Introduction

Type 2 diabetes mellitus (T2DM) is a worldwide epidemic. The International Diabetes Federation (IDF) predicts that the current figure of 415 million patients affected with diabetes will increase to 642 million by 2040 (1). In Ecuador, the prevalence of T2DM in the age-adjusted population is 9.2%, according to 2015 IDF estimates ¹.

Vitamin D deficiency has been linked to a wide range of health problems, including various cancers and autoimmune or metabolic diseases, such as type 1 diabetes mellitus and T2DM ^2).

Current studies confirm that the prevalence of vitamin D deficiency in the general world population is actually as high as 50-80% ³, even occurring in countries located in geographical areas which receive sunshine year-round.

Although the high prevalence of hypovitaminosis D has been considered a serious public health problem in Latin America and the Caribbean, the precise extent of the problem is not known due to the lack of information in the general population ⁴.

Previous studies have described a high rate of vitamin D deficiency in the general population ⁵. However, few have reported the status of vitamin D in patients with T2DM. The prevalence of vitamin D deficiency or insufficiency in patients with T2DM varies from 70 to 90% ^{6 7-8}, depending on the threshold used to define vitamin D deficiency or insufficiency.

In Ecuador, the status of serum vitamin D levels in the general population has recently been described ⁹, but not in patients with T2DM. This study was conducted to determine the prevalence of vitamin D insufficiency in Ecuadorian postmenopausal women with T2DM and to investigate whether there is a correlation between serum levels of vitamin D, markers of bone metabolism, bone density, and metabolic control variables of T2DM.

Results

Demographics of cases and controls

There were no differences between the two groups (T2DM versus non- T2DM) in terms of age, body mass index (BMI), intact PTH, osteocalcin, urinary deoxypyridinoline, and BMD in the lumbar region or femur. The groups presented significant differences in the variables of metabolic control: the HOMA-IR index (p=0.002) and glycosylated hemoglobin (p<0.001). Serum vitamin D levels were significantly lower (p<0.034) in the T2DM group.

Demographic data and characteristics of cases and controls are presented in table 1.

Table 1. Demographic data and characteristics of the 2 study groups 

*p<0.05 (Wilcoxon Signal Range Test). Data are expressed as medians and interquartile range. T2DM: type 2 diabetes mellitus; HOMA-IR: Homeostasis Model of Assessment-Insulin Resistance Index; PTH: parathyroid hormone; BMD: bone mineral density.

Severity and extent of vitamin D deficiency

In the T2DM group we found a significant reduction in serum vitamin D levels: 12.5% (95% CI=5.3-19.6) of the cases had vitamin D sufficiency (n=12) and 87.5% (95% CI=80.3-94.6) had vitamin D insufficiency (n=84), of which 52% (95% CI=51.1-63.6) (n=44) had insufficiency; 42% (95% CI=31.7-54) (n=36), moderate deficiency and 4.8% (95% CI=1.3-11.7) (n=4) severe deficiency. In the non-T2DM group, 67.8% (95% CI=48.8-87) (n=19) had vitamin D sufficiency and 33% (95% CI=13-51) (n=9) had insufficient vitamin D. Figure 1 shows the frequency distribution of vitamin D levels in postmenopausal women with DM2.

Figure 1 Distribution of vitamin D frequency frequencies in postmenopausal women with T2DM 

There were no differences in the T2DM group between subgroups of patients with adequacy and that of patients with vitamin D insufficiency in terms of age, BMI, HbA1c, PTH, ionic calcium, osteocalcin, urinary deoxypyridinoline, or bone mineral density. The subgroup with vitamin D insufficiency presented a higher HOMA-IR than that with sufficiency, although it did not reach statistical significance (p=0.093). Table 2 shows the demographic data, metabolic variables, bone density and vitamin D status in patients with T2DM.

Table 2 Demographic data, metabolic variables, bone density and vitamin D status in patients with T2DM 

^*p<0.05 (Wilcoxon Signal Range Test). Data are expressed as medians and interquartile range. T2DM: type 2 diabetes mellitus; HOMA-IR: Homeostasis Model of Assessment-Insulin Resistance Index; PTH: parathyroid hormone; ,BMD: bone mineral density.

