Low Levels of 25-hydroxyvitamin D in the Pediatric Populations: Prevalence and Clinical Outcomes

Michal L Melamed; Juhi Kumar

Disclosures

Pediatr Health. 2010;4(1):89-97. 

In This Article

Vitamin D & Diabetes Mellitus

Type 1 Diabetes Mellitus

Several experimental and epidemiological studies have demonstrated associations between vitamin D levels and diabetes mellitus. Type 1 diabetes mellitus (T1DM) is an autoimmune disease and vitamin D is thought to play a role in its pathogenesis by its immunomodulatory actions of reducing lymphocyte proliferation and cytokine production.[61,62]

Strong evidence of a vitamin D effect on T1DM risk first came from experiments in the non-obese diabetic (NOD) mice. The NOD mouse experiences disease pathogenesis similar to the human, including autoimmune destruction of β cells. When 1,25(OH)2D, the active form of the vitamin, was administered to NOD mice in pharmacologic doses, it prevented the development of diabetes.[63] NOD mice when raised in a vitamin D-deficient state were shown to develop diabetes at an earlier age than nondeficient NOD controls.[64]

Type 1 diabetes mellitus has a 350-fold range of age-standardized incidence rates, from an average of 0.1 per 100,000 in males younger than 14 years of age in China to 37 per 100,000 in boys younger than 14 years in Finland.[65] This pattern follows a latitudinal gradient that is the inverse of the global distribution of UVB irradiance. Exposure of the skin to sunlight is the source of 80–95%[65] of circulating vitamin D and its metabolites; thus, availability and intensity of sunlight, which are highly related to latitude, are strong correlates of 25(OH)D. Mohr et al. explored the possible association between UVB irradiance in 51 regions worldwide and incidence rates of T1DM in children.[66] They analyzed the relationship between UVB irradiance and age-standardized incidence rates of T1DM in children, according to regions of the world. Incidence rates were generally higher at higher latitudes (R2 = 0.25; p < 0.001). UVB irradiance adjusted for cloud cover was inversely associated with incidence rates (p < 0.05). Incidence rates of T1DM approached zero in regions worldwide with high UVB irradiance, adding new support to the concept of a role of vitamin D in reducing the risk of the disease.

There is evidence of lower plasma 25(OH)D levels at diagnosis of T1DM compared with controls.[67] A number of recent studies from different regions of the world have highlighted the high prevalence of 25(OH)D deficiency in children with T1DM. Greer et al. in Australia, found a three-times higher risk of having levels below 20 ng/ml in adolescents with newly diagnosed diabetes than in the controls.[68] Another study from Italy examined 25(OH)D levels in 88 children newly diagnosed with T1DM and 57 healthy age- and sex-matched controls. Levels of both 25(OH)D and 1,25(OH)2D were significantly lower in the diabetic adolescents (p < 0.01 and <0.03, respectively).[69] A recent study from Boston measured 25(OH)D levels in 128 children with established and newly diagnosed T1DM. A total of 24% had levels above 30 ng/ml, but 61% had levels between 21 and 29 ng/ml and 15% were deficient (<20 ng/ml).[70] Bener et al. compared 25(OH)D levels in 170 age-, race- and sex-matched TIDM cases and healthy controls in Qatar, a region with ample sunshine all year round. There was a high prevalence of deficiency/insufficiency (<30 ng/ml) in both the groups (90.6 vs 85.3%), but it was significantly higher (p < 0.009) in the diabetic children.[71]

