International Medical Journal Vol. 26, No. 4, pp.

303 - 310 , August 2019 303

D. M. AND VITAMIN D

Vitamin D Insufficiency in Type 2 Diabetic Patients Correlates

the Disease Prognostic Indices: A Northern Saudi Status

Abdulrahman A. Alduraywish1), Abdullah Z. Almani2), Abdulaziz D-A. Alanazi2),

Fahad S. Alruwaili2), Ahmed N. Alolaywi2), Abdulrahman H. Almaeen3),
Tarek H. El-Metwally3)

ABSTRACT
Objective: An epidemic of type 2 diabetes mellitus (T2DM) is attacking Saudi Arabia with the worst burden, necessitating a
drastic comprehensive preventive strategy. Blood level of vitamin D correlates the disease and its supplementation favors pre-
vention and management. However, the vitamin D status is not known in our area with the highest prevalence of the disease at
the national level.
Methods: In a case control study, we investigated plasma levels of vitamin D measured as 25-hydroxy vitamin D
(25-OH-VitD) in healthy controls (n = 126) and T2DM patients (n = 290) from Al-Jouf region. Its level was correlated to plasma
atherogenic index (AIP), C-reactive protein (CRP) and insulin resistance (as HOMA-IR) along with age, BMI, body shape index
(ABSI), disease duration and complication and treatment scores. Vitamin D deficiency was massive among controls (~50%) and
T2DM patients (~80%, where majority were very deficient). Treatment score correlated with worst prognostic changes. CRP,
HOMA-IR and AIP were significantly higher in patients than controls. 25-OH-VitD level significantly correlated with age, ABSI,
AIP, CRP, disease duration and treatment score in patients and correlated with age, BMI, ABSI, HOMA-IR, and AIP in con-
trols.
Conclusions: There is a wide spread vitamin D deficiency in the targeted sample of Al-Jouf healthy controls and was worse
in T2DM Saudi population (X2 = 41.3; p < 0.001). It significantly correlated with the negative prognostic indices of the disease.
As a part of a suggested disease prevention strategy, vitamin D replenishment is recommended.

KEY WORDS
type 2 diabetes mellitus, vitamin D deficiency, 25-hydroxy-vitamin D, C-reactive protein, atherogenic index of plasma, insu-

lin resistance, complication score, treatment score, disease duration

INTRODUCTION VitD (Calcitriol) hormone, mainly in the kidney, pancreas and immune
cells, is induced by parathormone. Extra-skeletally, calcitriol controls
immune and cellular growth, differentiation and fate, inflammation,
Nationally, type 2 diabetes mellitus (T2DM) as a significant global angiogenesis, renin-angiotensin-aldosterone system, neurotrophic factor
life-threatening challenge has highest prevalence (~31%), the worst expression, expression of both phases I and II drug-metabolizing
complication scenario and economic burden1). Despite the improvement enzymes, glucose disposal and insulin section and action, and vascular
in therapy and life style changes, incidence of T2DM is increasing at an health. Mechanistically, genomically and non-genomically this is
alarming rate. This fueled a shift toward disease prevention approaches. achieved by being the ligand for vitamin D nuclear receptor (VDR), the
With several limitations, the association of hypovitaminosis D and dia- transcription regulator, controlling a multitude of genes and protein
betes, and, the ability of vitamin D (Calciferol; VitD) replacement to kinases in relevant tissues including the pancreas3-5).
affect incidence, management and complications of diabetes, attracted The global epidemic of vitamin D deficiency - encompassing a wide
tremendous research attention to the extraskeletal effects of the vita- range of ethnically and geographically diverse countries, pathogeneti-
min2). 25-OH-VitD, the main body reservoir and transport form, and, cally inversely correlates a number of chronic clinical outcomes, name-
biomarker of vitamin D, is generated in the liver from its diet or skin ly, insulin resistance, metabolic syndrome, T2DM, autoimmune and car-
precursor. Its further activation into the biologically active 1,25-diOH- diovascular diseases, and cancer6-8). A pathogenetic role for vitamin D in

Received on May 4, 2018 and accepted on August 21, 2018

1) Department of Internal Medicine
2) College of Medicine
3) Department of Pathology, College of Medicine
Jouf University
2014 Sakaka 42421, Kingdom of Saudi Arabia
Correspondence to: Tarek H. El-Metwally
(e-mail: [email protected])

C 2019 Japan Health Sciences University

& Japan International Cultural Exchange Foundation
304 Alduraywish A. A. et al.

