Does sufficient 25-hydroxyvitamin D mean lower metabolic risk for women?

Abstract

OBJECTIVE:

There are conflicting results regarding the relationship between metabolic diseases and vitamin D deficiency. We aimed to show the possible relationship between 25-hydroxy (OH) vitamin D levels and obesity, insulin resistance and hyperlipidemia in women.

MATERIALS AND METHODS:

Three hundred fifty seven female were included retrospectively. Body mass index (BMI) was determined with body weight (kg)/height (m²) formula. Fasting plasma glucose, insulin, lipid profile, calcium, phosphorus, parathormone, 25 hydroxy vitamin D, thyroid stimulating hormone were evaluated. Insulin resistance was calculated with homeostatic model values for insulin resistance (HOMA-IR). Patients were grouped according to 25 (OH) vitamin D levels and BMIs.

RESULTS:

25 (OH) vitamin D was negative correlated with BMI, insulin and HOMA-IR, (respectively r = –0.156, –0.128, –0.123 and p = 0.003, 0.015, 0.020). It is positive correlated with HDL and HDL/LDL ratio (respectively r = 0.183, 0.185 and p = 0.003, <0.001) HDL-C was higher in 25(OH) vitamin D sufficient group. After multivariate analysis, 25 (OH) vitamin D was still positively related with HDL and HDL/LDL ratio (respectively r = 0.127, 0.118 and p = <0.05).

CONCLUSION:

25 (OH) Vitamin D is relationship with HDL, HDL/LDL ratio and invers relationship obesity. The normal 25 (OH) vitamin D supports the reduction of metabolik risk.

Keywords

25(OH) vitamin D obesity insulin resistance lipid

1 Introduction

Vitamin D is an important hormone for bone health. Numerous studies have also detected the relationship between vitamin D deficiency and many diseases, such as infections, autoimmune diseases, diabetes, cancers [1, 2]. Especially in many studies, vitamin D deficiency has been shown to be directly related to insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases [3].

Metabolic syndrome is a well-known condition associated with obesity. Other parameters of metabolic syndrome are hypertension, glucose metabolism disorders (hyperglycemia, insulin resistance, diabetes mellitus (DM)) and dyslipidemia [4]. Vitamin D deficiency leads to atherosclerotic plaque formation and increases the risk of atherosclerosis [5], it causes hypertension by upregulating the renin-angiotensin-aldosterone system [6], it causes insulin resistance and type 2 DM by disrupting insulin sensitivity and β cell function [7].

When talking about vitamin D deficiency, it is actually decided according to 25 hydroxy (OH) vitamin D levels, which is an intermediate product of vitamin D metabolism. 25(OH) vitamin D < 30 ng/ml is defined as deficiency. 30–50 ng/ml is insufficiency level and >50 ng/ml is sufficient [8]. According to some authors, <20 ng/ml level is defined as insufficiency and 20–50 ng/ml level is seen as sufficient level [9].

The aim of this study is to investigate the 25 (OH) vitamin D status, relationship between 25 (OH) vitamin D levels and metabolic syndrome components in a large sample of premenopausal and postmenopausal women in Turkey. If there is a significant relationship, it will increase the importance attributed to vitamin D deficiency for women. Cut off value 20 was taken as a sufficient level (When this value is taken 30, there is serious asymmetry in patient distribution).

Important note: In our study, while talking about vitamin D deficiency, we mean 25 (OH) vitamin D deficiency.

2 Materials and methods

2.1 Patient selection

The study was designed retrospectively and it was conducted on participants who applied to the endocrinology outpatient clinic between 1 January and 15 November 2019. Approximately 10000 people admitted to the outpatient clinic. Males, pregnants, applicants with <18 years of age, type 1 and type 2 diabetes mellitus, chronic kidney disease, liver disease, hypertension, heart failure, chronic disease, primary hyperparathyroidism, patients with Ca > 10.3 mg/dl, those with a TSH level outside the normal range were not included in the study. The patients using an drugs effective on blood pressure, calcium, carbohydrate and lipid metabolism during the examinations were excluded. Those with missing data were also removed. As a result, 357 women participants were included in the study.

