)2D levels as a result of parathyroid induced stimulation of renal 1-

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hydroxylase activity. Further 24- hydroxylation of 25(OH)D or 1,25(OH)2D is the main

degradation process which produces vitamin D metabolites [24,25(OH)2D or 1,24,25(OH)3D],

which are converted to water soluble inactive calcitroic acid that is excreted out of body.9,10
After circulation in the body, vitamin D metabolites exert their effects by binding to the

ubiquitously expressed cytoplasmatic vitamin D receptors expressed by all almost all cells.11,12

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The physiologic effects of vitamin D are mediated by the interaction of 1,25(OH)2D with these
receptor. Concentrations of 25(OH)D are up to 1000 times higher than plasma 1,25(OH)2D
concentrations moreover 25(OH)D also has a significantly longer half-life than that of
1,25(OH)2D (23 weeks vs 46 h). After binding the receptor forms a heterodimer with retinoid
X receptor (RXR) and translocates to the nucleus, where this complex interacts with specific
DNA regions, called vitamin D-responsive elements. By additional interactions with
coregulatory proteins, the VDR-RXR complex regulates approximately 3 percent of the human
genome.2
Serum concentrations of 25(OH) D are the best parameter to assess whole body vitamin D
status.13 Cut off levels for 25(OH) D is based on the effect of vitamin D on calcium metabolism.
So a poor vitamin D status is associated with decreased intestinal absorption of calcium which in
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turn leads to low serum calcium levels. This condition in turn stimulates parathyroid gland to
secrete parathyroid hormone (PTH), this is called secondary hyperparathyroidism. Hence, at the
expense of several deleterious effects of this secondary hyperparathyroidism, the resultant effects
of increased PTH levels on the intestines (enhanced 1,25(OH)2D production), bones (calcium

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mobilization) and kidneys (reduced calcium loss) ensure adequate serum calcium levels. On the
basis of this consideration, the 25(OH)D level below which PTH levels start to rise

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(approximately 75 nm; to convert 25(OH)D levels from ng/mL to nmol/L multiply by 2.496) is

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frequently used for the estimation of a sufficient vitamin D status (>/=75 nm).14
2. VITAMIN D AND METABOLIC SYNDROME RISK FACTORS

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2.1 ARTERIAL HYPERTENSION

A study conducted on 25 hypertensive patients showed a significant negative correlation between

25(OH)D levels and systolic and diastolic blood pressure and calf vascular resistance and a
significant positive correlation between 25(OH)D levels and calf blood flow.15 A large meta-

analysis performed by Kunutsor et al found a significant inverse correlation between baseline

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circulating serum vitamin D levels with the risk of incident hypertension. The pooled relative
risk (RR) for the disease was 0.70 (95% CI 0.570.86) when compared from the highest to the
lowest quartile of baseline 25(OH) D levels.16 The third US National Health and Nutrition
Examination Survey (NHANES III) analyzed the association of blood pressure with serum levels
of 25(OH) D in 12644 people above 20 years during 1988 to 1994. The mean serum 25(OH)D
level was lowest in non-Hispanic blacks (49 nmol/L), intermediate in Mexican Americans (68
nmol/L), and highest in non-Hispanic whites (79 nmol/L), after adjusting for age, sex, physical
activity and ethnicity. Serum 25(OH) D levels were found inversely associated with blood
pressure, stronger for participants aged above 50 years than younger (P = .021).17 In another
study subjects with deficient vitamin D status (<15 ng/mL) were at higher (3 to 6 times) risk of
developing hypertension during a 4 year follow up period when compared with subjects with
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optimal vitamin D status.18 Similar results for optimal vitamin D status and the development of
hypertension was reported on a group of female subjects in the Nurses Health Study.19 A large
cohort study from the United Kingdom reported an inverse relationship of vitamin D status with
the development of components of the metabolic syndrome including hypertension.20 In 554

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healthy patients aged 20-79 years vitamin D insufficiency was found associated with increased
arterial stiffness and endothelial dysfunction.21 Snijder et al22 evaluated the association of blood

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pressure with serum 25-hydroxyvitamin D and PTH levels in 1205 men and women aged 65

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years and above. After adjustments for age, sex, region, season and lifestyle factors no
significant relationship between serum 25(OH) D levels and diastolic (P = 0.98) or systolic (P =

