Vitamin D deficiency remains a major health problem in many parts of the world.1 The main marker of vitamin D status is the metabolite 25-hydroxyvitamin D (25(OH)D), which is synthesized in the liver.12 It is now increasingly recognized that vitamin D deficiency is defined as serum 25(OH)D concentration <50 nmol/L and a concentration <75 nmol/l are physiologically important, and probably indicate vitamin D insufficiency.3 Serum concentration of 25 (OH)D <25 nmol/l is widely accepted as indicative of severe deficiency. Studies confirmed that the prevalence of vitamin D deficiency in the general world population was as high as 50-80%.4 The Middle East region including Saudi Arabia has very high prevalence of vitamin D deficiency even in the normal asymptomatic population. 567

The prevalence of type 2 diabetes mellitus (T2DM) in Saudi Arabia is one of the highest reported in the world, reaching up to 30% in a recent study.8 It has been demonstrated that vitamin D deficiency was associated with T2DM.91011121314151617 It has been reported that insulin secretion was dependent upon vitamin D and there was a positive correlation of vitamin D concentration with insulin sensitivity.181920212223 The prevalence of vitamin D deficiency in patients with T2DM varied from 70 to 90%, depending on the threshold used to define vitamin D deficiency.242526Few published researches have found that surveyed the prevalence of severe vitamin D deficiency in patients with T2DM in Saudi Arabia. 27 We conducted a cross sectional study to investigate the prevalence severe vitamin D deficiency in patients with T2DM.

A cross-sectional single centre study was conducted in 4053 patients with T2DM. Patients with T2DM attending the Diabetes Centre at King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia between January 2018 and December 2018 were recruited. Eligible patients were 20 years or older. Exclusion criteria were known hepatic or renal disease, metabolic bone disease, malabsorption, hypercortisolism, malignancy, immobility for more than one-week, pregnancy, lactation, and medications influencing bone metabolism. The serum concentration of 25(OH)D was measured by competitive protein binding assay using kits (Immunodiagnostic, Bensheim, Germany). Severe vitamin D deficiency was defined as serum 25-OHD concentration < 25 nmol/L.1 Glycosylated hemoglobin (HbA1c) was measured by the high performance liquid chromatography method (Bio-Rad Laboratories, Waters, MA, USA). The total number of cohort were separated on basis of age values into five groups: 20-29 years, 30-40 years, 40-49 years, 50-59 years and ≥60 years. The study was approved by the ethical committee board of King Fahad Armed Forces Hospital.

There were 4053 patients with T2DM, 1145 male and 2908 female (28 % vs.72% respectively) (Table 1). The mean age was 53.9 ±16.5 years. The mean and median 25-OHD concentrations were 57.8±30.5 and 51.9 respectively. Severe vitamin D deficiency (25-OHD<25 nmol/l) was found in 1916 (9.5%) (Table 2). Moreover, severe vitamin D deficiency was not statistically significant more prevalent among females than males with male to female ratio 1:2.3 (70% vs. 30% respectively, p=0.6). In addition, severe vitamin D deficient patients were statistically significant younger than non-vitamin D deficient (48.0±16.7 vs. 54.6±16.3 respectively, p<0.0001). Severe vitamin D deficient patients have statistically significant higher HbA1c than non-vitamin D deficient (8.3 ±2.3 vs. 7.6±1.9 respectively, p<0.0001). As expected, the mean 25-OHD concentration was statistically significant lower in the vitamin D deficient patients compared to non-vitamin D deficient (20.2 ±3.8 vs. 61.7±29.4 respectively, p<0.0001).

The mean 25-OHD was upward as age advanced with highest frequency of vitamin D deficiency was found in the age group ≥60 years (27%) (Figure 1 A and B) with males statistically significant most frequent than females in the age group ≥60 years (39 s, 22 respectively, p=0.003) (Figure 2).

25-OHD concentration was not significantly positively correlated with age (r=0.079, p=0.1) and not significantly negatively correlated with HbA1c (r= - 0.055, p=0.4) (Figure 3 A and B).

Regression analysis of odd ratio of risk factors for patients with severe vitamin D deficiency showed that age and HbA1c were statistically significant associated with vitamin D deficiency, (OR=0.975; 95% CI=0.967,0.984), p<0.0001) and (OR=1.192;95% CI=1.118,1.271, p<0.0001) respectively (Table 3).

