nutrients

Review
The Effect of Vitamin D Supplementation on
Glycemic Control in Type 2 Diabetes Patients:
A Systematic Review and Meta-Analysis
Xinyi Li ID
, Yan Liu, Yingdong Zheng, Peiyu Wang and Yumei Zhang * ID

School of Public Health, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China;
[email protected] (X.L.); [email protected] (Y.L.); [email protected] (Y.Z.);
[email protected] (P.W.)
* Correspondence: [email protected]; Tel.: +86-134-2613-4251

Received: 14 January 2018; Accepted: 15 March 2018; Published: 19 March 2018

Abstract: Observational studies have indicated an inverse association between vitamin D levels
and the risk of diabetes, yet evidence from population interventions remains inconsistent. PubMed,
EMBASE, Cochrane Library and ClinicalTrials.gov were searched up to September 2017. Data
from studies regarding serum 25(OH)D, fasting blood glucose (FBG), hemoglobin A1c (HbA1c),
fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were pooled.
Twenty studies (n = 2703) were included in the meta-analysis. Vitamin D supplementation resulted in
a significant improvement in serum 25(OH)D levels (weighted mean difference (WMD) = 33.98;
95%CI: 24.60–43.37) and HOMA-IR (standardized mean difference (SMD) = −0.57; 95%CI:
−1.09~−0.04), but not in other outcomes. However, preferred changes were observed in subgroups
as follows: short-term (WMDFBG = −8.44; 95%CI: −12.72~−4.15), high dose (WMDFBG = −8.70;
95%CI: −12.96~−4.44), non-obese (SMDFasting insulin = −1.80; 95%CI: −2.66~−0.95), Middle
Easterners (WMDFBG = −10.43; 95%CI: −14.80~−6.06), baseline vitamin D deficient individuals
(WMDFBG = −5.77; 95%CI: −10.48~−1.05) and well-controlled HbA1c individuals (WMDFBG = −4.09;
95%CI: −15.44~7.27). Vitamin D supplementation was shown to increase serum 25(OH)D and reduce
insulin resistance effectively. This effect was especially prominent when vitamin D was given in large
doses and for a short period of time, and to patients who were non-obese, Middle Eastern, vitamin D
deficient, or with optimal glycemic control at baseline.

Keywords: vitamin D; type 2 diabetes; glycemic control; meta-analysis

1. Introduction
Type 2 diabetes (T2D) has become a global health care problem. In 2016, there were 38 million
diabetes patients worldwide, with 2.8 million years lived with disability [1]. Efforts have been devoted
to finding innovative approaches for diabetes prevention and treatment, and a recent focus has been on
vitamin D supplementation. Observational studies have indicated an association between vitamin D
deficiency and the onset and progression of T2D as well as future macrovascular events [2–6]. Moreover,
in vivo and in vitro studies have proposed potential roles of vitamin D in glucose metabolism, e.g.,
stimulating insulin secretion via the vitamin D receptor on pancreatic β cells; modulating immune
responses and lowering systematic inflammation; and reducing peripheral insulin resistance through
vitamin D receptors in the muscles and liver [7–9]. However, evidence from interventional studies
at a population level have been inconclusive. Recently, three meta-analyses observed no benefits of
vitamin D supplementation on glycemic indices and insulin resistance except for a modest reduction of
hemoglobin A1c (HbA1c) (0.32–0.39%), although they did not separate intramuscular injections from
oral supplementation, or fortified food from nutrient supplementation alone [10–12]. Additionally,

Nutrients 2018, 10, 375; doi:10.3390/nu10030375 www.mdpi.com/journal/nutrients

Nutrients 2018, 10, 375 2 of 15

co-supplementation of calcium plus vitamin D, versus a control group given vitamin C further
introduced more heterogeneity in the studies. On the contrary, Mirhosseini et al. found significant
positive effects of vitamin D supplementation on fasting blood glucose (FBG), HbA1c and a homeostasis
model assessment of insulin resistance (HOMA-IR), yet it calculated one study with considerable
influence twice in the pooled analysis and combined results reported as median and interquartile
range together with those reported as mean and standard deviation [13].
The aim of the current review was to evaluate the effects of oral vitamin D supplementation on
glycemic control in T2D patients compared with a placebo, and to assess various factors’ influences on
supplementation effects.