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0.11) blood pressure was found whereas higher PTH levels were found associated with higher
prevalence of hypertension.22 Possible mechanisms for the association of vitamin D and blood

pressure demonstrate the inverse relation of serum vitamin D with renin-angiotensin-aldosterone

system (RAAS) activity and the effect of vitamin D on improving endothelial function and

prevention of secondary hyperparathyroidism.23,24 Elevated parathyroid hormone (PTH) levels

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are an indication of vitamin D deficiency and are associated with myocardial hypertrophy and
high blood pressure levels.22 Kota et al. reported stimulation of rennin-angiotensin-aldosterone
activity in 50 hypertensive patients along with deficiency of vitamin D and obesity.25
Intervention Studies

Significantly negative correlation between intake of vitamin D and risk of hypertension was
observed in 283 black Americans at a very high risk of vitamin D deficiency. The participants
were given either 1000, 2000 or 4000 IU of vitamin D per day or placebo for three months.
Supplementation of vitamin D resulted in reduction of 0.2 mmHg of systolic BP for each
increase of 1 ng/mL of vitamin D over three months (p = 0.02).26 Similarly supplementation of
vitamin D (33000 IU of vitamin D3, after every 2 weeks, for 3 months) in 100 hypertensive
patients demonstrated significant decrease in systolic blood pressure.27 In a meta analysis by Wu
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et al.,28 oral supplementation of vitamin D was reported associated with significant reduction in
systolic blood but not diastolic blood pressure.28 Short term supplementation (8 weeks) of
vitamin D3 was found associated with reducing systolic blood pressure.29 In this study 148
women received either 1200 mg calcium plus 800 IU vitamin D3 or 1200 mg calcium alone per

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day. The study concluded that inadequate vitamin D3 and calcium intake could play a
contributory role in the pathogenesis and progression of hypertension and cardiovascular disease

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in elderly women.29 Weng et al.,30 studied mouse models of diet induced vitamin D deficiency

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resembling humans with diet-induced hypertension. Mice fed with vitamin D deficient feed for 6
weeks showed increased systolic and diastolic blood pressure and decreased urinary sodium

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excretion.30 Oral cholecalciferol administration at the rate of 25000 IU once a week for two
months along with constant salt free diet in 15 drug free patients with hypertension and

hypovitaminosis D resulted in a reduction (p < 0.05) in plasma renin and aldosterone

concentration but no difference was observed in blood pressure in the patients.31 Another study

did not detect any significant difference in 25(OH) D levels when comparing hypertensive

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patients with matched controls.32 In this study hypertension was diagnosed based on one blood
pressure reading raising the possibility that several normal patients could have been placed in the
hypertensive group.
2.2 OBESITY

Obesity as cardiovascular risk factor is closely associated with insufficient vitamin D.33
Vimaleswaran et al.,34 reported that obesity results in lower vitamin D levels but not the other
way around. The authors analyzed relationship of 12 established single nucleotide
polymorphisms (SNPs) with body mass index (BMI) and four typical vitamin D related SNPs in
42024 patients. The results showed that each unit increase of BMI was associated with a 1.15%
decrease of 25(OH) D. The study revealed obesity as a causal risk factor for vitamin D
deficiency, which accounts for approximately one third of vitamin D deficiency.34 Association of
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serum 25-hydroxyvitamin D (25[OH] D) concentrations with subcutaneous adipose tissue (SAT)

and visceral adipose tissue (VAT) volumes was observed in 1882 subjects. Inverse relation
between 25(OH) D concentrations with waist circumference (P < 0.005, SAT (P = 0.016) and
VAT P < 0.0001) concluded strong association of vitamin D status with subcutaneous and

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visceral adiposity.35 Aasheim et al.,36 compared blood and serum 25(OH) D concentration of 110
morbidly obese with that of 58 healthy subjects. The results revealed significant lower

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concentration of 25(OH D in obese subjects (P < 0.01).36 Lower serum vitamin D (below 50

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nmol/L) concentration was found associated with high body fat, glucose and decreased insulin
sensitivity levels.37 Carretero et al.,38 reported high prevalence of vitamin D deficiency in

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morbidly obese patients (Body mass index >/= 40 kg/m2).38 Possible reasons for lower vitamin D
status during obesity are lower intake of vitamin D by obese individuals,39,40 lesser exposure of

skin to sunlight in obese individuals leading to reduced cutaneous synthesis of vitamin D41,42 and
decreased intestinal absorption of vitamin D in individuals undergone bariatric surgery.43,44

Moreover vitamin D receptors are also present in adipocytes that make adipose tissues

