Significant Vitamin D Deficiency in Youth with Type 1 Diabetes Mellitus
Article Outline
Serum 25-hydroxyvitamin D was measured in 128 youth with type 1 diabetes mellitus. Less than 25% of the patients were vitamin D sufficient. Because individuals with type 1 diabetes mellitus possess multiple risk factors for skeletal fragility, ensuring vitamin D sufficiency throughout childhood and adolescence in this population seems especially warranted.
Abbreviations: 25OHD, 25-hydroxyvitamin D, A1c, Hemoglobin A1c, BMD, Bone mineral density, BMI, Body mass index, T1D, Type 1 diabetes mellitus
Chronic severe vitamin D deficiency in infants and children causes bone deformation from poor mineralization (ie, rickets). Less severe vitamin D insufficiency prevents youth from attaining their optimal peak bone mass and may contribute to increased fracture risk later in life.1 Vitamin D inadequacy constitutes a largely unrecognized epidemic in many populations.2, 3
See editorial, p 7 and related article, p 20
Type 1 diabetes mellitus (T1D) also negatively impacts bone health and is associated with a modest reduction in bone mineral density (BMD) and strength4, 5 and an increase in fracture risk among middle-age and older individuals.6 To date, several potential mechanisms for reduced BMD associated with diabetes mellitus have been proposed, including advanced glycation end products in bone collagen,7 hypercalciuria associated with glycosuria,8 inflammatory cytokines,9 and diabetic microangiopathy with reduced blood flow to bone.10 It is not known, however, whether aggressively treating diabetes mellitus can help preserve skeletal health.11
Because of the negative impact of vitamin D inadequacy and T1D on bone health, youth with both conditions have multiple risk factors for increased skeletal fragility. Studies examining vitamin D inadequacy in youth with T1D have been somewhat limited. In one study from Italy12 and a second study from Sweden,13 the mean level of vitamin D was found to be lower in patients with T1D at the time of diagnosis compared with control subjects. In a third, more recent study from Australia, 43% of adolescents with T1D were found to be vitamin D deficient.14 Therefore, our aims were to assess vitamin D status in youth with T1D from the northeastern United States and to examine the influence of specific patient and disease characteristics on vitamin D status.
Methods
Participants were enrolled in the cross-sectional study at the time of a regularly scheduled medical visit to the Pediatric, Adolescent, and Young Adult Section at the Joslin Diabetes Center. The study sample included youth with recently diagnosed T1D and youth with established T1D. A research assistant obtained written, informed consent from the parent and assent from the child. Participants and their families then completed a set of questionnaires, and youth provided a blood sample for analysis. The institutional review board at the Joslin Diabetes Center approved the study protocol.
Serum 25-hydroxyvitamin D (25OHD) is the standard indicator of vitamin D status, composed of cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). Levels of 25OHD were measured with the radioimmunoassay method (Diasorin) that detects both forms of 25OHD. The criteria used to define vitamin D sufficiency, insufficiency, and deficiency were 25OHD levels ≥30 ng/mL, from 21 to 29 ng/mL, and ≤20 ng/mL, respectively.1, 15
Because vitamin D status is associated with sunlight exposure, which varies by season, we categorized each participant's study visit according to this division of the calendar year: winter (December 22-March 21), spring (March 22-June 21), summer (June 22-September 21), and fall (September 22-December 21).
A1c was measured with high-performance liquid chromatography standardized to the DCCT assay (reference range, 4-6%; Tosoh Medics, Foster City, California). An age- and sex-adjusted z-body mass index (BMI) was calculated from weight and height.
Statistical analysis was performed with SAS software version 8.2 (SAS Institute, Cary, North Carolina). Means plus or minus SD and percentages are presented unless otherwise indicated. Group comparisons were performed with unpaired t tests, analysis of variance, χ2 analysis, and multivariate models.
Results
Of the 128 participants with T1D, most had inadequate levels of vitamin D: sufficiency, 24% (n = 31); insufficiency, 61% (n = 78); deficiency, 15% (n = 19). The Table displays patient characteristics for the entire sample and each of the 3 vitamin D subgroups.
Table. Participant characteristics
| Total sample (n = 128) | Vitamin D sufficient (n = 31; 24%) | Vitamin D insufficient (n = 78; 61%) | Vitamin D deficient (n = 19; 15%) | P value | |
|---|---|---|---|---|---|
| Age, years | |||||
 Mean±SD | 10.8±4.3 | 8.4±4.1 | 11.2±3.8 | 13.2±4.7 | <.001 |
| Range | 1.6-17.5 | 1.6-15.0 | 3.0-17.4 | 1.8-17.5 | |
| Sex | |||||
| Male | 69(54) | 19(61) | 41(53) | 9(47) | NS |
| Female | 59(46) | 12(39) | 37(47) | 10(53) | |
| Ethnicity | |||||
| White | 113(88) | 28(90) | 69(88) | 16(84) | NS |
| Other | 15(12) | 3(10) | 9(12) | 3(16) | |
| Visit season | |||||
| Spring | 31(24) | 6(19) | 19(24) | 6(32) | NS |
| Summer | 19(15) | 6(19) | 12(15) | 1(5) | |
| Fall | 29(23) | 11(35) | 15(19) | 3(16) | |
| Winter | 49(38) | 8(26) | 32(41) | 9(47) | |
| z-BMI (SDS) | |||||
| Mean±SD | 0.4±1.0 | 0.1±1.1 | 0.5±0.9 | 0.6±1.1 | NS |
| Range | −2.8-2.3 | −2.3-2.0 | −2.8-2.3 | −1.9-2.2 | |
| Duration of T1D (years) | |||||
| Mean±SD | 4.1±5.6 | 1.7±4.3 | 4.5±5.6 | 6.7±5.9 | <.01 |
| Range | 0-14.6 | 0-13.5 | 0-14.5 | 0-14.6 | |
| A1c (%) | |||||
| Mean±SD | 9.8±2.2 | 10.7±2.1 | 9.7±2.2 | 9.3±1.9 | .05 |
| Range | 6.5-15.8 | 7.2-15.8 | 6.5-15.3 | 6.8-13.6 | |
| 25OHD (ng/mL) | |||||
| Mean±SD | 26.8±6.7 | 35.5±5.4 | 25.7±2.5 | 17.2±2.9 | <.001 |
| Range | 11.0-52.6 | 30.0-52.6 | 21.4-29.9 | 11.0-20.8 |
In bivariate analyses, sex, ethnicity, visit season, and z-BMI were similar among participants with vitamin D sufficiency, insufficiency, and deficiency. Participants with vitamin D deficiency, however, were significantly older (P < .001), had longer diabetes duration (P < .01), and had lower A1c levels (P = .05).
