DOI: https://doi.org/10.21203/rs.3.rs-2427284/v1
Background: The impact of vitamin D on type 1 diabetes has been a controversial topic in public health. Furthermore, significant differences in the proportion of vitamin D have been noted. The purpose of this systematic review was to determine the overall proportion of vitamin D deficiency in children/adolescents with type 1 diabetes (T1D).
Methods: Based on six electronic databases (PubMed, Web of Science, Embase, Ovid Medline, ProQuest, and Cochrane Library), eligible studies since the databases’ inception up to April 2022 were searched. Reference lists were also manually searched to identify additional studies. Overall, studies with statistical information on vitamin D deficiency in children and adolescents with T1D were included, and a random effects model was applied for the meta-analysis. In addition, subgroup and sensitivity analyses were carried out to evaluate heterogeneity, and publication bias was evaluated by using Egger’s test.
Results: A total of 45 studies involving 6,995 participants were selected for the meta-analysis. The proportion of vitamin D deficiency in children/adolescents with T1D was found to be 45% (95% confidence interval [CI] 37-54%, I2 = 97.94%). Subgroup analysis further showed that the publication year, study design, classification of vitamin D, different seasons and geographical region could significantly contribute to variations in the reported proportion of vitamin D deficiency.
Conclusions: This systematic review analyzed the available literature and revealed that the proportion of vitamin D deficiency among T1D children/adolescents was 45%. In addition, the proportion remains higher, which has important implications for adapting health and social care systems.
Type 1 diabetes (T1D), an autoimmune disease that affects pancreatic beta cells, is one of the most common endocrine disorders that affect children and young adults worldwide [1-3]. According to statistics, 7,759 out of 3.61 million young people aged 19 and from only 6 regions of the United States were diagnosed with T1D in 2017 [4]. Furthermore, a pooled analysis conducted in 26 European centers revealed a yearly increase of 3.4% in the incidence rate of T1D [5]. This condition inflicts substantial lifetime morbidity, affecting patients both during their childhood and throughout their adult lives [6]. For example, diabetic ketoacidosis (DKA) has a high incidence of recurrence and is a leading cause of mortality among patients with T1D, resulting in an elevated burden for patients, families, hospitals, and healthcare providers [7]. Therefore, it is important to find ways to prevent the prevalence of T1D. In this context, one potential factor, vitamin D (VD), has attracted the attention of many scholars. Indeed, vitamin D deficiency/insufficiency represents a substantial but modifiable public health risk that deserves increased attention [8], as the number of T1D patients suffering from vitamin D deficiency has been increasing rapidly [9].
Vitamin D deficiency seems to be a common issue even in the general population. Measurement of the circulating form of vitamin D that best describes total body stores, namely, 25-hydroxyvitamin D, can be unreliable despite many sophisticated methodologies that have been proposed and implemented [10]. Likewise, evidence from clinical studies showing a beneficial role of vitamin D in different disease states has been controversial and at times speculative [11]. The effects of vitamin D on T1D remain a controversial topic.
Vitamin D deficiency has been shown to be commonplace in patients with T1D [12]. Vitamin D, also called calciferol, is one of the essential fat-soluble vitamins that has a considerable role in the growth and strength of bones by controlling calcium and phosphorus homeostasis [13]. In addition to its role in calcium homeostasis, it has an antiproliferative and immunosuppressive property that regulates cell proliferation and differentiation [14,15]. According to a review, vitamin D deficiency can potentially influence T1D incidence, comorbidity, and progression. Furthermore, in a cross-sectional study, 70% of children with T1D were reported to be vitamin D deficient [16].
However, epidemiological data based on various studies have shown that the prevalence of vitamin D deficiency among individuals with T1D varies greatly between 4% and 92% [17,18], indicating the inconsistency and uncertainty in the currently available information.
Several factors could explain the above variations in the prevalence of vitamin D deficiency between the different sources of data. First, different criteria are used to assess vitamin D deficiency. In addition, the quality and number of examined studies as well as the sampling procedures used in recorded studies tend to be heterogeneous, thereby leading to variable and possibly imprecise estimates. These methodological challenges highlight the importance of assessing the prevalence of vitamin D deficiency in children/adolescents with T1D through a systematic approach.
Although different reviews on the subject are already available, to our knowledge, no systematic reviews and meta-analyses have been conducted to reliably establish the proportion of vitamin D deficiency in children/adolescents with T1D. Therefore, by synthesizing information from different sources, the current systematic review not only sought to address the above knowledge gap but also to evaluate how the characteristics of studies influence estimations of the prevalence.
Protocol and registration
This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [19]. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD 42022301690).