Table 1. Age and anthropometrics indices (BMI and body shape index = ABSI) and the investigated parameters (atherogenic index
of plasma = AIP, insulin resistance = HOMA-IR and C-reactive protein = CRP) in the healthy control participants (HCs)
and type II diabetic patients (T2DM) distributed according to the plasma 25-hydroxy-vitamin D level in relation to treat-
ment score (TS), complication score (CS) and disease duration (DD) in patients.
HCs - All HCs - H HCs - N HCs - Def HCs - V-Def T2DM - All T2DM - H T2DM - N T2DM - Def T2DM - V-Def
(n = 126) (n = (n = (n = (n = (n = 290) (n = (n = (n = (n =
14/11.111%) 48/38.095%) 52/41.270%) 12/9.524%) 29/10%) 30/10.345%) 95/32.759%) 136/46.897%)
Age, 19 - 83 24 - 73 20 - 75 19 - 83 19 - 60 23 - 85 30 - 80 23 - 75 27 - 80 23 - 85
Years (44.45 ± (41 ± (39.06 ± (48.23 ± (37 ± (47.82 ± (48.32 ± (41.41 ± (50.77 ± (47.04 ±
16.96) 15.25) 13.56) 15.54) 11.87) 13.29) 11.32) 14.84) 13.47) 12.37)
ABSI 0.032 - 0.032 - 0.034 - 0.054 - 0.055 - 0.051 - 0.052 - 0.051 - 0.054 - 0.051 -
0.089 0.088 0.085 0.089 0.08 0.105 0.077 0.091 0.105 0.084
(0.068 ± (0.068 ± (0.062 ± (0.073 ± (0.072 ± (0.070 ± (0.067 ± (0.070 ± (0.069 ± (0.070 ±
0.013) 0.017) 0.012) 0.011) 0.01) 0.008) 0.008) 0.01) 0.008) 0.007)
BMI 17 - 41.1 23.06 - 19.38 - 17 - 20 - 18.26 - 22.27 - 21.36 - 20.2 - 18.26 -
39.97 38.67 41.1 34 42.46 37.04 37.32 42.46 39.84
(27.66 ± (29.52 ± (27.49 ± (26.72 ± (27.43 ± (29.07 ± (28.23 ± (28.69 ± (29.88 ± (28.82 ±
4.998) 5.322) 4.968) 4.951) 4.065) 4.595) 3.642) 4.231) 4.757) 4.838)
AIP -0.386 - -0.168 - -0.268 - -0.386 - -0.268 - 0.076 - 0.138 - 0.101 - 0.143 - 0.076 -
0.330 0.237 0.226 0.33 0.215 0.869 0.865 0.869 0.812 0.859
(0.011 ± (0.03 ± (-0.019 ± (0.026 ± (-0.001 ± (0.399 ± (0.452 ± (0.366 ± (0.431 ± (0.374 ±
0.139) 0.126) 0.133) 0.152) 0.155) 0.179) 0.248) 0.185) 0.154) 0.169)
HOMA- 0.4 - 3.4 0.4 - 1.986 0.4 - 3.4 0.4 - 2.3 0.5 - 2.1 0.3 - 13.7 0.6 - 7.5 0.3 - 8.8 0.4 - 12.4 0.3 - 13.7
IR (1.01 ± (0.919 ± (1.023 ± (0.936 ± (1.183 ± (3.971 ± (3.823 ± (3.709 ± (3.966 ± (3.959 ±
0.520) 0.417) 0.621) 0.421) 0.575) 2.51) 1.808) 2.42) 2.679) 2.448)
CRP, 0.179 - 0.982 - 0.179 - 0.179 - 0.179 - 0.527 - 1.273 - 0.768 - 0.93 - 0.527 -
mg/mL 10.550 3.658 3.994 7.014 10.55 6.948 4.494 6.296 6.101 6.948
(1.956 ± (2.258 ± (1.634 ± (1.805 ± (3.117 ± (3.408 ± (3.629 ± (3.316 ± (3.533 ± (3.307 ±
1.329) 0.829) 0.872) 1.083) 2.832) 1.011) 0.894) 1.171) 0.927) 1.038)
VitD, 6.197 - 51.9 - 20.81 - 10.01 - 6.197 - 3.415 - 51.44 - 19.08 - 10.05 - 3.415 -
ng/mL 80.700 80.7 50 19.85 9.864 170.5 170.5 50.0 19.7 9.9
(26.81 ± (64.44 ± (31.71 ± (14.75 ± (8.596 ± (21.22 ± (86.89 ± (27.31 ± (13.83 ± (6.442 ±
18.02) 8.364) 8.02) 2.619) 1.259) 27.85) 33.84) 6.445) 2.567) 1.79)
TS - - - - - 0.0 - 3.0 0 - 3.0 0 - 3.0 0.0 - 3.0 0 - 3.0
(1.959 ± (1.742 ± (2.088 ± (1.884 ± (2.051 ±
0.973) 0.965) 0.965) 0.999) 0.945)
CS - - - - - 0.0 - 4.0 0.0 - 2.0 0.0 - 2.0 0.0 - 3.0 0 - 4.0
(0.983 ± (0.710 ± (0.882 ± (1.242 ± (0.912 ±
0.986) 0.783) 0.844) 0.953) 1.05)
DD, Years - - - - - 0.0 - 30.0 0.0 - 27.0 0.0 - 20.0 0.0 - 30.0 0 - 30
(7.118 ± (7.277 ± (8.037 ± (8.558 ± (6.252 ±
6.511) 6.845) 5.802) 8.224) 5.539)
Data shown are frequencies (n/%), range and (mean ± SDM). H-, N-, Def- and V-Def = high, normal, deficient and very deficient 25-hydroxy-vitamin D levels.

diabetes is inferred from: 1) Diabetic patients have a higher incidence of vitamin D status among patients of various diseases from the Southern
hypovitaminosis D that associates decreased insulin synthesis, secretion area, 98% of them were vitamin D deficient, where nondiabetic were
and action, 2) Pancreatic tissue (β-cells in particular) as well as numer- even worse than diabetic patients12).
ous cell types of the immune system express a functional Because of the aforementioned pathophysiological importance of
1α-hydroxylase, VDR and binding protein, 3) Genetic polymorphisms vitamin D sufficiency particularly in the context of the national T2DM
of vitamin D-related genes (metabolism and VDR action) may predis- epidemic, we planned to assess a possible deficiency in vitamin D mea-
pose to impaired glycemic control, insulin secretion and sensitivity, sured as 25-OH-VitD in healthy controls and T2DM patients from the
inflammation and T2DM, 4) Its deficiency is implicated in obesity, a predominantly agricultural Al-Jouf area. Its correlation with the most
risk factor for T2DM, with low grade chronic inflammation against prognostic indices of the disease, namely, C-reactive protein (CRP) as a
which vitamin D is antiinflammatory, and, 5) Vitamin D prevents exper- chronic low-grade inflammatory marker, atherogenic index of plasma
imental diabetes and ameliorates pathogenetic domains of diabetes by (AIP) as a marker of the worst lipid profile, and insulin resistance (IR)
increasing insulin sensitivity and decreasing inflammation and dyslipid- calculated as HOMA-IR, disease treatment and complication scores and
emia9-11). T1 and T2DM have inverse correlation with 25-OH-VitD con- disease duration, was assessed.
centration and UVB dose or exposure. Data generally satisfy Hill’s cri-
teria for causality (specificity, temporality, biological gradient, plausibil-
ity, coherence, and experiment) regarding vitamin D and incidence of
diabetes10). Despite sunshine abundance, the Saudi community suffers
severe widespread hypovitaminosis D that is more common in young
and middle-aged - necessitating vitamin D replenishment6). Reviewing
 Vitamin D Insufficiency Is Prevailing among Saudi Type 2 Diabetic Patients 305

Table 2. Correlation analysis for plasma 25-hydroxy-vitamin D level vs. characteristics and investigated parameters in the
participating healthy controls and type 2 diabetic Saudi patients.
VitD Healthy Participants T2DM Patients
All N H Def V-Def All N H Def V-Def
0.185 0.290 0.618 -0.397
Age (0.05) ns ns (0.039) (0.05) ns (0.02) ns ns ns
0.221 -0.373 0.388 -0.215
ABSI (0.05) (0.02) ns (0.05) ns (0.003) ns ns ns -0.294 (0.015)
-0.242
BMI ns (0.05) ns ns ns ns ns ns ns ns
0.464 -0.339
AIP ns ns ns (0.001) ns 0.109 (0.04) (0.05) 0.589 (0.001) 0.299 (0.034) ns
-0.239
HOMA-IR ns (0.05) ns ns ns ns ns ns ns ns
0.167
CRP ns ns ns ns ns (0.004) ns ns ns ns
TS NA NA NA NA NA ns ns ns 0.257(0.017) 0.250 (0.009)
CS NA NA NA NA NA ns ns ns ns ns
DD NA NA NA NA NA 0.147 -0404
(0.01) (0.018) ns 0.205 (0.05) ns
Data shown are r and p < (value). NA = not applicable.