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responsive to vitamin D.45,46 A retrospective study evaluated the effect of PTH and 25(OH)D on
metabolic syndrome and atherogenic adiposity in 316 subjects for two years. The results revealed
higher prevalence of vitamin D deficiency with increased adiposity further an increase in
hyperparathyroidism was observed from 12 percent in non-obese to 47.5 percent in morbidly
obese individuals with BMI>50 kg/m2. Higher risk of metabolic syndrome and atherogenic
dyslipidemia was found strongly associated with low serum 25(OH) D and high PTH
concentrations.47 On the contrary, Kienreich et al.,7 reported no significant effect of vitamin D
status on obesity.
Intervention Studies
Vitamin D supplementation significantly reduced body fat mass and increased serum vitamin D
concentration (baseline concentration below 50 nmol/L) in 77 overweight and obese women who
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received 1000 IU of vitamin D daily for 12 weeks as compared to placebo.48 Carrillo et al.,49
demonstrated impact of supplementation of vitamin D during resistance training in 24
overweight and obese individuals. Intervention group who received vitamin D at the rate of
4000 IU per day against placebo reported elevated vitamin D status was associated with reduced

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waist-to-hip ratio. The study revealed higher efficiency of vitamin D in lowering complications
of obesity as compared to physical exercise.49 Significant reduction in serum vitamin D

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concentration and secondary hyperparathyroidism was observed in severely obese patients

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following jejunal bypass surgery.50 Significant reduction in visceral adipose tissue was observed
in 171 overweight and obese subjects when supplemented with calcium and vitamin D fortified

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orange juice (350 mg Ca and 100 IU vitamin D per serving of juice).51

2.3 INSULIN SENSITIVITY

Many observational studies suggest the association of vitamin D deficiency with insulin
resistance or impaired insulin secretion.52,53 The pancreas possesses vitamin D receptor cell and

1-hydroxylase and so has machinery to convert circulating 25(OH) D to 1,25(OH) 2D.54 Early

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studies suggest that vitamin D deficient rodents are not able to adequately secrete insulin when
compared with vitamin D sufficient controls.55 In a longitudinal study of 17 year follow up
period, 40 percent reduction in risk of developing type 2 diabetes was observed in men and
women with 25(OH) D levels above 28 ng/mL at baseline.56 Tsur et al.,57 evaluated the
association of development of impaired fasting glucose (IFG) and diabetes with serum 25 (OH)
D level in 4 million non diabetes subjects aged 40 to 70 years for 2 years. The subjects were
divided in 5 subgroups according to serum 25(OH) D subgroups (25, 25.137.5, 37.650, 50.1
75, and >75 nmol/L). Inverse correlation between serum 25(OH) D level and risk of progression
to IFG and diabetes was observed, moreover transition from normoglycemia to IFG, from
normoglycemia to diabetes and from IFG to diabetes in subjects with a 25-OHD level 25
nmol/L were greater than those of subjects with a 25-OHD level >75 nmol/L.57 Similarly
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baseline serum 25(OH) D levels were found inversely associated with 10 year risk of
hyperglycemia and insulin resistance in 524 nondiabetic subjects aged 40 to 69 years.58 Serum
levels of 25(OH) D was found positively correlated with insulin sensitivity index in 126 healthy
subjects at fasting, 60, 90 and 120 min during the oral-glucose-tolerance test.59 Similar results of

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negative correlation of serum vitamin D concentration with fasting insulin, visceral abdominal
fat and waist hip circumference was also observed.60,61

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On the contrary randomized trials have also failed to show beneficial effects of vitamin D

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supplementation on improving insulin resistance.62,63,64,65

Intervention Studies

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In a randomized, placebo-controlled trial supplementation with 4000 IU of vitamin D3 per day

for 12 weeks successfully improved vitamin D insufficiency, insulin secretion and sensitivity in

89 overweight or obese subjects with prediabetes.66 Insulin sensitivity was improved when 42
women aged 28 to 68 years were supplemented with 4000 IU of vitamin D3 for 6 months;

however there was no change in insulin secretion .67 In another study, the impact of vitamin D