2. Methods
This systematic review was performed according to the Preferred Reporting Items for Systematic
Reviews and Meta-analysis (PRISMA) statement [14].

2.1. Selection of Studies

Studies were regarded as eligible if they (1) were randomized controlled trials that evaluated the
glycemic effect of vitamin D supplementation in T2D patients; (2) used oral vitamin D formulations
containing cholecalciferol or ergocalciferol; (3) reported at least one of the following primary outcomes
of interest: serum 25(OH)D concentration, FBG, HbA1c, HOMA-IR and fasting insulin; and (4) had a
trial length ≥ 8 weeks.
Exclusion criteria were as follows: (1) intramuscular delivery of vitamin D with different
absorptions between oral and intramuscular routes; (2) studies involving participants with type 1
diabetes, gestational diabetes or conditions that could potentially alter vitamin D metabolism
(e.g., chronic kidney disease Stage 4 or higher, or hyperparathyroidism); (3) studies involving
participants < 18 years; (4) studies in which non placebo controls, such as calcium, were allowed
when given to both groups; and (5) observational studies, review articles, case reports, editorials and
poster abstracts.

2.2. Data Sources and Search Strategy

We searched databases including PubMed, EMBASE and Cochrane Central Register of Controlled
Trials (CENTRAL) from inception to September 2017 to identify relevant studies published in English.
We also searched NIH’s clinical trials registry (www.clinicaltrials.gov) for unpublished but completed
trials. The reference lists of the index reviews were also reviewed to identify additional eligible studies.
The following search strategy was run in PubMed and tailored to each database when necessary:
(randomized controlled trial OR controlled clinical trial OR random OR clinical trial OR controlled trial
OR RCT NOT review NOT animal) AND (vitamin D OR vitamin D2 OR vitamin D3 OR cholecalciferol
OR ergocalciferol OR alphacalcidol OR alfacalcidol OR paricalcitol OR doxercalciferol OR calcitriol
OR 25-Hydroxyvitamin D) AND (diabetes OR diabetes mellitus OR T2DM OR hyperglycemia OR
hyperglycaemia OR glucose OR HbA1c OR glycated hemoglobin OR insulin resistance OR insulin
sensitivity OR HOMA OR glucose homeostasis OR insulin secretion OR insulin OR beta-cell function
OR glycemic control OR glycemic control OR glucose tolerance OR glucose metabolism).

2.3. Data Extraction and Risk of Bias Assessment

Pairs of independent reviewers screened the titles and the abstracts of each study prior to full
text screening of candidate studies. Any discrepancies in terms of the decision on a given study
were dealt with via discussion and, if necessary, arbitration by a third reviewer. For all included
studies, two reviewers independently extracted information regarding basic information (authors, year,
country, sample size, attrition rate), participants’ characteristics (gender, age, body mass index (BMI),
ethnicity), intervention features (treatment, type, dose, and therapy duration) and results (baseline
and post-test serum vitamin D, FBG, HbA1c and fasting insulin). For studies assessing the differences
Nutrients 2018, 10, 375 3 of 15

between a placebo, a vitamin D, a calcium and a vitamin D plus calcium group, we only used the
vitamin D and placebo groups.
Two reviewers independently assessed the risk of bias of trials according to the Cochrane risk
of bias assessment tool and assigned “high” or “low” or “unclear” to the following items: random
sequence generation; allocation concealment; blinding of participants and personnel; blinding of
outcome assessment; selective reporting; and other sources of bias [15].