Our result confirmed the prevalence of severe vitamin D deficiency was 9.5% among the adult population and an even higher prevalence among older adults. It is of importance to state that the sample size is representative for a number of subjects suffering from T2DM in the area and study population of one institution does not represent the entire city of Jeddah, in addition the study sample confined to patients with T2DM but without comparable groups. The causes of vitamin D deficiency could be due to changing life style with people adopting a more sedentary life, little exposure to sunlight, reduced outdoor activity, changes in dietary habits. These factors also contributed to both development of T2DM and poor control of diabetes. Hashemipour et al. reported in Iran that the prevalence of severe vitamin D deficiencies was similar to our prevalence (9.5%) among the general population, aged 20-64 years.28 The prevalence of severe vitamin D deficiencies was 2% in Arizona, an area with high exposure to sun, using the same definition as we had used in this study. 29 In a study based on data from the National Health and Nutrition Examination Survey III (NHANES III) by Looker et al., the prevalence of severe vitamin D deficiency (25-OHD < 17.5 nmol/l) among adolescents and adult population of the United States was reported to be 1%.30 Prevalence of severe vitamin D deficiency (,25 nmol/l) was remarkably higher in one report from India (46·4 %) 31

Moreover, our findings showed that females were not significantly more likely to have severe vitamin D-deficient than males (OR=1.08). According to legislation, all females are required to wear a scarf and long-sleeve clothes. This is why they might have more severe vitamin D deficiency. Although other studies reported similar results in this field, however, seems that factors involved in vitamin D deficiency may be different more between males and females in some ethnic groups than others. 323334

Vitamin D deficiency was reported as quite common in young and normal Saudi adults in 1981. 6 Back then however, vitamin D deficiency was more common among the elderly. In our study, the prevalence of severe vitamin D deficiency was much higher among the older age-group (27%), however, serum 25(OH)D was not statistically significant positively correlated with age r= 0.079 (p=0.1), in consistent with most studies whereas other studies reported the higher prevalence of vitamin D deficiency among the young people. 7, 3536373839404142 The positive correlation of 25(OH)D to age is in disagreement with a study carried out in the US, where severe vitamin D deficiency was found to be more common among the young, and less common among the elderly. 43 Recent studies have shown vitamin D deficiency among healthy young Saudi women of age 25 to 35 years was 30% and 55% in women of 50 years or more, indicating that it is common in young and postmenopausal women.7 In another study on male population from Saudi Arabia, the prevalence of vitamin D deficiency was found to between 28% and 37%.42

We found severevitamin D deficient patients have statistically significant higher HbA1c than non-vitamin D deficient (8.3±2.3 vs. 7.6±1.9 respectively), p<0.0001. Moreover, 25-OHD concentration was inversely not statistically significantcorrelated with HbA1c (r= - 0.055, p=0.4). These findings are supported by a number of international studies. In contrast some studies show no association of a low vitamin D with HbA1c levels.44 But inverse correlation between the level of vitamin D and glucose level is well known. 454647 In many studies vitamin D levels were low in subjects having higher HbA1c values in patients with T2DM indicating that they are inversely related. 162548 Vitamin D has various effects on glucose homeostasis. Besides its role in insulin secretion, it also has an influence on insulin resistance directly or via Ca indirectly. 2149 The results from the trials on the effect of vitamin D and/or Ca supplementation on insulin resistance have showed improvement on insulin action. 50

Growing scientific evidence has implicated vitamin D deficiency in a multitude of chronic conditions including T2DM. 40 With the growing prevalence of vitamin D deficiency across Saudi Arabia and its association with these leading causes of mortality, it has become more important than ever to delineate vitamin D’s role in the pathogenesis of these diseases and use data to pinpoint established risk factors for vitamin D deficiency. The relationship between vitamin D deficiency and diabetes has long been explored, with growing evidence suggesting vitamin D deficiency is a contributing factor to the development of T2DM. 41 We had several limitations, the study was done at one centre and was done at one point of time. The study sample confined to patients with T2DM but without comparable groups. In conclusion, we report severe vitamin D deficiency in Saudis with T2DM patients and that more females with T2DM are affected with vitamin D deficiency than males. Intervention studies are needed to clarify if supplementation of vitamin D leads to improvement in insulin sensitivity or glycemia in Saudis with T2DM patients.

There is no any financial support or relationships that may pose conflict of interest.