Correlation between vitamin D, markers of bone metabolism and variables of metabolic control of T2DM

We found a slight but significant correlation between vitamin D and age (r=-0.21, p=0.03) but not with BMI and the metabolic control variables of T2DM (glycosylated hemoglobin, HOMA-IR index), nor with markers of bone remodeling (PTH, ionic calcium, osteocalcin, deoxypyridinoline). There is a slight (r=0.22) but significant correlation between vitamin D and bone density in the lumbar region (p=0.03), but not with femoral neck BMD. Table 3 shows the correlation coefficients between vitamin D, markers of bone metabolism and metabolic control variables of DM2.

Table 3. Correlation between vitamin D, markers of bone metabolism and variables of metabolic control of DM2 

^*p<0.05; r: Spearman correlation coefficient; 95% CI: 95% confidence interval; T2DM: type 2 diabetes mellitus; HOMA-IR: Homeostasis Model of Assessment-Insulin Resistance Index; PTH: parathyroid hormone; BMD: bone mineral density.

Discussion

The high incidence of T2DM worldwide ¹ and the accumulated evidence on the status of vitamin D under different conditions ² make it extremely important to determine the relationship between vitamin D and diabetes mellitus.

To our knowledge, this is the first study conducted in Latin America, which establishes the prevalence of hypovitaminosis D in postmenopausal women with T2DM.

Hypovitaminosis D appears to be a prevalent phenomenon in populations around the world, in which they influence the type of ethnicity, sex, body mass index, traditional dress, nutrition, consumption of vitamin supplements and level of urbanization ^5).

Most epidemiological information on hypovitaminosis D in the world population comes from studies in Europe, the Middle East, India, and Asia ^3,5, with few studies in our region ^{4) (9).}

Choosing the cut-off point to define vitamin D deficiency in the population remains a controversial issue. Some consider levels >30 ng/mL to define sufficiency, while others set adequate levels of 20 ng/mL. According to the definition of the Endocrine Society (USA), vitamin D values below 20 ng/mL are considered deficient, and values between 21 and 29 ng/mL are insufficient ². According to these cut-off points, it is estimated that 20 to 100% of elderly men and women have vitamin D deficiency in the United States, Canada and Europe ¹³.

In 3 studies conducted in Latin America, a cutoff point of <20 ng/mL ^{14 15-16}; and in another <20 and <30 ng/mL for deficiency and insufficiency, respectively ⁹.

With a cutoff <20 ng/mL, the prevalence of vitamin D deficiency among women in Santiago de Chile is 60% (14). In Argentina, the prevalence of vitamin D deficiency varies from 73% in southern cities to 50% in northern cities ¹⁵, and in Brazil it is 17%, much lower than in previous series ¹⁶.

In Ecuador, a recent study ⁹ in the elderly population has described a prevalence of vitamin D insufficiency and deficiency of 68 and 22%, respectively. Despite the abundant natural light throughout the year, this condition varies considerably among the different regions and zones of our country. It is more frequent in older women, the inhabitants of the Andean region and the indigenous race ⁹.

The prevalence of vitamin D deficiency or insufficiency in patients with T2DM also depends on the threshold used to define it. In our study, vitamin D insufficiency was defined as a vitamin D level <30 ng/mL, which is in accordance with the recommendation of the International Osteoporosis Foundation ^5,17.

In general, the prevalence of hypovitaminosis D in patients with T2DM reported in international series is high. In a previously published study, 74.6% of patients with T2DM had D hypovitaminosis ⁸. In another, prevalence (cutoff <20 ng/mL) was more frequent in diabetics compared to controls (83% vs 70%, p=0.07) (7). In a more recent study, prevalence was greater in diabetic patients than in control subjects (90% vs 83%, p<0.01) ¹⁸. Data on hypovitaminosis D in patients with T2DM are not available in Latin America.

The results of the present study are similar to those of recent studies in non-Latin American populations, which demonstrated a high prevalence of hypovitaminosis D in patients with T2DM ^{6,19 20-21}.

It is unclear whether vitamin D deficiency and poor glycemic control are causally related or represent two independent features of T2DM. Previous studies have reported inconclusive results regarding the association between vitamin D status and HbA1c ²². In our study, vitamin D-deficient women had lower levels of HbA1c compared to those who had sufficiency, although this did not reach statistical significance. This adds to the evidence that the vitamin D status is not associated with the metabolic control variable HbA1c.