Table 3. Correlation analysis for insulin resistance vs. characteristics and investigated parameters in the partici-
pating healthy controls and type 2 diabetic Saudi patients.
IR Healthy Participants T2DM Patients
All N H Def V-Def All N H Def V-Def
0.292 -0.684
Age ns (0.025) ns ns (0.017) ns ns ns ns ns
0.467 0.216 0.561 0.258
ABSI ns (0.006) ns ns ns (0.001) ns (0.026) (0.05) ns
0.444 0.630 0.554 0.285 0.267 0.640 0.235 0.304
BMI (0.001) (0.001) (0.043) (0.04) ns (0.001) (0.001) ns (0.03) (0.001)
0.244 0.249 0.413
AIP ns (0.05) ns (0.05) ns 0.179 (0.001) (0.015) ns 0.315 (0.002) ns
-0.239
VitD ns (0.05) ns ns ns ns ns ns ns ns
0.465 0.479 0.485 0.405 0.103 0.407
CRP (0.001) (0.001) (0.05) (0.002) ns (0.05) (0.017) ns ns ns
TS NA NA NA NA NA ns ns ns ns ns
NA NA NA NA NA -0.232
CS ns ns ns ns (0.007)
NA NA NA NA NA -0.232
DD ns ns ns ns (0.007)
Data shown are r and p < (value). NA = not applicable.

PARTICIPANTS AND METHODS age-matching normal healthy participants (n = 126; Male/Female,

70/55) and hospital-diagnosed T2DM patients (n = 290; Male/Female,
132/158). Among all patients, only 16 patients showed HbA1c below
the diagnostic > 48 mM/M (> 6.5%) level. Each of the two groups were
subdivided according to plasma 25-OH-VitD levels as whole group,
Setting
high (25-OH-VitD ≥ 50 ng/mL), normal (25-OH-VitD 20 - 50 ng/mL),
The present case-control cross-sectional study was conducted at the deficient (25-OH-VitD 10 - < 20 ng/mL) and very deficient
College of Medicine, Jouf University and Prince Meteb General (25-OH-VitD < 10 ng/mL) subgroups, as the most clinically relevant
Hospital, Sakaka, Saudi Arabia in the period from November 1, 2016 classification. Participants had to stop taking supplements containing
April 19, 2017. After securing the ethical clearance from both of vitamin D a week from collection of fasting plasma. Collection period
Ministry of Health Directorate and Jouf University Bioethics encompassed September to December. Patients with end-stage renal
Committees, we consecutively voluntarily and anonymously enrolled failure, chronic liver disease and failure, immobilization for any reason,
consented (written informed consent) socioeconomically and hypo-/hyper-parathyroidism and thyroidism, on anti-convulsion drugs,
306 Alduraywish A. A. et al.

Table 4. Correlation analysis for the plasma atherogenic index vs. characteristics and investigated parameters in
the participating healthy controls and type 2 diabetic Saudi patients.
AIP Healthy Participants T2DM Patients
All N H Def V-Def All N H Def V-Def
0.131 0.260
Age ns ns ns ns ns (0.013) ns ns ns (0.002)
ABSI ns ns ns ns ns ns ns ns ns ns
0.258 0.428 0.228 0.269
BMI ns (0.05) ns ns ns 0.261 (0.001) (0.013) ns (0.05) (0.002)
0.464 -0.339 0.589
VitD ns ns ns (0.001) ns 0.109 (0.04) (0.05) (0.001) 0.229 (0.034) ns
0.244 0.249 0.179 0.413 0.315
HOMA-IR ns (0.05) ns (0.05) ns (0.001) (0.015) ns (0.002) ns
0.465 0.281 0.893 0.137 0.442 0.512
CRP (0.001) (0.04) ns ns (0.012) (0.01) (0.009) (0.003) ns ns
NA NA NA NA NA 0.236
TS ns ns ns (0.022) ns
NA NA NA NA NA -0.247
CS ns ns ns (0.016) ns
DD NA NA NA NA NA ns ns ns ns ns
Data shown are r and p < (value). NA = not applicable.

Table 5. Correlation analysis for plasma C-reactive protein vs. characteristics and investigated parame-
ters in the participating healthy controls and type 2 diabetic Saudi patients.
CRP Healthy Participants T2DM Patients
All N H Def V-Def All N H Def V-Def
-0.624 0.371 -0.408
Age ns ns ns ns (0.034) ns (0.03) (0.023) ns ns
0.427 -0.158 -0.219
ABSI ns (0.012) ns ns ns (0.014) ns ns ns (0.033)
0.239 0.343 0.654 0.233 0.306
BMI (0.01) ns ns ns ns (0.001) (0.001) ns (0.03) (0.001)
0.218 0.281 -0.893 0.137 0.442 0.512
AIP (0.03) (0.04) ns ns (0.012) (0.01) (0.05) (0.003) ns ns
0.167
VitD ns ns ns ns ns (0.004) ns ns ns ns
0.479 0.485 0.405 0.103 0.407
HOMA-IR ns (0.001) (0.05) (0.002) ns (0.05) (0.017) ns ns ns
NA NA NA NA NA -0.198
TS ns ns ns (0.05) ns
NA NA NA NA NA -0.208
CS ns ns ns (0.04) ns
NA NA NA NA NA 0.426 -0.260
DD ns (0.012) ns (0.011) ns
Data shown are r and p < (value). NA = not applicable.

acute infections, autoimmune diseases, congenital and hemolytic anemi- 25-OH-VitD (25-OH-VitD2 + 25-OH-VitD3; Sunlong Biotech Co. Ltd,
as, pregnancy, malabsorption syndromes, active malignancy or with Zhejiang, PRC; Cat#SL1898Hu). The reliable atherogenic index of plas-
local or systemic inflammatory diseases were excluded. ma (AIP) was calculated [as Log (TG/HDL-C) in mM/L, where an AIP
> 0.21 is a high-risk index] (http://www.biomed.cas.cz/fgu/aip/calcula-
Measurements tor.php). Insulin resistance was calculated by homeostatic model assess-
ment of insulin resistance [HOMA-IR; as glucose (mg/dL) x insulin
Age- and gender-stratified body mass index (BMI; https://www.cdc. (mIU/L)/405, where an HOMA-IR ≥ 2.9 is an established resistance]
gov/healthyweight/assessing/bmi/adult_bmi/metric_bmi_calculator/ (http://www.thebloodcode.com/homa-HOMA-IR-calculator/).
bmi_calculator.html) and body shape index (ABSI; http://absi-calc. Investigations were also correlated to patient’s disease severity score
appspot.com) were calculated. Triacylglycerols (TAGs), HDL- (no complications = 0, one = 1, two = 2, three = 3, and, four complica-
cholesterol (HDL-C) and glucose were quantitatively assayed (Human, tions or more = 4), and treatment score (no treatment = 0, Metformin =
Gesellschaft fur Biochemica und Diagnostica mbH, Wiesbaden, 1, hypoglycemic/± = 2, and, insulin/± = 3).
Germany). ELISA kits were used to assay human insulin and CRP
(Wuhan, Hubei, PRC; cat# CEA190Hu and SEA821Hu) and
 Vitamin D Insufficiency Is Prevailing among Saudi Type 2 Diabetic Patients 307