2.4. Data Analysis and Rating Quality of Evidence

We combined the pre- and post-changes of each outcome with the random effects model due to
diverse participant demographics and intervention characteristics; this was reported with weighted
mean differences (WMD) for scales that were the same, or standardized mean differences (SMD)
otherwise. Substantial heterogeneity was indicated as p < 0.1 in the χ2 test and an I2 > 50% [16].
Sensitivity analyses were completed to detect the robustness of the statistical results and analyze
possible sources of heterogeneity, using an alternative summary statistic (standardized versus weighted
mean difference) and statistical model (fixed versus random effects model), excluding studies on a one
by one basis, followed by the exclusion of those with a high risk of bias.
When an adequate number of studies ensuring the power of tests, Funnel plots and Egger’s
test had been conducted, to identify any publication bias. Subgroup analyses were performed to
explore impacts of certain characteristics: supplementation dose, duration, ethnicity, BMI status
(normal ≤ 24.9 kg/m2 , overweight 25–29.9 kg/m2 , obese ≥ 30 kg/m2 ) [17], baseline vitamin D status
(deficiency < 50 nmol/L, insufficiency 50–75 nmol/L, sufficiency > 75 nmol/L) [18] and baseline
HbA1c condition. Univariate and multivariate meta-regressions, if possible, were performed to detect
whether %female, BMI, serum vitamin D concentration, FBG, or HbA1c at baseline were associated
with the results. All data were analyzed using Stata 14.0 and Cochrane Review Manager (RevMan) 5.3.
The GRADE approach was used to rate the quality of evidence for each outcome. The strength of
the evidence was categorized as high, moderate, low or very low [19].

3. Results
Of the 1963 articles, 32 remained as potentially eligible after title and abstract screening; of these,
20 randomized controlled trials involving 2703 participants were included in the review (Figure 1) [20–39].

3.1. Study Characteristics

Characteristics of all 20 studies are presented in Table 1. Among those, eight enrolled Middle
Easterners [21–23,29,31,34,36,38], four enrolled individuals from other Asian countries [26,32,33,39],
seven enrolled other ethnicities [20,24,25,27,28,35,37] and the one was conducted in 33 countries [30],
with participants mainly from 48 to 67 years old. The intervention duration ranged from 2 to 6 months
(median was 3 months). Vitamin D3 was used in 17 studies and vitamin D2 in one study [35], while
the other two failed to report the type in detail [31,38]. Only two trials applied vitamin D and calcium
co-supplementation (same doses of calcium also given to control groups) [32,33]. The other studies
provided vitamin D supplementation alone.

3.2. Risk of Bias

The risk of bias assessments of the included studies are summarized in Figure 2. Ten, six and
four studies were categorized as having high, low and unclear risks of bias, respectively. Attrition and
reporting bias were primary sources of bias.
Nutrients 2018, 10, 375 4 of 15

Table 1. Characteristics of studies included in the meta-analysis.