Search strategy
A thorough literature search was carried out to find published articles on the proportion of vitamin D deficiency in children and/or adolescents with T1D. The following electronic databases were used for the search: PubMed, Web of Science, Cochrane Library, Ovid Medline, Embase and ProQuest. The following key terms were used: ‘diabetes mellitus insulin dependent’ or ‘diabetes mellitus juvenile onset’ or ‘juvenile onset diabetes mellitus’ or ‘IDDM’ or ‘diabetes juvenile onset’ or ‘diabetes mellitus sudden onset’ or ‘type 1 diabetes mellitus’ or ‘diabetes autoimmune’ or ‘diabetes mellitus brittle’ or ‘Ketosis-Prone’ or ‘ketosis prone diabetes mellitus’ or ‘Adolescen*’ or ‘Teen*’ or ‘Youth*’ or ‘Child*’ or ‘Vitamin D’ and Medical Subject Headings (MeSH) terms ‘diabetes mellitus, type 1’, ‘diabetes mellitus’, ‘Adolescent’, ‘Child’ and ‘Vitamin D’. Studies published from the inception of the database up to the end of April 2022 were considered. The research team then created a search strategy based on the MeSH terms and free-text phrases. In this case, the team browsed through the references listed in published research to discover additional potentially suitable studies, with no restrictions regarding the date or language of publication. The search strategies are shown in Appendix S1.
Study selection and eligibility criteria
Materials that met the following requirements were selected: (1) observational studies (cross-sectional designs, longitudinal research baseline cross-sectional data, cohort studies, and case–control studies); (2) participants/subjects included children/adolescents with T1D; (3) the proportion of vitamin D deficiency in children and/or adolescents with T1D was described in peer-reviewed literature; and (4) the primary outcome measured the proportion of vitamin D deficiency in children and/or adolescents with T1D while vitamin D insufficiency and vitamin D sufficiency were secondary outcome indicators. Studies were excluded if they were commentaries, reviews, posters, case reports or letters to the editor; clear data were not provided; and articles reported duplicated data.
Data extraction
Two independent reviewers (XY and MC) examined the publications' titles and abstracts, followed by their entire texts to ensure that they met the inclusion criteria. Any discrepancies were settled through communication with a third reviewer (ML). Two separate researchers retrieved information from the selected papers, including the first author's name, year, title, country, study design, and sample size and characteristics (sex, age, diagnostic criteria of diabetes, classification of vitamin D, etc.).
Quality assessment
The methodological quality of the included studies was independently evaluated by different reviewers (XY and MC) using appropriate instruments. The Newcastle–Ottawa Scale (NOS) [20] was used to ensure the quality of cohort and case–control studies. In this case, NOS ratings ranged from 0 to 9, with studies with NOS scores greater than 6 considered to be of reasonably high quality, scores 5–6 considered to be of medium quality and scores below 5 deemed to be of low quality. In addition, using the "star system," each included study was evaluated in three domains: representativeness of the study group during selection, group comparability and exposure or outcome ascertainment. Finally, the Agency for Healthcare Research and Quality (AHRQ) methodology checklist was used to measure the validity of the cross-sectional studies. Each study was evaluated based on 11 items from the checklist [21], with the quality rated as follows: decent quality = 8–11, moderate quality = 4–7, and poor quality = 0–3. If no agreement could be reached, a third researcher (ML) was recruited to settle the dispute.
Statistical analysis
Data analysis was carried out using the meta-analysis function in STATA software (Stata version 12.0, StataCorp, College Station, TX, USA). For the evaluation of pooled effect, a 95% confidence interval (CI) was considered, and statistical significance was set at P < 0.05. Random effects were used to pool studies reporting the proportion of vitamin D deficiency in children and/or adolescents with T1D. The I2 index was then used to examine between-study heterogeneity. If the I2 value was less than 50%, a nonsubstantial level of heterogeneity was assumed and the meta-analysis applied a fixed effects model. Conversely, an I2 value greater than 50% was indicative of substantial heterogeneity, in which case a random effects model was used. The impact of a single study on the overall estimate of proportion was also investigated by eliminating each study in turn during a sensitivity analysis. Additionally, when there was more than one study in a subgroup, subgroup analyses were performed based on overall study design, vitamin D classification, different seasons (winter, summer, spring, and fall) and geographical location (Asia, Europe, Oceania, Africa, North America, and South America). Funnel plots and Egger’s test were eventually combined to explore the potential publication bias in this meta-analysis. The impact of publication bias on the results was assessed using a nonparametric trim and fill method.