Statistical Analysis showed lower BMI than patients deficient in 25-OH-VitD (p < 0.05) and
in healthy controls deficient in 25-OH-VitD compared to each of the
Data are presented as n, range and mean ± SDM. Prism 7.03 whole group of patients (p < 0.05) and patients deficient in 25-OH-VitD
GraphPad (GraphPad Software, Inc., La Jolla, CA, USA) was used for (p < 0.01).
the statistical analysis applying X 2 and one-way ANOVA Multiple Comparing AIP among healthy control subgroups showed nonsig-
Comparisons. Correlation among parameters within groups was ana- nificant differences. Similarly, differences among patients’ subgroups
lyzed using Spearman's nonparametric correlation analysis. Significance were non-significant. Comparing the whole group of healthy controls or
limit was set at p value of ≤ 0.05 at a confidence of 95%. healthy controls with normal 25-OH-VitD level vs. each of the patients
whole and subgroups showed highly significantly lower AIP (p <
0.001). Likewise, comparing the remaining respective healthy control
and patients’ subgroups was highly significantly different in AIP (p <
RESULTS 0.001). HOMA-IR comparisons showed same pattern, being highly sig-
nificantly higher in patients’ subgroups compared to the whole group of
healthy controls or healthy controls with normal 25-OH-VitD levels and
Among male patients, 68 cases (51.515%) suffered one or more as respective subgroups (p < 0.001 for all except for controls and
complications constituting; 58 cases of diabetic ophthalmopathy, 49 patients with high level of 25-OH-VitD, p < 0.01) - without significant
cases of neuropathy, 9 cases of kidney impairment, and 6 cases each of differences within the controls and patients. The same applies to CRP
myocardial infarction and ketoacidosis. 80.882% of complicated male where the whole group of healthy controls and controls with normal
cases were 25-OH-VitD deficient or very deficient and the remaining 13 25-OH-VitD levels were very highly significantly lower than all
cases included 7 with high level of 25-OH-VitD. Among the female patients’ subgroups (p < 0.001). Within patients, there were nonsignifi-
patients, 97 cases (61.392%) were complicated among which 77 cases cant differences in CRP. Within healthy controls, only those with very
(79.381%) had deficient or very deficient 25-OH-VitD and the remain- deficient levels of 25-OH-VitD had significantly higher CRP vs. each of
ing 20 cases included 6 cases showing high level of 25-OH-VitD. the whole group (p < 0.05), those with normal levels (p < 0.01) and
Female complications comprised 83 cases of diabetic neuropathy, 64 those with deficient levels (p < 0.01) of 25-OH-VitD.
cases of ophthalmopathy, 6 cases of kidney impairment and 3 cases of Considering treatment score that reflects insulin usage amongst
myocardial infarction. patients, it was highly significantly different comparing patients with
Along with the investigated parameters, Table 1 presents age, ABSI, high 25-OH-VitD to all the other subgroups (p < 0.001), and comparing
BMI and plasma 25-OH-VitD-stratified subgrouping of healthy controls each of the whole group and those with normal 25-OH-VitD level vs.
and T2DM patients. Using a normal cutoff value of ≥ 20 ng/mL for each of those deficient (p < 0.05) and very deficient (p < 0.001) in
25-OH-VitD, 10% of patients showed high (half of them had toxic lev- 25-OH-VitD. The same exact pattern of differences applies to the com-
els > 80 ng/mL; n = 15), 10.345% showed normal, 32.759% showed plication score and disease duration amongst patients.
deficient and 46.897% showed very deficient levels. And, using a nor-
mal cutoff value of ≥ 30 ng/mL for 25-OH-VitD, 86.552% of patients Correlation analysis
turned to be deficient/very deficient. ~50% of male and female patients
with high levels were having complications. In comparison, 11.111% of The significant correlations of 25-OH-VitD level vs. the disease
healthy controls showed high (none of them were toxic), 38.095% prognostic indices were negative in participants with normal
showed normal (i.e., 3-folds higher than patients), 41.270% showed 25-OH-VitD levels, and positive in other subgroups (Detailed in Table
deficient (i.e., 1.25-folds higher than patients) and 9.524% showed very 2).
deficient levels of 25-OH-VitD (i.e., 5-folds lower than patients). Using Correlations of HOMA-IR were positive in all subgroups except for
a normal cutoff value of ≥ 30 ng/mL for 25-OH-VitD, 72.8% of healthy negative correlations vs. each of 25-OH-VitD in controls with normal
participants turned to be deficient/very deficient. Comparing these dis- 25-OH-VitD levels and vs. age in control with very deficient levels of
tributions among healthy controls vs. T2DM patients there was a very 25-OH-VitD, and, vs. each of complication score and disease duration
highly significant difference (X2 = 41.3; p < 0.001). in patients with very deficient levels of 25-OH-VitD (Detailed in Table
Because of the wide range of concentration distribution, comparing 3).
the whole groups and those with normal 25-OH-VitD levels in patients Similarly, AIP showed positive correlations except for negative cor-
and healthy controls showed nonsignificant differences in plasma relations vs. 25-OH-VitD level in patients with normal 25-OH-VitD
25-OH-VitD levels. However, the whole group of controls was signifi- level and vs. complication score in patients with deficient 25-OH-VitD
cantly different from each of the remaining patients' subgroups (high, level (Detailed in Table 4).
deficient and very deficient in 25-OH-VitD; p < 0.001), and, controls Correlations with CRP were also positive with the exception of neg-
with normal 25-OH-VitD level were also significantly different from the ative correlations vs. age and AIP in controls with very deficient levels
whole group of patients (p < 0.05), and from each of patients' subgroups of 25-OH-VitD and vs. ABSI in the whole group of patients and patients
(high, deficient and very deficient) in 25-OH-VitD (p < 0.001). very deficient in 25-OH-VitD, age in patients with high 25-OH-VitD
Remaining respective patients' and controls' subgroups (high, normal levels, and vs. each of disease duration and treatment and complication
deficient and very deficient) were non-significantly different. Within scores in patients with deficient levels of 25-OH-VitD (Detailed in
controls, the whole group was higher in 25-OH-VitD than those defi- Table 5).
cient and very deficient in it (p < 0.001), those with normal 25-OH-VitD Among the whole group of patients, treatment score correlated posi-
were significantly higher than each of the deficient and very deficient tively vs. each of age (r and p < ; 0.165/0.002), BMI (0.157/0.005),
subgroups (p < 0.001), and off course those with high 25-OH-VitD were complication score (0.423/0.001) and disease duration (0.663/0.001),
significantly higher than all subgroups (p < 0.001). Within patients, each complication score correlated positively vs. each of age (0.446/0.001),
of the whole group and those with normal 25-OH-VitD level were sig- ABSI (0.217/0.001), BMI (0.280/0.001), treatment score (0.423/0.001),
nificantly different from each of those deficient (p < 0.05) and very and, disease duration (0.462/0.001), and disease duration correlated pos-
deficient (p < 0.001) in it, and, the high 25-OH-VitD subgroup was itively vs. each of age (0.437/0.001), ABSI (0.190/0.004) and BMI
highly significantly higher than all of the others (p < 0.001). (0.133/0.015). Most of these correlations disappeared in patients with
ANOVA comparison of age among participants showed nonsignifi- high plasma 25-OH-VitD levels. Complication and treatment scores and
cant differences comparing the two whole groups and comparing the disease duration correlated very strongly amongst each other in all of
respective subgroups. However, 25-OH-VitD deficient healthy partici- the patients' subgroupings (0.663/0.001).
pants (p < 0.05) and patients (p < 0.01) were mildly significantly older
than their normal 25-OH-VitD level counterparts. Comparison for ABSI
within healthy controls revealed significantly lower ABSI comparing
healthy controls with normal level of 25-OH-VitD vs. each of the whole DISCUSSION
group of healthy controls (p < 0.01), healthy controls deficient (p <
0.001) and very deficient in 25-OH-VitD (p < 0.05), and comparing the
whole group of healthy controls vs. the 25-OH-VitD deficient subgroup We investigated the prevalence of vitamin D deficiency - measured
(p < 0.05). ABSI of the healthy controls with normal 25-OH-VitD levels as fasting plasma 25-OH-VitD, among healthy controls and T2DM
was significantly lower than each of the whole group of diabetic inhabiting Sakaka, Al-Jouf, Saudi Arabia and correlated its level with
patients (p < 0.001), patients with normal 25-OH-vitamin levels (p < prognostic and risk factors of the disease in patients. Like the global and
0.05), and patients deficient (p < 0.01) and very deficient in national reports, we observed massive vitamin D deficiency amongst
25-OH-VitD (p < 0.001). Considering BMI, the whole healthy controls both groups, although they belonged to a largely agricultural population
308 Alduraywish A. A. et al.