Baseline Vitamin D
Participants Female Attrition Age(y) BMI (kg/m2 ) 1 Study Vitamin Dose &
Author Year Country Level (nmol/L) Supplementation Outcomes 2
(T/C 1 ) (%) Rate (%) (Mean ± SD) (Mean ± SD) Duration D Type Frequency
(Mean ± SD)
T: 50.34 ± 6.71 T: 27.33 ± 1.64 T: 37.26 ± 15.21
Baziar 2014 [21] Iran 41/40 33.3 6.9 8 weeks Vit D VD3 50,000 IU/week 1 2 3 4
C: 52.75 ± 6.34 C: 27.25 ± 1.35 C: 40.30 ± 14.43
T: 27.79 ± 10.81
Maggi 2014 [28] Italy 14/16 23.3 0.0 69 29 24 weeks Vit D VD3 300,000 IU once 1 2
C: 33.73 ± 17.13
T: 52.5 ± 2.2 T: 17.9 ± 2.3
Anyanwu 2016 [20] Nigeria 17/16 57.6 21.4 NR 1 12 weeks Vit D VD3 3000 IU/day 1 2
C: 51.1 ± 1.9 C: 19.2 ± 5.5
T: 53.8 ± 8.9 T: 28.3 ±4.4 T: 112.6 ± 83.5
Eftekhari 2011 [22] Iran 35/35 50.0 0.0 12 weeks Vit D VD3 20 IU/day 1 2 3 4
C: 52.4 ± 7.8 C: 27.0 ± 3.4 C: 100.1 ± 77.7
Ghavamzadeh T: 52.26 ± 2.09 T: 28.9 ± 0.86 T: 21.46 ± 4.65
Iran 26/25 58.8 57.5 14 weeks Vit D VD3 400 IU/day 1 3
2014 [23] C: 49.28 ± 2.00 C: 27.9 ± 0.93 C: 22.16 ± 5.32
T: 57.7 ± 9.7 T: 32.8 ± 6.8 T: 60.0 ± 14.0
Jorde 2009 [24] Norway 16/16 43.8 11.1 6 months Vit D VD3 40,000 IU/week 1 2 3 4
C: 54.8 ± 5.9 C: 31.3 ± 6.3 C: 58.5 ± 21.0
11,200 IU/day ×
T: 61.6 ± 4.4 T: 35.3 ± 2.9 T: 31.0 ± 4.9 2 weeks, then
Kampmann 2014 [25] Denmark 7/8 53.3 6.3 12 weeks Vit D VD3 1 2 3 5
C: 57 ± 4.5 C: 32.4 ± 2.0 C: 34.8 ± 3.8 5600 IU/day ×
10 weeks
The T: 67 ± 8 T: 28.7 ± 4.6 T: 60.6 ± 23.3
Krul-Poel 2015 [27] 129/132 34.9 5.1 6 months Vit D VD3 50,000 IU/month 1 2 3
Netherlands C: 67 ± 9 C: 28.5 ± 4.5 C: 59.1 ± 23.2
T: 83.9 ± 52
Nasri 2014 [29] Iran 30/30 71.7 0.0 55 ± 10.7 NR 12 weeks Vit D VD3 50,000 IU/week 1 3
C: 105.7 ± 64
T: 54.5 ± 7.4 T: 24.4 ± 5.0 T: 32.0 ± 7.8
Ryu 2014 a [32] Korea 32/30 NR 23.5 6 months Vit D + Ca VD3 2000 IU/day 1 2 3
C: 56.7 ± 7.9 C: 25.3 ± 3.4 C: 27.8 ± 6.8
6000 IU/day ×
T: 49 ± 8 T: 37.9 ± 6.1 T: 28.5 ± 9.2 3 months, then
Sadiya 2015 [34] UAE1 43/39 81.6 5.7 6 months Vit D VD3 1 2 3
C: 48 ± 8 C: 37.6± 7.7 C: 30.5 ± 11.3 3000 IU/day ×
3 months
T: 50.03 T: 27.94 ± 0.92 T: 40.43 ± 4.97
Yousefi 2014 [38] Iran 28/30 37.9 10.8 2 months Vit D NR 4000 IU/day 1 2 3 4 5
C: 49.90 C: 28.75 ± 0.95 C: 38.06 ± 5.77
T: 50.2 ± 6.6 T: 30.5 ± 5.3 T: 28.0 ± 13.9
Tabesh 2014 [36] Iran 29/30 50.0 1.7 2 months Vit D VD3 50,000 U/week 4
C: 51.0 ± 6.1 C: 30.3 ± 3.8 C: 45.7 ± 16.4
T: 65.3 ± 11.1 T: 31.1 ± 6.7 T: 41 ± 14
Witham 2010 [37] UK 1 19/21 32.8 2.4 4 months Vit D VD3 100,000 IU once 1 3 4
C: 66.7 ± 9.7 C: 33.3 ± 7.1 C: 45 ± 17
T:54.8 ± 7.6 T: 25.0 ± 3.3 T: 28.08 ± 13.26
Ryu 2014 b [33] Korea 64/65 50.0 18.4 6 months Vit D +Ca VD3 2000 IU/day 1 2 3
C:55.9 ± 8.1 C: 25.6 ± 3.6 C: 26.26 ± 10.14
T: 66.7 ± 6.7 T: 30.6 ± 5.3
Punthakee 2012 [30] 33 countries 607/614 40.9 0.9 NR 4 months Vit D VD3 1000 IU/day 2 3
C: 66.6 ± 6.3 C: 30.7 ± 5.3
1 T: 64.9 ± 10.3 T: 31.7 ±6.4 T: 40.2 ± 10.3
Sugden 2008 [35] UK 17/17 47.1 21.0 2 months Vit D VD2 100,000 IU once 1 3
C: 63.5 ± 9.5 C: 31.7 ± 6.5 C: 36.4 ± 8.5
T: 28.08 ± 3.46 50,000
Rashidi 2016 [31] Iran 48/46 41.7 13.0 47 NR 3 months Vit D NR 3
C: 28.65 ± 2.9 IU/2 weeks
T: 73.27 ± 2.06 T: 24.08 ± 0.73 T: 27.14 ± 4.68
Kim 2014 [26] Korea 11/13 100.0 13.3 3 months Vit D VD3 1200 IU/day 3 4 5
C: 70.08 ± 1.37 C: 23.72 ± 0.68 C: 30.32 ± 7.28
T: 25.05 ± 3.30 T: 32.21 ± 21.76
Zhou 2015 [39] China 31/31 38.7 9.7 58.85 ± 6.18 3 months Vit D VD3 1000 IU/day 1 3
C: 24.09 ± 3.77 C: 34.58 ± 20.18
1 Abbreviations: T: treatment group; C: control group; NR: not reported; UAE: The United Arab Emirates; UK: United Kingdom; BMI: body mass index.2 1 serum vitamin D levels;
2 fasting blood glucose; 3 HbA1c; 4 HOMA-IR; 5 fasting serum insulin.
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Nutrients 2018, 10, 375 5 of 15