Search results and study characteristics
A total of 2085 titles and abstracts were retrieved from electronic database searches, and after removing 254 duplicates, 1831 were screened based on their titles and abstracts. This yielded 61 full-text studies that were subsequently evaluated for eligibility. Six supplementary articles were also found to be eligible from the reference lists of the included studies. After reviewing the full texts, 45 studies were ultimately included in the meta-analysis. A summary of the selection process for the studies is presented in Fig. 1
Descriptions of included studies
Out of the 45 studies, 19 had cross-sectional designs [22-40], 23 were case–control studies [41-63], 2 had baseline cross-sectional data from a longitudinal study [64,65] and one was based on the baseline data of a cohort study [66]. The reported data also included 6,995 participants, mostly aged ≤ 18 years old, of which 2,436 were children/adolescents with T1D as well as vitamin D deficiency (sample size n=13~1,426). Overall, T1D cases were mainly ascertained on the basis of criteria laid out by the World Health Organization (WHO), the American Diabetes Association and the European Diabetes (EURODIAB) collaboration, while levels of 25-hydroxyvitamin D (25(OH)D) were measured using a radioimmunoassay kit or by high-performance liquid chromatography (HPLC). Similarly, vitamin D status was mainly ascertained based on the Endocrine Society Clinical Practice Guideline, the Institute of Medicine guidelines, the Australian consensus statement criteria and the Central European Guidelines. Regarding the countries covered in the studies, seven were conducted in America, four were conducted in Turkey, three were carried out each in Korea, Iran and India, two studies each were conducted in Australia, the UK, Egypt, Spain, Italy and the Kingdom of Saudi Arabia, and one study was performed in China, Indonesia, Poland, Kuwait, Canada, Bangladesh, Slovakia, Switzerland, Boston, Ukraine, Tunisia, Iraq and Germany. The main characteristics of the 45 included studies are shown in Table 1. In accordance with the recommended NOS and AHRQ criteria, only studies of acceptable quality were included in the present meta-analysis; eight studies received 9 stars [51,53,56-58,62,63,66], ten studies received 8 stars [43,48-50,52,54,55,59-61], five studies received 7 stars [42,44-47] and one study received 6 stars [41]. When using the quality assessment criteria from the AHRQ, three studies received a score of 11 [24,29,65], ten received a score of 10 [22,25,28,29,31,33,34,36,39,40], three received a score of 9 [23,32,35], one received a score of 8 [27], one received a score of 7 [37] and two received a score of 5 [26,38], the quality assessment are shown in Appendix S2. Therefore, no article from the meta-analysis was excluded for quality reasons.
Meta-analyses and data synthesis
For the whole sample of 6,995 individuals, the proportion of vitamin D deficiency in children and/or adolescents with T1D was 45% (95% CI; 37-54%; P < 0.01; Fig. 2). The analyses further indicated the heterogeneity between studies (I-square [I2] = 97.94%, P < 0.001), and publication bias could be observed on the funnel plot. Publication bias in studies assessing the total proportion of vitamin D deficiency in T1D was analyzed using Begg’s test (z= 1.88; P= 0.060), Egger’s test (P= 0.000) and the funnel plot (Fig. 3).
Subgroup analyses were carried out depending on the publication year, study design, classification of vitamin D, season and geographical region of the studies, with Table 2 presenting the estimated proportion of vitamin D deficiency after the analysis.
All included studies were from 2009 to 2022. Twenty-one studies were published between 2009 and 2015, and 24 were published between 2016 and 2022. In contrast with the literature data of the previous six years (48%, 95% CI; 36-59%), more recent publications tended to yield a low proportion of vitamin D deficiency (43%, 95% CI; 31-56%). By comparing study designs, the subgroup analysis showed that a higher proportion of vitamin D deficiency could be noted in case‒control studies (58%, 95% CI; 45-72%), followed by one cohort study (51%, 95% CI; 45-58%) and 19 cross-sectional studies (31%, 95% CI; 22-40%), with the lowest proportion identified for 2 longitudinal studies (22%, 95% CI; 20-25%), but with significant heterogeneity. The proportion of vitamin D deficiency in children and/or adolescents with T1D was highest in Africa (65%, 95% CI; 42-85%), followed by Asia (54%, 95% CI; 40-68%), Europe (50%, 95% CI; 32-69%), North America (24%, 95% CI; 15-34%) and Oceania (15%, 95% CI; 12-18%), with a significant difference among the five subgroups (P < 0.01). The proportion of vitamin D deficiency in children and/or adolescents with T1D in low-mid latitudes was 56% (95% CI; 38-72%), followed by low latitudes (50%, 95% CI; 12-88%), mid-high latitudes (42%, 95% CI; 37-47%) and middle latitudes (39%, 95% CI; 29-50%). By vitamin D status, the results showed that a higher proportion of vitamin D deficiency could be noted at 30 ng/ml (87%, 95% CI; 82-92%), followed by one at 25 ng/ml (80%, 95% CI; 71-87%), 10 ng/ml (67%, 95% CI; 26-97%), 20 ng/ml (49%, 95% CI; 39-60%), and 15 ng/ml (24%, 95% CI; 11-41%), with the lowest proportion identified at12 ng/ml (14%, 95% CI; 9-20%). The subgroup analyses for different seasons showed that the proportion of vitamin D deficiency in winter tended to be significantly higher than that in summer (50%, 95% CI; 37-64% vs. 17%, 95% CI; 8-27%). In addition, studies conducted in spring reported a higher proportion of vitamin D deficiency (28%, 95% CI; 23-33%) than those conducted in autumn (20%, 95% CI; 12-29%), but this was not significant (P > 0.01).
Sensitivity analysis was carried out to examine the influence of any particular study. To determine whether potential publication bias existed in the reviewed literature, Egger’s test was also carried out. The results of Egger’s test (P < 0.05) did suggest the existence of publication bias. Thus the publication bias of this study was corrected using the trim-and-fill method. The results showed that publication bias had little effect on the combined amount of results, indicating that the robustness of the results of this study was high.