and samples were collected at the most suitable season to harvest the levels was reported in 25-OH-VitD deficient T2DM patients on chronic
cumulative effect of sun exposure. Several potential causes for vitamin hemodialysis42). There is no relationship between 25-OH-VitD and CRP
D deficiency apply to our population that include dietary vitamin D sup- in diabetics40).
ply, sun exposure, liver function, bioavailability, and, genetic compo- In this study, AIP was very significantly higher in the whole group
nents13-15). On the contrary, hypervitaminosis D is rare, and is only seen of patients compared with controls, in each patients’ subgrouping vs.
after prolonged exposure to extremely high doses of vitamin D and in healthy controls with normal 25-OH-VitD levels, and in the respective
granulomatous diseases16). patients vs. control subgroups. This reflects atherogenic dyslipidemia.
Using the clinically relevant ≥ 20 ng/mL cutoff value17,18), we report AIP levels correlated positively with most prognostic indices particular-
an intriguing wide-spread vitamin D deficiency in the targeted Al-Jouf ly upon 25-OH-VitD deficiency. This is supported by studies from Iran
community among both healthy controls (~50%) and T2DM patients and China 43,44). Iranian diabetic patients with vitamin D deficiency
(~80%; with very deficient majority). Nationally, in 2010, a report showed greater serum levels of total cholesterol, triglycerides and LDL-
showing wide spread vitamin D deficiency in healthy participants was C, and, lower HDL-C43). Triglycerides, HbA1c and early-phase insulin
surprising19). In Saudi boys, vitamin D deficiency showed stronger sig- secretion index independently associated with serum 25-OH-VitD3 in
nificant inverse associations with cardiometabolic indices, T2DM and both diabetes patients and healthy controls44). Oxidative stress, total cho-
abdominal obesity6). Only 1.2% of tested T2DM patients showed normal lesterol, and LDL (but not TAGs and HDL-C) were significantly higher
25-OH-VitD20). Vitamin D replacement therapy and increased sunlight in T2DM patients with the lowest vitamin D status45).
exposure significantly improved 25-OH-VitD levels, serum insulin, HOMA-IR was significantly higher in the whole group of patients
HOMA-IR, HDL-C, glucose, LDL-C, total cholesterol and HOMA-β than healthy controls, in each patients’ subgrouping vs. healthy controls
function in non-diabetic and diabetic subjects20-22). Studies from the cen- with normal 25-OH-VitD levels, and in the respective patients vs. con-
tral and southern Saudi regions reported higher vitamin D deficiency trol subgroups. HOMA-IR correlated positively with most prognostic
(up to 98%); worse in nondiabetics12,23). These Saudi reports used a cut- indices and negatively with 25-OH-VitD levels. Reportedly, Chinese
off value of < 30 ng/mL for vitamin insufficiency and did not pay much T2DM patients showed a negative correlation between 25-OH-VitD and
attention to season of sample collection. Studies on T2DM patients from HOMA-IR adjusted by age, BMI, and eGFR36). Newly diagnosed T2DM
Korea, Qatar, the Netherlands, Iran, Russia, UAE, and France detected patients with low 25-OH-VitD3 showed positive correlation with ear-
vitamin D deficiency of varying severities24-29). Discrepancies could be ly-phase insulin secretion index and area under the insulin curve44).
ascribed at least in-part to differences in the cutoff level values applied Vitamin D deficiency that increases the risk for T2DM and obesity cor-
along with inherent bias in settings used27-29). related with male gender and BMI with high glucose level and reduced
It has been suggested that insolation may be the major and accurate β-cell function in normoglycemic obese46). Insufficient/low 25-OH-VitD
determinant of 25-OH-VitD level18). However, the sun exposure seems correlated with HOMA-IR index, HbA1c, fasting serum insulin, insulin
to play an inconsistent role. A persistent high rate of vitamin D deficien- resistance, and C-peptide47-50). In a cohort of nondiabetic adult Canadians
cy in T2DM patients despite the increase in insolation from winter to and consistent with the sigmoidal threshold response characteristic typi-
summer was reported in Germany 30) . The higher reduction in cal of nutrients, the inverse association between each of insulin respon-
25-OH-VitD levels in Brazilian T2DM patients did not correlate sun siveness and blood pressure vs. serum 25-OH-VitD was localized only
index 15). In Russia, vitamin D deficiency negatively correlated with to a range of ~16 - < 32 ng/mL6). Contrarily, other studies showed no
female gender, BMI, and waist circumference, and, positively with fish association between low vitamin D levels and the risk of T2DM and
intake but not insolation28). Similarly, a French study showed that the glycemic control indices51-54).
reduced plasma 25-OH-VitD correlated with female gender, older age, Calcitriol is not only a metabolic regulator through insulin secretion
obese/underweight, sampling time of the year (early spring), less physi- and action, but it also rejuvenilizes the whole-body cells through acti-
cally activity, and reduced sun exposure29). In addition, ethnic variation vating autophagy. The latter prevents hepatic steatosis of nonalcoholic
is associated with vitamin D levels and diabetes risk31,32). However, fatty liver disease55). This may explain the high rates of complications in
national6) and international studies33) showed contrary increasing levels our patients. Diabetic neuropathy was most prevailing particularly
with age. Weight loss increases plasma 25-OH-VitD concentration in among females followed by ophthalmopathy with higher rate among
adults with prediabetes11,34,35). The low 25-OH-VitD levels in Italian pre- males. These results are supported by many others55-63), although not uni-
diabetic and T2DM participants negatively correlated with age, BMI versally consistent3,64). Serum 25-OH-VitD concentration was lowest in
and HbA1c34). Studies on T2DM patients reported a strong inverse cor- diabetic patients with nephropathy53). Complication score worsens very
relation between hypovitaminosis D and each of macrovascular disease, significantly with increases in disease duration and treatment score (i.e.,
age, smoking, HOMA-IR adjusted by age, BMI, eGFR and LDL- insulin usage). Treatment score correlated positively with each of AIP,
C7,8,36,37). Fatness and fat distribution obscure vitamin D effects on glu- and 25-OH-VitD and negatively vs. CRP. Disease duration correlated
cose homeostasis in cross-sectional studies38). However, there was a neg- negatively with each of CRP and HOMA-IR. Treatment score, compli-
ative correlation between vitamin D and BMI without increases in risk cation score, and disease duration were lowest among patients with high
of T2DM or cardiovascular disease among American male veterans and deficient 25-OH-VitD levels compared to the other patients’ sub-
during a 5-years follow-up study39). groups. Among T2DM patients with chronic kidney disease, vitamin D
Low levels of vitamin D are associated with a pro-inflammatory negatively correlated HbA1c and urine albumin-to-creatinine ratio63).
state5,18). In our study, CRP was very significantly higher in the whole One of the potential limitations of the present study is the inability
group of patients than healthy controls, in all patients' subgroupings vs. to dissect the association with disease complication as data were collect-
healthy controls with normal 25-OH-VitD levels, and in the respective ed from charts rather than direct patients interview. This warrants spe-
patients vs. control subgroups. It correlated positively with most prog- cial future prospective studies. Assessment of the functional levels of
nostic indices and 25-OH-VitD levels did modify such association. 25-OH-VitD as 1,25-diOH-VitD/25-OH-VitD ratio was not planned for.
Systemic chronic low-grade inflammation is implicated in the develop- Dietary/supplementation, recall analysis, and lifestyle factors - particu-
ment of metabolic diseases including obesity, insulin resistance, T2DM, larly rate of sun exposure, were not addressed in the present study; they
and cardiovascular disease. However, correlating 25-OH-VitD with spe- are currently planned for.
cific disease biomarkers and or risk factors showed clear discrepancy
among the national and global reports. Our results showed significantly
higher CRP levels in T2DM patients vs. controls correlating BMI, AIP,
and IR in both, and with 25-OH-VitD in patients. Certain studies are CONCLUSIONS
supportive18) and others26,40) are not. Reportedly, 25-OH-VitD levels nega-
tively correlated with age, female gender, renal function impairment,
TAGs, total cholesterol, total cholesterol/HDL-C ratio, diabetes/insulin Treatment with insulin, longer disease duration, larger BMI and
resistance and serum TNF-α, IL-17, IL-13, and CRP levels 18,26,41). ABSI correlated positively with bad prognostic markers. Vitamin D
Although calcitriol has an antiinflammtory effect, most of the clinical deficiency, measured as fasting plasma 25-OH-VitD level, is wide-
supplementation trials on obese vs. lean and T2DM subjects showed no spread in both healthy (~50%) and T2DM patients (~80%; with a very
effect on the inflammatory makers including CRP14). 25-OH-VitD level deficient majority) from Al-Jouf community. CRP, IR and AIP were
inversely correlated with TNF-α, serum hs-CRP did not have significant highly significantly higher in patients than controls. Treatment score
relationships with 25-OH-VitD in Iranian T2DM patients26). The lowest that reflects insulin usage amongst patients, was highly significantly dif-
25-OH-VitD concentration in Turkish T2DM patients was most promi- ferent when comparing patients with high 25-OH-VitD vs. other sub-
nent among patients with diabetic peripheral neuropathy, where it sig- groups. Similarly, the complication score and disease duration were sig-
nificantly correlated higher proinflammatory blood IL-17 and IL-13 lev- nificantly different when comparing subjects with normal 25-OH-VitD
els41). A significant correlation between CRP and Von Willebrand factor level with each of the whole groups, those deficient and very deficient
 Vitamin D Insufficiency Is Prevailing among Saudi Type 2 Diabetic Patients 309