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supplementation (400 IU daily) for 3 years on diabetic subjects showed less rise in fasting
glucose concentrations when compared to placebo.56 Giulietti et al.,68 observed that deficiency
of vitamin D in early life increases the expression of type 1 diabetes on non obese diabetic mice.
This emphasizes the importance of controlling vitamin D deficiency in early childhood to
reduce the incidence of type 1 diabetes at later age in individuals who are genetically
predisposed.68 Similarly vitamin D supplementation at the rate of 2000 IU daily for 1 year was
associated with decreased frequency of type 1 diabetes against placebo in birth cohort of 10366
children.69 Significant improvement in serum insulin and HOMA-IR and reduction in insulin
resistance was reported in 100 subjects supplemented with 50000 unit of vitamin D3 orally per
week for the period of 8 weeks.70
2.4 DYSLIPIDEMIA
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Observational studies indicate relationship of vitamin D deficiency with lower high density
lipoprotein, higher triglycerides, higher apolipoprotein E levels71,72 and hypercholesterolemia.73
A cross sectional study reported that patients with hyperlipidemia had lower vitamin D levels.74
The study was conducted on 59 hyperlipidemic subjects against 48 healthy controls. Vitamin

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insufficiency was related to atherogenic dyslipidemia.74 In the Third National Health and
Nutrition Examination Survey (NHANES III) 8421 subjects aged above 20 years were assessed

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for relationship of serum 25(OH) D levels and metabolic syndrome. The results revealed that

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concentration of 25(OH) D was 67.1 nmol/l in subjects with metabolic syndrome compared to
75.9 nmol/l in subjects without metabolic syndrome. The incidence of metabolic syndrome

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decreased progressively across increasing quintiles of concentration of 25 (OH) D,75 significant

inverse relationship was observed between higher concentration of serum 25(OH) D and

hypertriglyceridemia, hyperglycemia, abdominal obesity75 and total cholesterol, total cholesterol

/ HDL ratio and positive relationship of vitamin D with HDL cholesterol was observed in 274

individuals aged 30 to 75 year.76 Deficiency of 25-hydroxyvitamin D was found associated with

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dyslipidemia in 150 asymptomatic Indian subjects.77 Similarly Lu et al.,78 reported high

prevalence of vitamin D deficiency in middle aged and elderly population, associated with risk
of metabolic syndrome and insulin resistance and dyslipidemia.78 Similar findings were reported
in 499 rheumatoid arthritis patients by Baker et al.,79 Low levels of serum vitamin D were found
associated with low HDL and high levels of total cholesterol, LDL cholesterol and
triglycerides.80 Shivaprakash and Joseph,81 demonstrated positive association of low levels of
25(OH) D levels in children and adolescents with higher plasma glucose and lower HDL
concentrations. The study concluded that such children would be more prone to develop type 2
diabetes and cardio metabolic diseases in later life.81 On the other hand Gupta et al.,82 reported no
significant association between vitamin D deficiency with ischemic stroke or its risk factors.82 In

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another study parathyroid hormone instead of vitamin D was found as an indicator of metabolic
syndrome in African and Asian subjects.83
Intervention Studies
Chai et al.,84 studied effect of combination of calcium and vitamin D supplementation or alone

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on lipid profile of 92 subjects. 800 IU of vitamin D3 and 2g of elemental calcium was

supplemented for 6 months. Calcium alone or combined with D3 but not vitamin D3 alone

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showed reduction in serum lipid levels.84 Similarly short term supplementation of oral calcitriol

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with calcium for 6 months resulted in significant decrease in triglyceride and fasting blood sugar
levels.85 Supplementation of calcium along with vitamin D (600 mg elemental calcium and 200

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IU vitamin D/tablet) in the way of 2 tablets for 15 weeks resulted in significant improvement in
blood lipid profile in 68 obese or overweight women.86 Wang et al.,87 in a meta analysis reported

significant effect of vitamin D supplementation on LDL cholesterol level but not on total
cholesterol, HDL cholesterol and triglycerides level.87 Other clinical reported no significant

impact of vitamin D supplementation on blood lipids.88,48 Vitamin D supplementation at the rate

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of 1200 IU per day for 8 weeks was found insufficient to improve serum lipid profile and
cardiovascular disease risk.89 Moreover long term supplementation of vitamin D3 along with
hormone replacement therapy in postmenopausal women found associated with unfavorable
effects on serum lipids.90

2.5 CARDIVASCULAR DISEASES

An inverse relationship of cardiovascular disease mortality and UVB radiation was first reported
in 1981 showing the possible positive link between incident solar UV radiation and
cardiovascular risk factors.91 Many observational studies indicated the association of lower
vitamin D levels with higher incidence of cardiovascular events and mortality.92,93,94,95 Vitamin
D status and risk of cardiovascular diseases in 3000 subjects was evaluated in subjects with
established cardiovascular disease and end-stage kidney disease for 7 years. Patients with severe
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vitamin D deficiency (25[OH] D <10 ng/mL) were at 3 to 5 times higher risk of dying from
sudden cardiac death or heart failure when compared with patients with optimal levels of vitamin
D (25(OH)D >30 ng/mL), moreover vitamin D deficiency resulted in 50 per cent increase in fatal
stroke.96 Similar findings were reported in hemodialysis patients.97 Joergensen et al.,98 reported