Demographic and anthropometric data were obtained from the hospital information system.

The reason why women are selected for the study is that the number of male patients who have the necessary criteria for the study is insufficient. Therefore, like many other studies, results were made by making analyzes on female patients. Also, we considered the menopausal status of women.

2.1.1 Laboratory

Fasting plasma glucose (FPG, normal range 70–100 mg/dl), fasting plasma insulin (normal range 2.6–24.9μIU/ml), total cholesterol (normal range 20–200 mg/dl), triglyceride (normal range 20–200 mg/dl), high density lipoprotein-cholesterol (HDL-C, normal range 45–65 mg/dl), low density lipoprotein-cholesterol (LDL-C, normal range 20–130 mg/dl), creatinine (Cre, normal range 0.5–1.1 mg/dl), calcium (Ca, normal range 8.5–10.5 mg/dl), phosphorus (P, normal range 2.5–4.5 mg/dl), magnesium (Mg,normal range 1.6–2.6 mg/dl), 25(OH) vitamin D (25(OH) D, normal range 30–100 ng/ml), parathormone (PTH, normal range 12–88 pg/ml), albumin (normal range 3.5–5.2 mg/dl), thyroid stimulating hormone (TSH, normal range 0.27–4.2 mU/L), antithyroid antibodies were evaluated. PTH and 25(OH) vitamin D were measured using chemiluminescence method on the Cobas E-801 analyzer (Roche Diagnostics GmbH, Mannheim, Germany). The minimum detectable level of 25(OH) vitamin D with the device is 3 ng/ml. Cut off value 20 ng/ml was taken as a sufficient level according to reference 9. (When this value is taken 30, there is serious asymmetry in patient distribution). Due to the large number of patients with a vitamin D value of <10 ng/ml, participants were divided into 3 groups as vitamin D level <10 ng/ml, 10–20 ng/ml, and >20 ng/ml.

In all participants, insulin resistance was calculated with the formula HOMA-IR (fasting plasma glucose (mg/dl) X insulin (mU/ml)/405). For corrected calcium, the participant’s serum calcium level (mg/dl) + 0.8× (4-participant albumin) was used. BMI was determined with body weight (kg)/height (m²) formula, non-HDL cholesterol was calculated with total cholesterol-HDL cholesterol formula. Triglyceride/HDL and HDL/LDL ratios were calculated.

2.2 Data analysis

Statistical analyzes were performed using IBM SPSS for Windows Version 17.0. Numerical variables were summarized by mean±standard deviation. Categorical variables were represented by numbers and percentages. The differences between the groups in terms of categorical variables were investigated by chi-square test or Fisher’s exact test. The Kolmogorov Smirnov test was used to determine whether the numerical variables showed normal distribution. Homogeneity of variance was examined by Levene test. One Way ANOVA was used for normally distributed parameters; Kruskal Wallis Test was used for non-normally distributed parameters. Pearson’s correlation analysis was used for relationship between parameters. Univariate and multivariate regression analysis were used for effects of 25 (OH) vitamin D level on risk factors. Significance level was taken as p < 0.05. A post-hoc sample size calculation was made with G-power and it was detected as 0,98.

According to Durazo-Arvizu et al. (10), effect size for found to be 0.1666667 for linear multiple regression fixed model a priori required sample size calculation. At 0.95 power with 0.05 alpha error level, minimum required sample for each group was found to be 67. In the research, three sub groups were subjected, and minimum required samples was found to be 201. In the research, 357 patients were subjected to the study.

3 Results

Some baseline characteristics of patient groups were given in the Table 1. The participants were divided into 25(OH) vitamin D groups as <10 ng/ml, >10–20 ng/ml and > 20 ng/ml. 25 (OH) vitamin D deficiency was 76,4% of all participants.