Thirty-five studies involving 5,862 participants were included in the meta-analysis of the rate of vitamin D insufficiency among children and/or adolescents with T1D. In this case, the random effects model indicated that the cumulative proportion was 33.0% (95% CI; 27-38%). Considerable heterogeneity was also observed across studies (I2 = 94.27%, P < 0.01). Analyses of publication bias for studies estimating the total proportion of vitamin D insufficiency were also conducted, with biases determined based on Begg’s test (z = 0.67; P = 0.504), Egger’s test (P = 0.614) and the funnel plot.
Thirty-nine studies, grouping 6,490 individuals from Europe (n = 11), Asia (n = 17), Africa (n = 1), North America (n = 9), and Oceania (n = 1), assessed the proportion of vitamin D sufficiency in children and/or adolescents with T1D. In this case, the proportion was estimated to be 27% (95% CI; 19-35%; I2 = 97.87%). Analyses of publication bias for studies estimating the total proportion of vitamin D sufficiency were also performed, with biases determined as before (i.e., with Begg’s test (z = 0.11; P = 0.913) and Egger’s test (P= 0.007) and the funnel plot). Sensitivity analyses further revealed 2 studies were found to be off-center, and after omitting it [38,65], the biases were again determined by both Begg’s test (z= 0.29; P= 0.773) and Egger’s test (P = 0.509).
This systematic review and meta-analysis comprehensively assessed the proportion of vitamin D deficiency in children and/or adolescents with T1D from a global perspective. The pooled estimate showed that vitamin D deficiency was prevalent among children and/or adolescents with T1D. As suggested by the present study, the rate of vitamin D deficiency in this particular group was high at 45%, with this value based on 45 studies involving 6,995 respondents. In addition, the proportions of vitamin D insufficiency and vitamin D sufficiency were 33% and 27%, respectively. These results may help to improve public health interventions for decreasing the proportion of vitamin D deficiency in children and/or adolescents with T1D. At the same time, they may serve as a reminder that greater attention should be given to vitamin D deficiency in clinical practice.
The high proportion of vitamin D deficiency in children and/or adolescents with T1D may be explained by the fact that vitamin D is lipophilic and is mainly absorbed in the small intestine before further processing in the skin, liver and kidneys to the biologically active compound 1,25-dihydroxyvitamin D. In addition, absorption of lipophilic substances is dependent on a variety of intricate processes that require an intact epithelium in the small intestine but also on extraintestinal factors, such as the release of lipase from the pancreas and bile from the liver [67].
High heterogeneity was identified across the included studies. Subgroup analysis further revealed marked between-study variability in estimates of the proportion of vitamin D deficiency proportion. For instance, the result of subgroup analysis by publication year showed that more recent publications tended to yield low vitamin D deficiency proportion estimates. This discrepancy might be due to increasing awareness of the importance of vitamin D supplements and sun exposure. Furthermore, by comparing study designs, the present study found that the proportion of vitamin D deficiency in case‒control studies tended to be higher than that in other studies. This inconsistency clearly indicated that different study designs could yield different estimates of the proportion of vitamin D deficiency proportion.
The other study-specific factor that we considered in the subgroup analysis was geographical region. Compared to other regions, we found that the proportion of vitamin D deficiency in children and/or adolescents with T1D in Africa tended to be higher than in Asia (65% vs. 54%), followed by Europe (50%), North America (24%) and Oceania (15%), thus indicating that geographical regions could partly explain some of the variances. This could have been due to differences in culture, religion, ethnicity, dietary habits and forms of exercise. Indeed, low vitamin D levels in some populations have been related to social customs such as the avoidance of sunlight or even breastfeeding without any vitamin D supplement [68]. In addition to the fact that individuals originated from different territorial areas, participant characteristics such as age and ethnicity also varied among studies. Some participants could also have had higher vitamin D requirements for bone growth, especially during pubertal growth spurts [69], further contributing to the heterogeneity.
In our subgroup analysis, one of the most important factors was the cutoff value for vitamin D deficiency. Compared with a cutoff value of <25ng/ml, a cutoff value of <30ng/ml was associated with a significantly higher proportion of vitamin D deficiency. This was followed by a cutoff value of <10ng/ml, a cutoff value of <20ng/ml, and a cutoff value of <15ng/ml, with the lowest proportion identified for a cutoff value of <12ng/ml. This may be due to the small sample size. The variability could be partly attributed to a lack of standardized 25(OH)D measurements in vitamin D research. Beyond that, within a given methodology, there are several possible causes for differences, such as lot-to-lot variation in manufacturer reagents or differences in subjects included in different studies.
Subgroup analysis also revealed an interesting finding. The present study found that the proportion of vitamin D deficiency in children and/or adolescents with T1D in winter tended to be significantly higher than that in summer. In addition, this surprising finding adds weight to the conclusion that the proportion of vitamin D deficiency in children and/or adolescents with T1D in mid-low latitudes tends to be higher than that in low latitudes (56% vs. 50%), followed by mid-high latitudes (42%) and lowest in middle latitudes (39%). This discrepancy might be because there is a longer sunlight duration in summer than in winter. While separating research into subgroups revealed numerous noteworthy differences, post hoc comparisons should be interpreted with caution. The heterogeneity in proportion between studies was not satisfactorily explained by any of the parameters examined, with I2 values being over 65% for all subgroups.