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association of asymptomatic coronary artery disease with lower vitamin D levels in high risk
type 2 diabetic patients.98 On the other hand Rajasree et al.,99 reported no benefit of having

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optimal levels of 25(OH)D in subjects with established CVD. The study reported positive

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association of high levels of 25(OH)D (>89 ng/mL) with incidence of heart diseases.99 Risk of
cerebrovascular disease100 and stroke101 was significantly lower in subjects with high 25(OH) D

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levels compared to those with insufficient vitamin D status. Similar results were demonstrated in
40000 individuals,102 coronary angiography and diabetic patients103,104 and in 203 individuals

with subclinical carotid atherosclerosis.105 Associations of vitamin D deficiency with incident

cardiovascular diseases was particularly strong in heart patients and pronounced increase in

cardiovascular diseases risk was demonstrated at 25(OH) D concentrations below approximately

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37.5 nm.106,107,108,109,110,111,112 Grandi et al.,113 reported increase in risk of cardiovascular mortality

by 83 percent in individuals with low 25(OH) D levels when compared with individuals with
serum 25(OH) D levels below a cut-off ranging from approximately 25 to 50 nm.113 The
concentration of serum 25(OH) D was measured in 701 subjects aged 14-18 years to evaluate its
association with cardiometabolic risk indices (adipokines, inflammatory markers, fasting
glucose, homeostatic model assessment-insulin resistance (HOMA-IR), lipid profile, and blood
pressure). A significant increase was observed for adiponectin (P = 0.01) and HDL cholesterol
(P = 0.04) and decrease for glucose (P < 0.01), HOMA-IR (P < 0.01) and systolic BP (P < 0.01)
for increasing serum 25(OH) D concentration.114 Serum vitamin D concentration was found
independently associated with aortic distensibility in 131 newly diagnosed diabetic patients
providing the role of vitamin D in pathogenesis of cardiovascular disease.115 Significant positive
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correlation of higher concentration of serum 25(OH) D levels with cardiometabolic risk factor
like high-density lipoprotein cholesterol (HDL-C), lower level of fasting insulin and C-reactive
protein was observed in children aged 7 to 12 years.116,117,118
The first evidence of manifestation of vitamin D deficiency in human cardiovascular disease

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came from patients with end-stage renal disease (ESRD). The damaged kidney fails to convert
25(OH) D to 1,25(OH) 2D resulting in a severe vitamin D deficiency and secondary

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hyperparathyroidism resulting in blood pressure, cardiac contractility, cardiac hypertrophy and

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heart failure.119 The target tissues for vitamin D are heart and blood vessels and they express
both VDR and 1-hydroxylase.120 It was reported that vitamin D receptor and 1-hydroxylase

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knockout mice develop heart failure despite normal calcium levels.121 Hyper activation of the
rennin angiotensin aldosteron system (RAAS) is suspected as the mediating pathway because

blockade of RAAS with the angiotensin converting enzyme is reported to decrease cardiac
abnormalities in the mouse models.2,122 Increased vitamin D receptor cells expression in

myocardial hypertrophy supports the crucial role of vitamin D for myocardial health.123,124 The

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activation of VDR further enhances cardiac calcium flux thereby inducing a rapid relaxation of
cardiomyocytes, which may improve diastolic function of the heart.123,125 Moreover, the
regulation of cardiac extracellular matrix turnover by the help of vitamin D may be important to
maintain cardiac health.126 Significant decrease in the elevated levels of matrixmetalloproteinase9 was reported in 171 vitamin D deficient adults after supplementation with 25(OH) D.126
Further vasculoprotective action of vitamin D may be caused by increased nitric oxide (NO)
production that in turn inhibit macrophage to form foam cell and thereby reduce the expression
of adhesion molecules in endothelial cells.127,128,129 This is in line with data obtained from crosssectional observational studies which reported association of lower vitamin D levels with
endothelial

dysfunction,

increased

arterial

stiffness

and

atherosclerosis.120,130

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antiatherosclerotic effects of vitamin D include inhibition of macrophage cholesterol uptake and