Table 1
Some baseline characteristics of patient groups

25 (OH) vitamin D groups P

10 < (n = 125) 10–20 (n = 148) > 20 (n = 84)

Age, mean±SD 39.25±11.71 40.16±12.06 44.39±12.58 0.007^a

BMI (kg/m²), n (%)

25< 26 (20.8) 36 (24.3) 26 (31.0)

25–29.99 33 (26.4) 42 (28.4) 30 (35.7) 0.148^c

30–34.99 30 (24.0) 38 (25.7) 16 (19.0)

≥35 36 (28.8) 32 (21.6) 12 (14.3)

Obesity, n (%) 66 (52.8) 70 (47.3) 28 (33.3) 0.020^c

Premenopausal, n (%) 95 (76.0) 107 (72.3) 53 (63.1) 0.123^c

Menopause, n (%) 30 (24.0) 41 (27.7) 31 (36.9)

25 (OH) Vitamin D, mean±SD 7.70±1.78 14.50±2.75 26.84±7.37 < 0.05^c

Calcium (mg/dl) 9.22±0.34 9.21±0.34 9.30±0.33 0.102^b

Phosporus (mg/dl) 3.28±0.55 3.38±0.53 3.41±0.52 0.149^b

PTH (ng/L) 62.40±27.60 50.10±18.89 44.01±21.04 < 0.001^a

	25 (OH) vitamin D groups	P
Age, mean±SD	39.25±11.71	40.16±12.06	44.39±12.58	0.007^a
BMI (kg/m²), n (%)
25<	26 (20.8)	36 (24.3)	26 (31.0)
25–29.99	33 (26.4)	42 (28.4)	30 (35.7)	0.148^c
30–34.99	30 (24.0)	38 (25.7)	16 (19.0)
≥35	36 (28.8)	32 (21.6)	12 (14.3)
Obesity, n (%)	66 (52.8)	70 (47.3)	28 (33.3)	0.020^c
Premenopausal, n (%)	95 (76.0)	107 (72.3)	53 (63.1)	0.123^c
Menopause, n (%)	30 (24.0)	41 (27.7)	31 (36.9)
25 (OH) Vitamin D, mean±SD	7.70±1.78	14.50±2.75	26.84±7.37	< 0.05^c
Calcium (mg/dl)	9.22±0.34	9.21±0.34	9.30±0.33	0.102^b
Phosporus (mg/dl)	3.28±0.55	3.38±0.53	3.41±0.52	0.149^b
PTH (ng/L)	62.40±27.60	50.10±18.89	44.01±21.04	< 0.001^a

BMI: body mass index. ^aOne Way ANOVA, ^bKruskal Wallis, ^cChi-Square Test, SD: Standard Deviation.

Age mean was higher in the >20 ng/ml group (p < 0.05). After post-hoc analysis, the difference was dependent to >20 ng/ml group. (<10 ng/ml versus >20 ng/ml p = 0.08, 10–20 ng/ml versus >20 ng/ml p = 0.028, <10 ng/ml versus 10–20 ng/ml p = 0,810). In all groups, BMI level differences were insignificant (p > 0.05), but obesity was lesser in >20 ng/ml group. Premenopause-menopause and Hashimoto’s thyroiditis distribution differences between groups were statistically insignificant (p > 0.05).

According to difference analysis results, HDL level differences were significant between the groups (p < 0.05). HDL mean was the highest in the >20 ng/ml group. After post-hoc analysis for HDL, significant difference was between 25(OH) vitamin D < 10 ng/ml and >20 ng/ml groups. Correlation analysis results between 25 (OH) vitamin D level and risk parameters were given in the Table 3.

Table 2

Some laboratory parameters including risk factors and difference analysis results

	25 (OH) vitamin D groups			P
	10 < (n = 125)	10–20 (n = 148)	> 20 (n = 84)
10 < (n = 125)	10–20 (n = 148)	> 20 (n = 84)
FPG (mg/dl)	92.15 ± 10.12	91.53±9.74	92.12±9.29	0.827^a
Total cholesterol (mg/dl)	197.48±42.54	202.32±38.07	203.39 ± 50.78	0.546^b
LDL-C (mg/dl)	123.18±35.71	125.97 ± 31.53	120.88±44.42	0.597^b
HDL-C (mg/dl)	51.33±11.20	53.70±10.67	59.54 ± 35.25	0.015^a
Triglyceride (mg/dl)	117.63±56.70	119.35±60.49	120.57 ± 65.31	0.990^a
Insulin (μIU/ml)	12.25 ± 8.70	11.89±10.14	9.54±4.92	0.069^a
Non-HDL-C (mg/dl)	146.15±41.72	148.62 ± 36.71	145.78±47.65	0.838^b
HOMAIR	2.83 ± 2.07	2.76±2.51	2.20±1.26	0.073^a
HDL/LDL ratio	0.45±0.15	0.45±0.15	0.64 ± 0.87	0.109^a
Triglyceride/HDL ratio	2.47±1.42	2.34±1.39	2.29±1.40	0.631^a
TSH (mU/l)	2.20±1.10	2.09±1.04	2.08±1.00	0.630