An inverse association has been reported between serum vitamin D levels and BMI >30, and therefore, obesity would be associated with vitamin D deficiency ²³. In postmenopausal women with T2DM, obesity is also considered a risk factor for vitamin D deficiency (20). However, our data do not confirm previous reports of a negative association between vitamin D and BMI. In contrast, in our sample cases and controls were not different in their BMI, although both groups were overweight.

The main finding of this cross-sectional study is the high prevalence (85.7%) of vitamin D insufficiency (<30 ng/mL) in patients with T2DM, with an average vitamin D level of 22 ng/mL. However, this value is higher than the average vitamin D reported for patients with diabetes and obesity in other series in Africa and Asia (16 to 17 ng/mL) ^{24) (25} and similar to a sample of patients in the United States (23 ng/mL) ²⁶.

In Ecuador, there is no definite four-season separation as in the northern and southern hemispheres. The city of Guayaquil, where this study was conducted, is located on the coast of the Pacific (2º11'00"S), and its inhabitants enjoy open skies, warm weather and sunlight throughout the year, their garments of clothing are light and expose much of their skin.

The results of this study contradict the assumption that abundant exposure to sunlight throughout the year reduces the risk of hypovitaminosis D. The discrepancy between our results and outcomes in other ethnic groups may reflect racial differences, lifestyle factors (physical inactivity, limited sun exposure) and/or insufficient intake of vitamin D, or all.

Vitamin D deficiency is associated with an increased risk of fracture ²⁷, and is associated with diffuse muscular pain, muscle weakness and increased risk of falls ^{28) (29}. However, despite the increased risk of fracture, bone mineral density is generally higher in patients with T2DM ³⁰. In our study, we did not investigate the prevalence of fragility fractures, so we cannot confirm this evidence.

Previous studies indicate that even a slight reduction in serum vitamin D levels may be associated with secondary hyperparathyroidism, increased remodeling, and accelerated bone loss, which increase the risk of bone fractures ³¹. In the present study, intact PTH and ionic calcium levels were within the normal range, so our results do not confirm the association between vitamin D, PTH and calcium that has been described in the literature.

There are some strengths and limitations related to the present study. Although the sample of population was relatively small, we were able to compare it with a control group, which allows us to establish inferences with the general population.

The present study does not provide data that could explain the higher prevalence of hypovitaminosis D in patients with T2DM.

It is generally accepted that vitamin D levels vary with daily activity and exercise level. In our study we do not consider these variables, and although in our country we only have one dry season and one rainy season, we do not know if in our population the measured variables are modified with the time of year.

The prevalence of hypovitaminosis D in the general population has been overestimated due to improper use of a high cut-off point for vitamin D. Geographic latitude with a large amount of sunlight exposure or low calcium consumption ⁹, which generally occurs in Ecuador, will undoubtedly affect the cut-off point for the development of vitamin D deficiency. In this sense, the cut-off point chosen to define vitamin D insufficiency may not be adequate for our predominantly mestizo population, using the one for predominantly Caucasian populations, as these values vary widely even from region to region ¹².

Considering that in this sample the average vitamin D was very close to 20 ng/mL, further studies are required to evaluate the adequacy of the vitamin D cutoff points chosen in Ecuadorian women with T2DM. In this study, a lower cutoff point for vitamin D normality would undoubtedly have resulted in a much lower prevalence of hypovitaminosis D.

Despite these limitations, the present study is the first to report the prevalence of vitamin D insufficiency among Ecuadorian postmenopausal women with T2DM, and allows us to infer that this prevalence is higher in patients with T2DM than in the population without T2DM.

In conclusion, our study found that vitamin D deficiency was significantly more frequent among Ecuadorian postmenopausal women with T2DM compared to those without T2DM.

Our data indicate that the availability of abundant sunlight is not sufficient for the prevention of vitamin D deficiency. This warns us of the risk of hypovitaminosis D in the diabetic population, regardless of geographical location.

The high prevalence of hypovitaminosis D in postmenopausal women with T2DM highlights the need for prospective studies to evaluate the impact of vitamin D supplementation on glucose metabolism. Additional studies should clarify the relationship between hypovitaminosis D and osteoporosis in patients with T2DM.

The results of our study may help the country's public health authorities implement vitamin D supplementation policies, especially among the population at risk of this condition.