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foam cell formation, lowering of vascular smooth muscle cell proliferation and migration,
suppression of endothelial activation triggered by inflammation 129,131 and by antioxidant activity
that inhibits lipid peroxidation.132 Moreover vitamin D may also reduce vascular calcification by
inhibiting the formation of bone morphogenic proteins,120,133 so poor vitamin D status contribute

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to vascular calcification134 which aggravate the risk of cardiovascular diseases. Vitamin D also
plays a role in the regulation of several important inflammatory and antiinflammatory

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cytokines.135,136

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Intervention Studies

Bjelakovic et al.,137 in a meta analysis reported that vitamin D supplementation results in

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significant reduction of total mortality rate for cardiovascular diseases when compared to
placebo.137 In a randomized trial evaluating vitamin D supplementation 123 heart failure patients

received 500 mg calcium along with 2000 IU of cholecalciferol per day for 9 months.138 The
results reported significant decrease in TNF-levels and increase in serum levels of the

antiinflammatory cytokine IL-10 emphasizing the positive impact of vitamin D supplementation

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in modifying cytokine profile cardiovascular disease patients.138 Vitamin D supplementation is

very often combined with calcium intake making it hard to conclude whether intake of calcium
or vitamin D is associated with decreased incident risk of cardiovascular diseases.139 In the
Womens Health Initiative study 36000 postmenopausal women received 500 mg calcium
together with 200 IU of vitamin D3 (cholecalciferol) twice per day or matching placebo for 7
years to evaluate its association with occurrence of cardiovascular events and death. Occurrences
of cardiovascular events (myocardial infarction, stroke, transient ischemic attack, and confirmed
angina) and cardiovascular death were similar between the two groups during and after
supplementation.2 As the limitations of the study, women in the placebo group were permitted to
take vitamin D supplements and baseline 25(OH) D levels were not measured.2 In a similar
study, 1259 postmenopausal women who received calcium and vitamin D supplement (1 g
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elemental Ca as carbonate with 400 IU vitamin D3 per day) for 5 years demonstrated no
significant reduction in serum concentration of LDL cholesterol, total cholesterol, triglycerides
and lipoprotein (a). The study reported no association of Ca and vitamin D supplementation on
risk factors of cardiovascular diseases.140 In both studies participants received a daily dose of

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only 400 IU of vitamin D which is below the recommended daily intake of 800 IU of vitamin D
for postmenopausal women.

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On the other hand there are studies that report no effect of vitamin D supplementation of the

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cardiovascular risk factors. Sun et al.,141 evaluated association between dietary and supplemental
intake of vitamin D and cardiovascular risk in 74272 women and 44592 men free from cardio

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vascular diseases at baseline. Higher intake of both dietary and supplemental vitamin D was
associated with decreased risk of cardiovascular diseases in men but not in women.141

Supplementation of 100000 IU oral vitamin D3 in subjects with blood pressure above 140/90 mm
for 6 months demonstrated no significant changes in blood pressure, blood cholesterol and

glucose levels in the intervention group. The study found 6 month follow up period insignificant

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to have any impact on cardiovascular risk factors.142 Similar results were obtained for short term
supplementation of 50000 IU of vitamin D3 on 151 adults with elevated risk of cardiovascular
diseases.88

CONCLUSION

Vitamin D deficiency is common in population and degenerative diseases are direct

manifestation of vitamin D deficiency. Several epidemiologic studies have established a strong
association between vitamin D deficiency and risk factors of metabolic syndrome. Clinical and
intervention studies have also indicated that metabolic syndrome and mortality are associated
with vitamin D insufficiency. However available data from epidemiological and intervention
studies are not consistent to draw final conclusions on the effect of vitamin D supplementation
on risk factors of metabolic syndrome. Since there is sufficient biologic plausibility to explain
16

Page 16 of 33

the role of vitamin D in the prevention and treatment of metabolic syndrome so more studies are
required to be carried out to establish the relationship.
There are currently no universal guidelines for the screening and treatment of vitamin D
insufficiency. Furthermore, the adequate intake levels established by the Institutes of Medicine

ip
t

have been recognized to be inadequate. Currently available data suggest that 25(OH) D levels of
approximately 75 100 nm are associated with the best health outcomes.130 There is immediate

cr

need to conduct intervention trials to recommend a precise intake of vitamin D to treat or prevent

us

risk factors of metabolic syndrome. Moreover sufficient knowledge pool about rich dietary
sources of vitamin D in form of functional or supplementary foods is required to be generated to

an

reduce the dependence of patients and at risk population on the pharmaceutical sources of

DECLARATION OF INTEREST

vitamin D.

no competing interest.

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