FPG: fasting plasma glucose, HOMA-IR: homeostatic model values for insulin resistance, LDL-C: Low density lipoprotein, HDL- C: high density lipoprotein, non-HDL-C: lipoproteins other than HDL. ^aKruskal Wallis Test, ^bOne Way ANOVA Test. ^cPost -hoc analysis

Table 3

Correlation analysis results between 25 (OH) vitamin D level and risk parameters

	R	P
BMI (kg/m²)	–0,156^*	0,003
FPG (mg/dl)	0.006	0.912
Total cholesterol (mg/dl)	0.013	0.812
LDL-C (mg/dl)	–0.053	0.319
HDL-C (mg/dl)	0.183^**	0.001
Triglyceride (mg/dl)	–0.023	0.670
Insulin (μIU/ml)	–0.128^*	0.015
Non-HDL-C (mg/dl)	–0.051	0.333
HOMAIR	–0.123^*	0.020
HDL/LDL ratio	0.185^**	<0.001
Triglyceride/HDL ratio	–0.086	0.103

BMI: body mass index, FPG: fasting plasma glucose, HOMA-IR: homeostatic model values for insulin resistance, LDL-C: Low density lipoprotein, HDL-C: high density lipoprotein, non-HDL-C: lipoproteins other than HDL. ^*: statistically significant negative correlation. ^**: statistically significant positive correlation.

Correlation analysis results showed that there was significant and positive correlation between Vitamin D and HDL and HDL/LDL levels (p < 0.05). In addition, correlation between Vitamin D and insulin, HOMA-IR and BMI were significant and negative direction (p < 0.05). Age was an effective factor as seen in table-1 so univariate and multivariate analyses were done for controlling this. According to these analyses vitamin D significantly correlated with HDL and HDL/LDL ratio (Table 4).

Table 4

Univariate and multivariate analysis results for Vitamin D and significantly correlated parameters

	Univariate	Multivariate
HDL-C (mg/dl)	0.183^**	0.127^*
Insulin (μIU/ml)	–0.128^*	–0.442
HOMAIR	–0.123^*	0.331
HDL/LDL ratio	0.185^**	0.118^*

HOMA-IR: homeostatic model values for insulin resistance, HDL-C: high density lipoprotein. ^*p < 0.05, ^**p < 0.01.

4 Discussion

Although all correlated parameters had significant relation with 25 (OH) vitamin D at univariate level; HDL and HDL/LDL levels had still significant relation with 25 (OH) vitamin D level at multivariate level. Multivariate analysis was performed in order to minimize the effect of different age groups and BMIs.

Vitamin D deficiency is a common public health problem that is increasingly common all over the world. According to a study, 25 (OH) vitamin D deficiency was 29.8% in the world [11]. In a meta-analysis, it was performed with 136 different countries and 25 (OH) vitamin D deficiency was found to be 82.5% [12]. In our study, 25 (OH) vitamin D deficiency was found in 76,4 % of the participants.

Vitamin D has potential effects on glucose metabolism. Findings supporting this idea are as follows: Presence of vitamin D receptors (VDR) in pancreatic β cells and skeletal muscle, expression of 1-αhydroxylase enzyme (in these cells) catalyzing the reaction that converts 25 (OH) vitamin D into 1,25 dihydroxy vitamin D, presence of vitamin D response element in human insulin gene promoter. In many animal experiments, insulin resistance improved when 25 (OH) vitamin D was replaced [13]. Skeletal muscle cells and adipose tissue also have VDR and 1 α hydrocylase enzyme and these tissues are the main determinants of peripheral insulin sensitivity [14, 15].