Epidemiological studies suggest that supplementation with vitamin D in infants might be important in conferring protection against the development of T1DM. A prospective study of vitamin D supplementation in infants and T1DM was published in 2001 by Hyppönen et al. A total of 12,055 pregnant women who lived in Northern Finland and 91% of their living children who had multiple assessments of vitamin D supplementation during their first year recorded by medical personnel at health examinations were enrolled in the study. Incident cases of diabetes over the subsequent 30 years were identified from national databases. Compared with children who were not given vitamin D supplements, the relative risk of developing T1DM was only 0.12 among children given vitamin D supplements regularly and 0.16 among children given them irregularly. Among infants who were given supplements regularly, risk of diabetes was lower at doses of over 50 µg/day or 2000 IU/day (relative risk 0.14) and exactly 50 µg/day (relative risk 0.22) compared with doses less than 50 µg/day. This large, well-designed, prospective study provides evidence that vitamin D supplementation of 50 µg/day (2000 IU/day) or more during infancy may reduce the risk for T1DM, at least in very northern parts of the world where sunlight is severely limited during a greater part of the year.[72] Zipitis et al. in a recent systematic review and meta-analysis of five studies[67,72–76] performed in Europe assessed the effect of vitamin D supplementation on the risk of developing T1DM. Five observational studies (four case–control studies and one cohort study) met the inclusion criteria. Meta-analysis of data from the case–control studies showed that the risk of T1DM was significantly reduced in infants who were supplemented with vitamin D compared with those who were not supplemented (pooled OR: 0.71; 95% CI: 0.60 to 0.84). The result of the cohort study was in agreement with that of the meta-analysis. There was also evidence of a dose–response effect, with those using higher amounts of vitamin D being at lower risk of developing T1DM.[77]

Two observational studies found a higher risk of T1DM in children whose mothers had low oral intake of vitamin D during pregnancy: the EURODIAB study found that children whose mothers consumed vitamin D supplements during pregnancy had a lower risk of T1DM than those whose mothers did not (OR: 0.67; 95% CI: 0.53–0.86),[78] and a case–control study by Stene and colleagues found that the risk of diabetes in children of mothers who took cod liver oil during pregnancy was lower than in mothers who did not (OR: 0.30; 95% CI: 0.12–10.75).[79] Neither study measured serum 25(OH)D in the participants.

In a cohort study performed in Colorado, intake of vitamin D during the third trimester of pregnancy was assessed in the mothers of 233 children. The children were followed for an average of 4 years. Maternal intake of vitamin D from food had a protective effect against the appearance of islet cell autoantibodies (multiple-adjusted HR: 0.37; 95% CI: 0.17–10.78).[80]

Although none of the above studies are randomized, controlled, clinical trials they provide intriguing evidence for a link between vitamin D levels and the development of T1DM.

Insulin Resistance/Type 2 Diabetes Mellitus

Vitamin D is thought to improve insulin sensitivity by its effects on muscle mass, and possibly fat metabolism or direct islet cell effects. The efficacy of vitamin D to promote muscle growth is supported by laboratory experiments. Rodents receiving diets containing high levels of vitamin D for 12 weeks had 8% greater muscle mass compared with animals receiving suboptimal vitamin D levels.[81] In support of an important physiological role for 1,25(OH)2D on muscle, vitamin D receptor (VDR)-null mice experience myopathy characterized by smaller muscle fibers.[82] Several intervention studies also support the conclusion that improved vitamin D status improves muscle function.[83–85] In a meta-analysis that included five double-blind, randomized, controlled trials in elderly populations (mean age 60 years; n = 1237), vitamin D supplementation reduced the corrected odds ratio of falling by 22% compared with patients receiving calcium or placebo, independent of calcium supplementation.[83]

Evidence that supports a link between vitamin D status and an increase in energy expended from a meal[86] provides a possible explanation of the role of vitamin D to reduce adiposity. In the Women's Health Initiative, women who were randomized to calcium and vitamin D experienced less weight gain compared with women on placebo.[87] These studies suggest that vitamin D and calcium may play a role in fat metabolism. 1,25(OH)2D, via VDR-mediated modulation of calbindin expression, appears to control intracellular calcium flux in the pancreatic islet cells, which in turn affects insulin release.[88]

The evidence regarding insulin resistance and T2DM in the pediatric population are mostly cross-sectional studies. A recent cross-sectional study of 51 adolescent girls (mean BMI 43 ± 9) revealed that 61% had 25(OH)D levels below 15 ng/ml and that low 25(OH)D levels were associated with a lower Matsuda index of insulin sensitivity.[89] Another cross-sectional study of 127 adolescents (mean age: 13 years) showed an inverse relationship between 25(OH)D levels and hemoglobin A1c levels.[90] Reis et al., in their analysis of NHANES 2001–2004 data, showed an inverse relationship between 25(OH)D levels and plasma glucose concentrations.[60] In our analysis of the same data, we did not see an association between low 25(OH)D levels and diagnosed diabetes mellitus.[15]

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