Figure 1. Flow
Figure 1. Flow diagram
diagram of
of search
search and
and selection
selection of
of studies.
studies.

3.3. The Effect on Serum Vitamin D Level

Sixteen trials
trials(n (n = 1284)
= 1284) reported
reported the inchange
the change in serum
serum vitamin vitamin
D level D intervention
after the level after [20–the
intervention [20–25,27–29,32–35,37–39].
25,27–29,32–35,37–39]. There was
There was a significant a significant
increase increase
in the serum in theDserum
vitamin vitamin
level in D level
the vitamin D
in the vitamin D supplementation
supplementation group (WMD = group 33.98; (WMD
95%CI:= 24.60–43.37;
33.98; 95%CI:p 24.60–43.37; p < 0.001)
< 0.001) (Figure 3A), (Figure 3A),
albeit with
albeit with heterogeneity
substantial substantial heterogeneity
(p < 0.001; I2(p= < 0.001;
97%). I2 = 97%).
Subgroup Subgroup
analyses analyses
suggested suggested
similar findingssimilar
in all
findings
subgroups in except
all subgroups except for
for participants participants
with with sufficient
sufficient vitamin D priorvitamin D prior to the
to the intervention intervention
(Table 2).
(Table 2).
3.4. The Effect on FBG
3.4. The Effect on FBG
Thirteen trials (n = 2198) measured the effect of vitamin D supplementation on FBG [20–22,24–
28,30,32–34,38].trials
Thirteen (n we
Overall, = 2198)
observedmeasured the effect
no difference in FBGofreduction
vitamin between
D supplementation
intervention and on
FBG [20–22,24–28,30,32–34,38]. Overall, we observed no difference in FBG reduction
control groups (WMD = −3.59; 95%CI: −7.94–0.76; p = 0.11). The heterogeneity was moderate (p = 0.005; between
intervention and control
I2 = 57%) (Figure groups (WMD
3B). However, vitamin =− D3.59; 95%CI: −7.94–0.76;
supplementation p = 0.11).
produced The heterogeneity
significant decreases inwas the
moderate (p = 0.005; I 2 = 57%) (Figure 3B). However, vitamin D supplementation produced significant
following subgroups: Middle Easterners, dose > 2000 IU/day, study duration ≤ 3 months and baseline
decreases
vitamin D in the following
deficient (Table 2).subgroups: Middle Easterners, dose > 2000 IU/day, study duration ≤
3 months and baseline vitamin D deficient (Table 2).
3.5. The Effect on HbA1c
3.5. The Effect on HbA1c
Changes in HbA1c was assessed in 15 trials (n = 2454) [22–25,27,29–35,37–39]. Compared with
Changes in HbA1c was assessed in 15 trials (n = 2454) [22–25,27,29–35,37–39]. Compared with
controls, the difference in HbA1c reduction was insignificant (WMD = −0.11; 95%CI: −0.35–0.13; p =
controls, the difference in HbA1c reduction was insignificant (WMD = −0.11; 95%CI: −0.35–0.13;
0.38) (Figure 3C) and had high heterogeneity (p < 0.001; I2 = 92%). Nevertheless, effects shown in other
p = 0.38) (Figure 3C) and had high heterogeneity (p < 0.001; I2 = 92%). Nevertheless, effects shown in
ethnicities and obesity subgroups were significantly in favor of the control group (Table 2).
other ethnicities and obesity subgroups were significantly in favor of the control group (Table 2).
Nutrients 2018, 10, 375 6 of 15