in 25-OH-VitD levels. However, we could not ascribe the deficiency to Saudi type 2 diabetic patients. Saudi Med J 2015; 36(12): 1432-8.
a specific type of disease complication. Plasma 25-OH-VitD level nega- 23) Al-Zahrani MK, Elnasieh AM, Alenezi FM, Almoushawah AA, Almansour M,
tively correlated ABSI, positively correlated each of AIP, CRP and dis- Alshahrani F, et al. A 3-month oral vitamin D supplementation marginally improves
ease duration in the whole group of patients but only vs. treatment score diastolic blood pressure in Saudi patients with type 2 diabetes mellitus. Int J Clin Exp
in deficient and very deficient patients. As an integral part of a T2DM Med 2014; 7(12): 5421-8.
preventive strategy, regular vitamin D supplementation and/or food for- 24) Nam H, Kim HY, Choi JS, Kweon SS, Lee YH, Nam HS, et al. Association between
tification is mandatory. In addition, effective preventive and therapeutic Serum 25-hydroxyvitamin D Levels and Type 2 Diabetes in Korean Adults. Chonnam
strategies to combat vitamin D deficiency in the whole population need Med J 2017; 53(1): 73-7.
to be encouraged. 25) Bener A, Al-Hamaq AO, Kurtulus EM, Abdullatef WK, Zirie M. The role of vitamin D,
obesity and physical exercise in regulation of glycemia in type 2 diabetes mellitus
patients. Diabetes Metab Syndr 2016; 10(4): 198-204.
26) Haidari F, Zakerkish M, Karandish M, Saki A, Pooraziz S. Association between serum
REFERENCES vitamin D level and glycemic and inflammatory markers in non-obese patients with
type 2 diabetes. Iran J Med Sci 2016; 41(5): 367-73.
27) Haq A, Svobodová J, Imran S, Stanford C, Razzaque MS. Vitamin D deficiency: A sin-
1) Al-Rubeaan K, Youssef AM, Ibrahim HM, Al-Sharqawi AH, AlQumaidi H, AlNaqeb gle centre analysis of patients from 136 countries. J Steroid Biochem Mol Biol 2016;
D, et al. All-cause mortality and its risk factors among type 1 and type 2 diabetes mel- 164: 209-13.
litus in a country facing diabetes epidemic. Diabetes Res Clin Pract 2016; 118: 130-9. 28) Karonova T, Andreeva A, Nikitina I, Belyaeva O, Mokhova E, Galkina O, et al.
2) Grammatiki M, Rapti E, Karras S, Ajjan RA, Kotsa K. Vitamin D and diabetes mellitus: Prevalence of Vitamin D deficiency in the North-West region of Russia: A cross-sec-
Causal or casual association? Rev Endocr Metab Disord 2017; 18(2): 227-41. tional study. J Steroid Biochem Mol Biol 2016; 164: 230-34.
3) Alam U, Arul-Devah V, Javed S, Malik RA. Vitamin D and Diabetic Complications: 29) Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and
True or False Prophet? Diabetes Ther 2016; 7(1): 11-26. 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1-alpha-hy-
4) Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: droxylase knockout mice. Kidney Int 2008; 74: 170-9.
Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev 30) Langer J, Penna-Martinez M, Bon D, Herrmann E, Wallasch M, Badenhoop K.
2016; 96(1): 365-408. Insufficient Vitamin D Response to Solar Radiation in German Patients with Type 2
5) Garbossa SG, Folli F. Vitamin D, sub-inflammation and insulin resistance. A window Diabetes or Gestational Diabetes. Horm Metab Res 2016; 48(8): 503-8.
on a potential role for the interaction between bone and glucose metabolism. Rev 31) Christensen MH, Scragg RK. Consistent ethnic specific differences in diabetes risk and
Endocr Metab Disord 2017; 18(2): 243-58. vitamin D status in the National Health and Nutrition Examination Surveys. J Steroid
6) Al-Daghri NM, Al-Saleh Y, Aljohani N, Alokail M, Al-Attas O, Alnaami AM, et al. Biochem Mol Biol 2016; 164: 4-10.
Vitamin D Deficiency and Cardiometabolic Risks: A Juxtaposition of Arab 32) McDonnell SL, Baggerly LL, French CB, Heaney RP, Gorham ED, Holick MF, et al
Adolescents and Adults. PLoS One 2015; 10(7): e0131315. Incidence rate of type 2 diabetes is > 50% lower in Grassroots Health cohort with
7) Pan GT, Guo JF, Mei SL, Zhang MX, Hu ZY, Zhong CK, et al. Vitamin D Deficiency in median serum 25-hydroxyvitamin D of 41 ng/ml than in NHANES cohort with median
Relation to the Risk of Metabolic Syndrome in Middle-Aged and Elderly Patients with of 22 ng/ml. J Steroid Biochem Mol Biol 2016; 155(PtB): 239-44.
Type 2 Diabetes Mellitus. J Nutr Sci Vitaminol (Tokyo) 2016; 62(4): 213-9. 33) Miettinen ME, Kinnunen L, Leiviskä J, Keinänen-Kiukaanniemi S, Korpi-Hyövälti E,
8) Ding YH, Wei TM, Qian LY, Ma Y, Lao DB, Yao B, et al. Association between serum Niskanen L, et al. Association of Serum 25-Hydroxyvitamin D with Lifestyle Factors
25-hydroxyvitamin D and carotid atherosclerotic plaque in Chinese type 2 diabetic and Metabolic and Cardiovascular Disease Markers: Population-Based Cross-
patients. Medicine (Baltimore) 2017; 96(13): e6445. Sectional Study (FIN-D2D). PLoS One 2014; 9(7): e100235.
9) Lips P, Eekhoff M, van Schoor N, Oosterwerff M, de Jongh R, Krul-Poel Y, et al. 34) Zagami RM, Di Pino A, Urbano F, Piro S, Purrello F, Rabuazzo AM. Low circulating
Vitamin D and type 2 diabetes. J Steroid Biochem Mol Biol 2017; 173: 280-5. vitamin D levels are associated with increased arterial stiffness in prediabetic subjects
10) Altieri B, Grant WB, Della Casa SD, Orio F, Pontecorvi A, Colao A, et al. Vitamin D identified according to HbA1c. Atherosclerosis 2015; 243(2): 395-401.
and pancreas: the role of sunshine vitamin in the pathogenesis of Diabetes Mellitus 35) Garanty-Bogacka B, Syrenicz M, Goral J, Krupa B, Syrenicz J, Walczak M, et al.