The current research was not without limitations. Firstly, all the studies were clinic- or hospital[1]based, which could have affected the true prevalence in the general populations. Secondly, The selected literature included cross-sectional, case‒control, cohort and longitudinal studies that were limited by study design and therefore had an inevitable risk of bias. Thirdly, there is currently no internationally agreed upon classification standard for vitamin D deficiency, and as such, there may be significant variations during reporting. Finally, the possibility of publication bias could not be fully excluded by Egger’s test. The trim and fill analysis was also conducted and it does not change the estimate indicating that the results are robust to the possibility of unpublished studies.
Vitamin D may have direct effects on β cells, including improving insulin secretion, enhancing the expression of the vitamin D receptor and improving islet morphology [70]. As vitamin D intake is a potentially important and modifiable behavioral target, clinical professionals need to screen for vitamin D deficiency in children and/or adolescents with T1D to guide appropriate supplementation.
This review demonstrated that vitamin D deficiency affected 45% of children and/or adolescents with T1D, and children and/or adolescents with T1D in winter had an increased susceptibility to vitamin D deficiency compared with other seasons. These results contribute to a better understanding of vitamin D deficiency in children and/or adolescents with T1D and demonstrate the importance of assessing vitamin D deficiency in children and/or adolescents with diabetes. Preventive strategies and interventions to address vitamin D deficiency in children and/or adolescents with T1D should be considered in healthcare settings. Future research should focus on increasing our understanding of the temporal relationship between diabetes and vitamin D deficiency.
T1D: Type 1 diabetes; DKA: Diabetic Ketoacidosis; CI: Confidence Interval; VD: vitamin D; PRISMA: the Preferred Reporting Items for Systematic Reviews and Meta-Analyses; MeSH: Medical Subject Headings; NOS: The Newcastle–Ottawa Scale; AHRQ: the Agency for Healthcare Research and Quality; WHO: the World Health Organization; ADA: the American Diabetes Association; EURODIAB: the European Diabetes collaboration; HPLC: High-Performance Liquid Chromatography.
Acknowledgements
Not applicable.
Authors' contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by XY, MC, and ML. The first draft of the manuscript was written by XY and ML. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
This research did not receive any funding.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding/first author on reasonable request.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Department of Pediatric Genetics, Metabolism and Endocrinology Nursing, West China Second University Hospital, Sichuan University/West China School of Nursing, Sichuan University.
2 Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, 610041, Chengdu, Sichuan, China.
Table 1 | Characteristics of the selected studies |
|||||||||||||||
Study |
Year |
Design |
Country |
Sample |
Age |
Gender |
Diabetes duration |
Definition |
Vitamin D measure |
Definition of vitamin D |
25(OH)D |
Vitamin D |
Vitamin D deficiency |
NOS/ |
|
(year) |
(M/F) |
of diabetes mellitus |
(ng/ml) |