Insulin resistance is an insufficient response of skeletal muscle, liver and adipose tissue to endogenous insulin secretion. It and β cell dysfunction lead to the development of type 2 diabetes mellitus [16]. In a meta-analysis, a significant decrease in insulin and HOMA-IR levels has been shown with vitamin D and calcium replacement [17]. In many studies conducted with children and adolescents, there was an inverse relationship between insulin resistance and vitamin D [18, 19]. In studies related to women, Vitamin D was shown to be negative correlated with HOMA-IR and insulin [3, 20]. In our study, a negative correlation was found between serum insulin level, HOMA-IR and 25 (OH) 25(OH) vitamin D (Table 3). However, this correlation disappeared in the multivariate analysis (Table 4). So we couldn’t say precisely a significant relationship between 25 (OH) vitamin D and glucose metabolism. Although vitamin D deficiency is associated with higher HOMA-IR and insulin levels, much work has been done on the effect of 25 (OH) vitamin D replacement on these parameters, and the results of these studies are contradictory [21 –24]. In a study with Al Thani et al. with prediabetic women, they found that 6-month 25 (OH) vitamin D replacement alone did not improve glycemic control, and that there were multiple factors affecting this [24]. Vitamin D deficiency and insulin resistance are very common in the community, and 25 (OH) vitamin D replacement is not effective in every patient with insulin resistance. Thus, although speculative, the coexistence of these two pathological conditions can be random.

Obesity is characterized by increased body mass index and adipose tissue. It is a cardiometabolic risk factor. It leads to type 2 DM, cardiovascular disease and cancer, and so increases mortality. Vitamin D deficiency is associated with these diseases [25]. Many observational studies have found an inverse relationship between vitamin D and obesity [26]. The reason is that vitamin D is stored in both adipose and nonadipose tissues [27]. According to animal studies, if VDR is present in adipose tissue, vitamin D leads to an increase in adipose tissue through its receptor, so it is sequestered into adipose tissue and serum vitamin D level decreases. Initially, vitamin D causes obesity by increasing fat mass, then it decreases due to obesity [25].

In our study, a negative correlation was found between BMI and 25 (OH) vitamin D (Table 3). In >20 ng/ml group, obesity was lesser than the others (Table 1). This finding supports the literature above.

When we examined the relationship between lipid markers and 25 (OH) vitamin D, there was a significant difference in HDL between the groups. HDL was higher in 25 (OH) vitamin D > 20 ng/ml group. The positive correlation of HDL and HDL/LDL with vitamin D was also found in univariate and multivariate analysis. There was no significant relationship between other lipid parameters and 25 (OH) vitamin D. A similar result was obtained in children [28], women [29] and men [30]. Although the mechanisms are not clear, it suppresses Vitamin D PTH and increases Ca absorption from the intestine. It also increases insulin sensitivity. It reduces the inflammatory response. It leads to an increase in HDL and a decrease in other lipid parameters through all these mechanisms. The decrease in lecithin-cholesterol-acyl-transferase enzyme activity in inflammation is thought to cause a decrease in HDL [31].

Our study has limitations. Since the study was retrospective, the blood pressure and waist circumferences at the time of admission were not known. Smoking status could not be reached in all participants and could not be included in the study. One of the factors that affect the level of vitamin D is the season, hence sunlight exposure. We couldn’t add this analysis due to time constraints. The difference between the groups in terms of age in our study restricts the study. However, this problem was solved by multivariate analysis. Since the number of male participants -suitable for the study- was low, we conducted the study only with women. However, the number of female participants is 357 and strengthened our work.

In conclusion, according to the results of our study, 25 (OH) vitamin is correlated with HDL and HDL/LDL ratio and inversely related to obesity. 25 (OH) vitamin D deficiency is not associated with insulin resistance. The normal 25 (OH) vitamin D does not neutralize the cardiometabolic risk but supports the reduction of this risk.

Footnotes

Acknowledgments

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