and Pancreatic Cancer. Crit Rev Food Sci Nutr 2017; 57(16): 3472-88. Serum 25-hydroxyvitamin D (25-OH-D) in obese adolescents. Endokrynol Pol 2011;
11) Ceglia L, Nelson J, Ware J, Alysandratos KD, Bray GA, Garganta C, et al; Diabetes 62(6): 506-11.
Prevention Program Research Group. Association between body weight and composi- 36) Zhang J, Ye J, Guo G, Lan Z, Li X, Pan Z, et al. Vitamin D status is negatively correlat-
tion and plasma 25-hydroxyvitamin D level in the Diabetes Prevention Program. Eur J ed with insulin resistance in Chinese type 2 diabetes. Int J Endocrinol 2016; 2016:
Nutr 2017; 56(1): 161-70. 1794894.
12) Alhumaidi M, Agha A, Dewish M. Vitamin D deficiency in patients with type-2 diabe- 37) Rolim MC, Santos BM, Concei o G, Rocha PN. Relationship between vitamin D status,
tes mellitus in southern region of Saudi Arabia. Maedica (Buchar) 2013; 8(3): 231-6. glycemic control and cardiovascular risk factors in Brazilians with type 2 diabetes
13) Hollis BW, Wagner CL. Clinical review: The role of the parent compound vitamin D mellitus. Diabetol Metab Syndr 2016; 8: 77.
with respect to metabolism and function: Why clinical dose intervals can affect clini- 38) Heaney RP, French CB, Nguyen S, Ferrea M, Baggerly LL, Brunel L, et al. A novel
cal outcomes. J Clin Endocrinol Metab 2013; 98(12): 4619-28. approach localizes the association of vitamin D status with insulin resistance to one
14) Wamberg L, Pedersen SB, Rejnmark L, Richelsen B. Causes of Vitamin D Deficiency region of the 25-hydroxyvitamin D continuum. Adv Nutr 2013; 4(3): 303-10.
and Effect of Vitamin D Supplementation on Metabolic Complications in Obesity: a 39) Cartier JL, Kukreja SC, Barengolts E. Lower serum 25-hydroxyvitamin d is associated
Review. Curr Obes Rep 2015; 4(4): 429-40. with obesity but not common chronic conditions: an observational study of African
15) Gondim F, Carib A, Vasconcelos KF, Segundo AD, Bandeira F. Vitamin D deficiency is American and Caucasian male veterans. Endocr Pract 2017; 23(3): 271-8.
associated with severity of acute coronary syndrome in patients with type 2 diabetes 40) Šebeková K, St mer M, Fazeli G, Bahner U, Stäb F, Heidland A. Is vitamin D deficien-
and high rates of sun exposure. Clin Med Insights Endocrinol Diabetes 2016; 9: 37-41. cy related to accumulation of advanced glycation end products, markers of inflamma-
16) Dankers W, Colin EM, van Hamburg JP, Lubberts E. Vitamin D in Autoimmunity: tion, and oxidative stress in diabetic subjects? Biomed Res Int 2015; 2015: 958097.
Molecular mechanisms and therapeutic potential. Front Immunol 2017; 7: 697. 41) Bilir B, Tulubas F, Bilir BE, Atile NS, Kara SP, Yildirim T, et al. The association of
17) Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et vitamin D with inflammatory cytokines in diabetic peripheral neuropathy. J Phys Ther
al; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: Sci 2016; 28(7): 2159-63.
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96(7): 42) Cohen-Hagai K, Rashid G, Einbinder Y, Ohana M, Benchetrit S, Zitman-Gal T. Effect
1911-30. of vitamin D status on Von Willebrand factor and ADAMTS13 in diabetic patients on
18) Katrinaki M, Kampa M, Margioris A, Castanas E, Malliaraki N. Vitamin D levels in a chronic hemodialysis. Ann Lab Med 2017; 37(2): 155-8.
large Mediterranean cohort: reconsidering normal cut-off values. Hormones (Athens) 43) Saedisomeolia A, Taheri E, Djalali M, Moghadam AM, Qorbani M. Association
2016; 15(2): 205-23. between serum level of vitamin D and lipid profiles in type 2 diabetic patients in Iran.
19) Al-Daghri NM, Al-Attas OS, Al-Okail MS, Alkharfy KM, Al-Yousef MA, Nadhrah Journal of Diabetes & Metabolic Disorders 2014; 13(1): 7.
HM, et al. Severe hypovitaminosis D is widespread and more common in non-diabet- 44) Yang Y, Zhang X, Bao M, Liu L, Xian Y, Wu J, et al. Effect of serum 25-hydroxyvita-
ics than diabetics in Saudi adults. Saudi Med J 2010; 31(7): 775-80. min D3 on insulin resistance and ?-cell function in newly diagnosed type 2 diabetes
20) Alkharfy KM, Al-Daghri NM, Sabico SB, Al-Othman A, Moharram O, Alokail MS, et patients. J Diabetes Investig 2016; 7(2): 226-32.
al. Vitamin D supplementation in patients with diabetes mellitus type 2 on different 45) Mohammad Hassan J, Hamed M, Koorosh F, Maryam R, Mahnaz Z, Mahmoud D. Are
therapeutic regimens: a one-year prospective study. Cardiovasc Diabetol 2013; 12: serum Llvels of F2-isoprostane and oxidized-LDL related to vitamin D status in type 2
113. diabetic patients? A case-control study. Rep Biochem Mol Biol 2016; 5(1): 26-32.
21) Al-Daghri NM, Al-Attas OS, Alkharfy KM, Khan N, Mohammed AK, Vinodson B, et 46) Sanghera DK, Sapkota BR, Aston CE, Blackett PR. Vitamin D status, gender differenc-
al. Association of VDR-gene variants with factors related to the metabolic syndrome, es, and cardiometabolic health disparities. Ann Nutr Metab 2017; 70(2): 79-87.
type 2 diabetes and vitamin D deficiency. Gene 2014b; 542(2): 129-33. 47) Lima-Martínez MM, Arrau C, Jerez S, Paoli M, González-Rivas JP, Nieto-Martínez R,
22) Al-Shahwan MA, Al-Othman AM, Al-Daghri NM, Sabico SB. Effects of 12-month, et al. Relationship between the Finnish Diabetes Risk Score (FINDRISC), vitamin D
2000 IU/day vitamin D supplementation on treatment naïve and vitamin D deficient levels, and insulin resistance in obese subjects. Prim Care Diabetes 2017; 11(1):
310 Alduraywish A. A. et al.