n(%) |
AHRQ |
||||||||||
Bener |
2009 |
Case-control |
UK |
170 |
<16 |
88/82 |
NR |
venous blood glucose values equal or >6.7mmol/L |
RIA |
NR |
15.8 ± 9.2 |
① |
154 (90.6) |
9 |
|
Borkar |
2010 |
Case-control |
Indian |
50 |
6~12 |
29/21 |
NR |
ADA |
HPLC |
NR |
20.02 ± 10.63 |
② |
29 (58.0) |
9 |
|
Daga |
2012 |
Case-control |
Indian |
13 |
<18 |
6/7 |
NR |
NR |
RIA |
NR |
11.36 ± 4.74 |
② |
12(92.3) |
8 |
|
Azab |
2013 |
Case-control |
Egypt |
80 |
6~16 |
34/46 |
17 (3~52) (m) |
WHO criteria |
ELISA |
AAP |
24.7 ± 5.6 |
③ |
44 (55) |
9 |
|
Lieberman |
2013 |
Case-control |
USA |
211 |
12~19 |
51/160 |
10.9 ± 3.2 |
Islet cell antibody |
Clinical lab |
IMG |
27.7 ± 0.7 |
② |
47 (22) |
9 |
|
Greer |
2013 |
Case-control |
Australia |
56 |
NR |
28/28 |
NR |
NR |
Clinical lab |
ACSC |
31.53 (28.77-34.29) |
③ |
5 (8.9) |
8 |
|
Franchi |
2013 |
Case-control |
Italy |
58 |
1.1~16 |
32/26 |
NR |
ADA |
Chemiluminescent assay |
NR |
NR |
② |
39 (67.2) |
8 |
|
Jung |
2014 |
Case-control |
Korea |
102 |
<18 |
41/61 |
NR |
NR |
Chemiluminescent assay |
NR |
14.5 ± 6.4 |
② |
77 (75.4) |
8 |
|
Wierzbicka |
2016 |
Case-control |
Poland |
60 |
<18 |
28/32 |
5.1 ± 3.9 |
NR |
ECLIA |
ESCPG |
15.3 ± 7.0 |
② |
49 (81.7) |
8 |
|
Rasoul |
2016 |
Case-control |
Kuwait |
216 |
<15 |
104/112 |
NR |
ISPAD/WHO |
EIA |
ESCPG |
13.84 ± 6.66 |
② |
182 (84.3) |
9 |
|
Kim |
2017 |
Case-control |
Korea |
42 |
9~14 |
12/30 |
6.4 ± 3.0 |
NR |
125I-labeled radioimmunoassay |
ESCPG |
20.0 ± 6.4 |
③ |
24 (57.1) |
8 |
|
Ziaei-Kajbaf |
2018 |
Case-control |
Iran |
85 |
1~15 |
40/45 |
NR |
NR |
ELISA |
NR |
5.13 ± 4.24 |
② |
65 (76.5) |
7 |
|
Liu |
2018 |
Case-control |
China |
296 |
8.99±3.75 |
147/149 |
NR |
NR |
Non-radioactive EIA |
the Global Consensus 1 |
19.51 ± 6.11 |
④ |
39 (13.2) |
7 |
|
Federico |
2018 |
Case-control |
Italy |
82 |
2~18 |
44/38 |
9.4 ± 3.9 |
NR |
HPLC |
ESCPG |
21.79 ± 10.94 |
② |
41 (50.0) |
7 |
|
Study |
Year |
Design |
Country |
Sample |
Age |
Gender |
Diabetes duration |
Definition |
Vitamin D measure |
Definition of vitamin D |
25(OH)D |
Vitamin D |
Vitamin D deficiency |
NOS/ |
|
(year) |
(M/F) |
of diabetes mellitus |
(ng/ml) |
n(%) |
AHRQ |
||||||||||
Bae |
2018 |
Case-control |
Korea |
85 |
6~20 |
37/48 |
NR |
NR |
RIA |
ESCPG |
21.6 ± 8.5 |
② |
41 (48.2) |
8 |
|
Sonia |
2016 |
Case-control |
Tunisia |
29 |
12~18 |
14/15 |
35.03 ± 42.4(m) |
ADSC |
RIA |
NR |
17.4 ± 1.0 |
② |
15 (51.7) |
8 |
|
Mansi |
2021 |
Case-control |
Iraq |
104 |
<5 |
36/68 |
NR |
NR |
NR |
NR |
NR |
⑨ |
83 (79.8) |
7 |
|
Soliman |
2015 |
Case-control |
Egypt |
53 |
6~18 |
27/26 |
NR |
ADA |
Immun-diagnostik EIA |
NR |
7.65 ± 2.52 |
⑤ |
45 (84.9) |
9 |
|
Rochmah |
2022 |
Case-control |
Indonesia |
31 |
<18 |
18/13 |
1.0 (0~11) |
ISPAD |
ELFA |
ESCPG |
26.11 (13.95-52.11) |
② |
4 (12.9) |
8 |
|
Setty-Shah |
2014 |
Case-control |
USA |
22 |
2~13 |
12/22 |
NR |
ADA |
Chemiluminescent assay |
AAP and IMG |
24.44 ± 6.04 |
③ |
3 (13.6) |
9 |
|
Ghandchi |
2012 |
Case-control |
Iran |
60 |
5~25 |
32/28 |
NR |
NR |
HPLC |
NR |
NR |
⑤ |
51 (85.0) |
8 |
|
Biliaieva |
2022 |
Case-control |
Ukraine |
94 |
10~18 |
NR |
NR |
NR |
Electrochemiluminescence |
EPGC and IMG |
NR |
② |
64 (68.1) |
6 |
|
Polat |
2022 |
Case-control |
Turkey |
29 |
9~16 |
NR |
NR |
NR |
NR |
ESCPG |
NR |
① |
16 (55.2) |
7 |
|
Raab |
2014 |
Cohort |
Germany |
244 |
3~9 |
132/112 |
NR |
ADA |
RIA |
NR |
19.91 ± 0.60 |