In a multivariate model controlling for age, sex, ethnicity, visit season, z-BMI, diabetes duration, and A1c, age was most significantly associated with 25OHD (P < .0001); older age was associated with lower 25OHD concentrations. Only ethnicity (P = .05) was also significantly associated with 25OHD, with lower 25OHD levels more common in non-white patients.
To further explore the relationship between age and 25OHD, participants were stratified in 3 groups by age: youngest (0-5 years), middle (6-11 years), and oldest (12-18 years). The percentage of participants in each age group meeting criteria for vitamin D sufficiency, insufficiency, or deficiency is shown in the Figure (A). Inadequate 25OHD concentrations were most prevalent in the oldest age group, with only 15% meeting criteria for vitamin D sufficiency. Mean adjusted 25OHD concentrations for the 3 age groups are shown in the Figure (B). The mean adjusted 25OHD concentration was significantly lower in the oldest group than in the youngest group (P < .01).
Figure.
A, Vitamin D status. Among 0- to 5-, 6- to 11-, and 12- to 18-year-old children, the percentage of participants with either vitamin D insufficiency or deficiency was 56%, 69%, and 85%, respectively. B, Adjusted 25OHD levels. A mean adjusted 25OHD value was calculated for each age group, controlling for patient ethnicity, visit season, sex, z-BMI, A1c, and diabetes duration. The 12- to 18-year-old children had significantly lower 25OHD levels compared with the 0- to 5-year-old children (<0.01).
Discussion
It is important for those who care for children, particularly children with T1D, to be aware of the high prevalence of vitamin D inadequacy and its adverse effect on skeletal health. In our sample of youth, vitamin D inadequacy was most common in adolescents aged 12 to 18 years, with >4 of 5 meeting criteria for vitamin D insufficiency or deficiency. In comparison, a recent study of adolescent youth without diabetes mellitus from Philadelphia found that 51% of white participants had vitamin D levels <30 ng/mL when tested between the months of November and March.16 For the white participants in our cohort tested during the winter, 84% had 25OHD levels <30 ng/mL. Thus, our data suggest excessive vitamin D inadequacy in youth with T1D compared with a geographically, age-, and race-matched sample.
Although glycemic control, duration of diabetes mellitus, and age were associated with vitamin D inadequacy in bivariate analyses, only age remained a significant predictor in multivariate analyses. The youngest participants were over-represented by youth with short duration diabetes and higher A1c levels reflective of their recently diagnosed diabetes mellitus.
In addition to inadequate levels of vitamin D, adolescent patients with T1D potentially possess multiple risk factors for increased skeletal fragility. Earlier studies have shown that the early adolescent years are often associated with a rapid decrease in vitamin D-fortified milk intake.17 Sugar-free colas, which are frequently consumed by adolescents with diabetes mellitus, convey additional risk for poor bone health because they contain phosphoric acid, which is known to reduce intestinal calcium absorption.18 Hyperglycemia, hypercalciuria resulting in a calcium deficit, inflammatory cytokines, and microangiopathy could also potentially impair bone strength. Because many of these risk factors may not be modifiable because of the inherent presence of diabetes mellitus, ensuring vitamin D sufficiency throughout childhood and during the time of maximal bone mineral accrual seems particularly warranted in this population.
Future studies need to confirm our findings of vitamin D inadequacy in youth with T1D, identify mechanisms leading to insufficient or deficient states, and assess BMD in youth with T1D with dual energy X-ray absorptiometry.
We acknowledge contributions from the laboratory of Thomas O. Carpenter, MD, at Yale University School of Medicine, where the vitamin D metabolite assays were performed. In addition, we recognize contributions from the Pediatric Team at the Joslin Diabetes Center.
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Supported by grants from the National Institutes of Health (RO1DK046887 to L.L. and K12DK63696 to B.S.). Support was also received from the Charles H. Hood Foundation and Eli Lilly and Company. The authors declare no affiliations, financial agreements, or other involvements that would constitute a conflict of interest.
PII: S0022-3476(08)00597-0
doi:10.1016/j.jpeds.2008.07.015
© 2009 Mosby, Inc. All rights reserved.
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