94-100. associated with peripheral arterial disease in type 2 diabetes patients. Arch Med Res
48) Pham TM, Ekwaru JP, Loehr SA, Veugelers PJ. The Relationship of serum 2016; 47(1):49-54.
25-hydroxyvitamin D and insulin resistance among nondiabetic Canadians: A longitu- 57) Shao Y, Lv C, Yuan Q, Wang Q. Levels of serum 25(OH)VD3, HIF-1α, VEGF, vWf,
dinal analysis of participants of a preventive health program. PLoS One 2015; 10(10): and IGF-1 and their correlation in type 2 diabetes patients with different urine albumin
e0141081. creatinine ratio. J Diabetes Res 2016; 2016: 1925424.
49) Iqbal K, Islam N, Mehboobali N, Asghar A, Iqbal MP. Association of vitamin D defi- 58) Jung CH, Kim K, Kim B, Kim CH, Kang SK, Mok JO. Relationship between vitamin D
ciency with poor glycaemic control in diabetic patients. J Pak Med Assoc 2016; status and vascular complications in patients with type 2 diabetes mellitus. Nutr Res
66(12): 1562-5. 2016; 36(2): 117-24.
50) Saif-Elnasr M, Ibrahim IM, Alkady MM. Role of vitamin D on glycemic control and 59) Freedman DM, Cahoon EK, Rajaraman P, Major JM, Doody MM, Alexander BH, et al.
oxidative stress in type 2 diabetes mellitus. J Res Med Sci 2017; 22: 22. Sunlight and other determinants of circulating 25-hydroxyvitamin D levels in black
51) Nielsen NO, Bjerregaard P, Rønn PF, Friis H, Andersen S, Melbye M, et al. and white participants in a nationwide U.S. study. Am J Epidemiol 2013; 177: 180-92.
Associations between vitamin D status and type 2 diabetes measures among Inuit in 60) Alcubierre N, Valls J, Rubinat E, Cao G, Esquerda A, Traveset A, et al. Vitamin D
Greenland may be affected by other factors. PLoS One 2016; 11(4): e0152763. deficiency is associated with the presence and severity of diabetic retinopathy in type
52) Marques-Vidal P, Vollenweider P, Guessous I, Henry H, Boulat O, Waeber G, et al. 2 diabetes mellitus. J Diabetes Res 2015; 2015: 374178.
Serum vitamin D concentrations are not associated with insulin resistance in Swiss 61) Jha P, Dolan LM, Khoury PR, Urbina EM, Kimball TR, Shah AS. Low Serum Vitamin
adults. J Nutr 2015; 145(9): 2117-22. D Levels Are Associated With Increased Arterial Stiffness in Youth With Type 2
53) Usluogullari CA, Balkan F, Caner S, Ucler R, Kaya C, Ersoy R, et al. The relationship Diabetes. Diabetes Care 2015; 38(8): 1551-7.
between microvascular complications and vitamin D deficiency in type 2 diabetes 62) Kondo M, Toyoda M, Miyatake H, Tanaka E, Koizumi M, Komaba H, et al. The
mellitus. BMC Endocr Disord 2015; 15:33. Prevalence of 25-hydroxyvitamin D deficiency in Japanese patients with diabetic
54) Fondjo LA, Owiredu WKBA, Sakyi SA, Laing EF, Adotey-Kwofie MA, Antoh EO, et nephropathy. Intern Med 2016; 55(18): 2555-62.
al. Vitamin D status and its association with insulin resistance among type 2 diabetics: 63) Reddy GB, Sivaprasad M, Shalini T, Satyanarayana A, Seshacharyulu M, Balakrishna
A case -control study in Ghana. PLoS One 2017; 12(4): e0175388. N, et al. Plasma vitamin D status in patients with type 2 diabetes with and without ret-
55) Holmes D. NAFLD: Vitamin D-induced autophagy prevents steatosis. Nat Rev inopathy. Nutrition 2015; 31(7-8): 959-63.
Endocrinol 2017; 13(4): 190. 64) Nayak SB, Ramnanansingh TG. Evaluation of vitamin D relationship with type 2 diabe-
56) Li DM, Zhang Y, Li Q, Xu XH, Ding B, Ma JH. Low 25-hydroxyvitamin D level is tes and systolic blood pressure. BMJ Open Diabetes Res Care 2016; 4(1): e000285.