② |
125 (51.2) |
9 |
|
Janner |
2010 |
Cross-sectional |
Switzerland |
129 |
NR |
69/60 |
NR |
ADA |
Chemiluminescent assay |
NR |
18.31 (16.51-20.15) |
② |
78 (60.5) |
10 |
|
Svoren |
2009 |
Cross-sectional |
Boston |
128 |
<18 |
69/59 |
4.1 ± 5.6 |
NR |
RIA |
NR |
26.8 ± 6.7 |
② |
19 (15.0) |
10 |
|
Mutlu |
2011 |
Cross-sectional |
Turkey |
120 |
3~20 |
65/55 |
3.2 ± 2.3 |
NR |
ELISA |
AAP |
25.6 ± 16.2 |
⑦ |
27 (22.5) |
10 |
|
Thnc |
2011 |
Cross-sectional |
Turkey |
100 |
<20 |
NR |
56.4 ± 3.7 (m) |
NR |
HPLC |
NR |
NR |
⑤ |
28 (28.0) |
7 |
|
Vojtkova |
2012 |
Cross-sectional |
Slovakia |
58 |
9~19 |
30/28 |
NR |
ADA |
Biochemical |
NR |
NR |
⑥ |
21 (36.2) |
10 |
|
Ataie-Jafari |
2012 |
Cross-sectional |
Iran |
53 |
8~18 |
14/39 |
13.2 ± 6.1 |
NR |
RIA |
NR |
NR |
② |
41 (77.0) |
9 |
|
The |
2013 |
Longitudinal |
USA |
1426 |
<20 |
730/696 |
10.2 ± 3.9 (m) |
NR |
Chemiluminescent assay |
IMG |
NR |
④ |
300 (21.0) |
11 |
|
Savastio |
2016 |
Longitudinal |
Italy |
64 |
<12 |
NR |
5.6 ± 3.9 |
ADA |
Chemiluminescent assay |
ESCPG |
17.71 ± 9.62 |
⑥ |
41 (64.0) |
10 |
|
Al-Zubeidi |
2016 |
Cross-sectional |
USA |
185 |
<19 |
81/94 |
NR |
NR |
Chemiluminescent assay |
ESCPG |
NR |
⑥ |
33 (17.8) |
10 |
|
Study |
Year |
Design |
Country |
Sample |
Age |
Gender |
Diabetes duration |
Definition |
Vitamin D measure |
Definition of vitamin D |
25(OH)D |
Vitamin D |
Vitamin D deficiency |
NOS/ |
|
(year) |
(M/F) |
of diabetes mellitus |
(ng/ml) |
n(%) |
AHRQ |
||||||||||
Al |
2016 |
Cross-sectional |
Kingdom of Saudi Arabia |
301 |
1~18 |
140/161 |
7.7 ± 3.7 |
ADA |
Chemiluminescent assay |
PES |
14.06 ± 6.37 |
⑦ |
103 (34.2) |
11 |
|
Zambrana-Calví |
2016 |
Cross-sectional |
Spain |
90 |
<18 |
46/44 |
NR |
ISPAD |
HPLC |
NR |
NR |
⑦ |
12 (13.3) |
10 |
|
Al Sawah |
2016 |
Cross-sectional |
USA |
197 |
7~18 |
85/112 |
NR |
NR |
(LC-MS/MS) |
NR |
21.88 ± 7.13 |
② |
80 (40.6) |
9 |
|
Giri |
2017 |
Cross-sectional |
UK |
271 |
7.7 ± 4.4 |
NR |
NR |
NR |
Tandem Mass Spectrometry |
the Global Consensus1 |
12.90 ± 3.29 |
④ |
40 (14.8) |
8 |
|
ALkharashi |
2019 |
Cross-sectional |
Kingdom of Saudi Arabia |
100 |
2~12 |
50/50 |
NR |
NR |
Biochemical |
NR |
14.06 ± 0.56 |
③ |
70 (70.0) |
10 |
|
Zabeen |
2021 |
Cross-sectional |
Bangladesh |
60 |
11~15 |
18/42 |
NR |
ISPAD |
RIA |
NR |
12.97 (9.3-18.0) |
⑦ |
31 (51.7) |
10 |
|
Segovia-Ortí |
2020 |
Cross-sectional |
Spain |
67 |
0~14 |
31/36 |
NR |
ISPAD |
Chemiluminescent assay |
ESCPG |
NR |
② |
13 (19.4) |
9 |
|
Carakushansky |
2020 |
Cross-sectional |
USA |
395 |
3~18 |
202/193 |
NR |
NR |
(LC-MS/MS) |
NR |
NR |
⑧ |
17 (4.7) |
11 |
|
KOR |
2018 |
Cross-sectional |
Turkey |
106 |
2~18 |
44/65 |
4.46 + 2.8 |
ISPAD |
Chemiluminescent assay |
NR |
27.11 ± 14.33 |
④ |
7 (6.6) |
5 |
|
Yeshayahu |
2012 |
Cross-sectional |
Canada |
271 |
12~18 |
138/133 |
7.2 ± 3.6 |
NR |
(LC-MS/MS) |
NR |
NR |
⑧ |
89 (32.8) |
10 |
|
Saki |
2017 |
Cross-sectional |
India |
85 |
8~18 |
39/46 |
4.4 ± 2.8 |
Two positive autoantibody tests |
HPLC |
ESCPG |
18.0 ± 12.2 |
② |
52 (61.2) |
10 |
|
Kaur |
2011 |
Cross-sectional |
Australia |
517 |
8~20 |
NR |
7.2 ± 3.5 |
NR |
LIAISON |
ANZ |
28.09 ± 9.21 |
③ |
80 (15.5) |
5 |
|
† NR, not reported; ACSC, Australian consensus statement criteria; LC-MS/MS, liquid chromatography-mass spectrometry; RIA, radioimmunoassay; ADAC, American Diabetes Association criteria; ECLIA, Electrochemilumines-cence immunoassay; EIA, enzyme immunoassay; ADSC, American diabetes society criteria; ELISA, ELISA assay kit; ADA, American Diabetes Association; AAP, The American Academy of Pediatrics; HPLC, high-performance liquid chromatography ESCPG, Endocrine Society clinical practices Guideline; IMG, the Institute of Medicine guidelines; EPGC, the Endocrine Practice Guidelines Committee; ELFA, enzyme immunoassay with enzyme-linked fluorescence assay;PES, the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society; ANZ, Australia and New Zealand: a consensus statement; 1the Global Consensus, the Global Consensus Recommendations on Prevention and management of Nutritional Rickets ;①vitamin D deficiency<30ng/mL;vitamin D sufficiency = 30~80ng/mL; ②vitamin D deficiency <20ng/mL; vitamin D insufficiency = 20~30ng/mL; VDS>30ng/L; ③vitamin D deficiency<20ng/mL;vitamin D sufficiency>20ng/L; ④vitamin D deficiency<12ng/ml; vitamin D insufficiency =12~20ng/ml; vitamin D sufficiency ≥ 20ng/ml; ⑤vitamin D deficiency <10ng/mL; vitamin D insufficiency =10~20ng/mL; vitamin D sufficiency ≥20ng/mL; ⑥vitamin D deficiency =10~20ng/mL; vitamin D insufficiency = 20~30ng/mL; vitamin D sufficiency ≥ 30ng/mL; ⑦vitamin D deficiency ≤15ng/mL;vitamin D insufficiency =15~20ng/mL;vitamin D sufficiency ≥20ng/ml; ⑧vitamin D deficiency ≤15ng/mL;vitamin D insufficiency =15~29ng/mL;vitamin D sufficiency ≥30ng/ml; ⑨vitamin D deficiency<25ng/mL; vitamin D sufficiency ≥25ng/mL; ng/ml*2.496=nmmol/L. |
Table 2 | Summary of meta-analysis for the proportion of vitamin D deficiency in children/adolescents with T1D
Variable |
Studies |
Sample size |
Cases |
Vitamin D deficiency |
||
95%CI |
I2 (%) |
P-value |
||||
Total proportion |
45 |
6995 |
2436 |
0.45 (0.37, 0.54) |
97.94 |
0.00 |
Year |
|
|
|
|
|
|
2009-2015 |
21 |
3921 |
1314 |
0.48 (0.36, 0.59) |
97.91 |
0.00 |
2016-2022 |
24 |
3074 |
1122 |
0.43 (0.31, 0.56) |
98.05 |
0.00 |
Design |
|
|
|
|
|
|
Cross-sectional |
19 |
3233 |
841 |
0.31 (0.22, 0.40) |
96.91 |
0.00 |
Case-control |
23 |
2028 |
1129 |
0.58 (0.45, 0.72) |
97.33 |
0.00 |
Cohort |
1 |
244 |
125 |
0.51 (0.45, 0.58) |
- |
- |
Longitudinal |
2 |
1490 |
341 |
0.22 (0.20, 0.25) |
- |
- |
Geographical region |
|
|
|
|
|
|
Africa |
3 |
162 |
104 |
0.65 (0.42, 0.85) |
- |
- |
Oceania |
2 |
573 |
85 |
0.15 (0.12, 0.18) |
- |
- |
Europe |
11 |
1323 |
636 |
0.50 (0.32, 0.69) |
97.82 |
0.00 |
North America |
9 |
2899 |
629 |
0.24 (0.15, 0.34) |
96.42 |
0.00 |
Asia |
20 |
2038 |
982 |
0.54 (0.40, 0.68) |
97.39 |
0.00 |
Latitude |
|
|
|
|
|
|
Low |
3 |
307 |
217 |
0.50 (0.12, 0.88) |
- |
- |
Mid-Low |
13 |
1749 |
636 |
0.56 (0.38, 0.72) |
97.86 |
0.00 |
Mid |
27 |
4608 |
1445 |
0.39 (0.29, 0.50) |
97.85 |
0.00 |
Mid-High |
2 |
331 |
138 |
0.42 (0.37, 0.47) |
- |
- |
VD Classify |
|
|
|
|
|
|
<30ng/ml |
2 |
199 |
170 |
0.87 (0.82, 0.92) |
- |
- |
<25ng/ml |
1 |
104 |
83 |
0.80 (0.71, 0.87) |
- |
- |
<20ng/ml |
29 |
3143 |
1394 |
0.49 (0.39, 0.60) |
96.87 |
0.00 |
<15ng/ml |
6 |
1237 |
279 |
0.24 (0.11, 0.41) |
97.31 |
0.00 |
<12ng/ml |
4 |
2099 |
386 |
0.14 (0.09, 0.20) |
89.17 |
0.00 |
<10ng/ml |
3 |
213 |
124 |
0.67 (0.26, 0.97) |
- |
- |
Seasons |
|
|
|
|
|
|
Winter |
6 |
530 |
240 |
0.50 (0.37, 0.64) |
85.06 |
0.00 |
Summer |
6 |
530 |
99 |
0.17 (0.08, 0.27) |
81.52 |
0.00 |
Spring |
4 |
412 |
117 |
0.28 (0.23, 0.33) |
4.19 |
0.37 |
Fall |
4 |
412 |
74 |
0.20 (0.12, 0.29) |
53.33 |
0.09 |