Table 2. Subgroup analyses.

Serum Vitamin D FBG 1 HbA1c 1 HOMA-IR 1 Fasting Insulin

Subgroups
WMD 1 95%CI p WMD 95%CI p WMD 95%CI p SMD 95%CI p SMD 95%CI p
Ethnicity
Middle Easterners 40.03 (27.71, 52.34) <0.001 −10.43 (−14.80, −6.06) <0.001 −0.36 (−0.87, 0.15) 0.170 −0.65 (−1.37, 0.08) 0.081 −1.48 (−3.59, 0.63) 0.170
Other Asians 32.23 (22.72, 41.73) <0.001 −1.83 (−7.80, 4.15) 0.549 −0.18 (−0.77, 0.42) 0.565 −1.59 (−2.42, −0.76) <0.001 −1.80 (−2.66, −0.95) <0.001
Other ethnicities 30.72 (12.25, 49.19) 0.001 1.67 (−1.50, 4.85) 0.301 0.17 (0.00, 0.33) 0.044 0.01 (−0.45, 0.47) 0.961 1.67 (0.47, 2.87) 0.006
BMI 1
Normal 2 38.20 (27.89, 48.51) <0.001 −5.21 (−11.76, 1.34) 0.119 0.16 (−0.13, 0.45) 0.274 −1.59 (−2.42, −0.76) <0.001 −1.80 (−2.66, −0.95) <0.001
Overweight 2 33.01 (23.94, 42.09) <0.001 −5.71 (−14.09, 2.66) 0.181 −0.32 (−0.70, 0.06) 0.102 −0.84 (−1.78, 0.11) 0.084 −1.48 (−3.59, 0.63) 0.170
Obese 2 39.34 (18.71, 59.97) <0.001 0.64 (−3.32, 4.60) 0.751 0.22 (0.05, 0.38) 0.010 −0.04 (−0.38, 0.30) 0.825 1.67 (0.47, 2.87) 0.006
Dose
≤2000 IU/day 25.16 (18.16, 32.16) <0.001 0.35 (−3.18, 3.89) 0.844 −0.21 (−0.53, 0.11) 0.189 −0.50 (−1.35, 0.35) 0.249 −1.80 (−2.66, −0.95) <0.001
>2000 IU/day 48.45 (29.94, 66.97) <0.001 −8.70 (−12.96, −4.44) <0.001 0.05 (−0.41, 0.51) 0.832 −0.64 (−1.42, 0.14) 0.107 −0.50 (−2.44, 1.45) 0.617
Duration
≤3 m 35.51 (18.84, 52.18) <0.001 −8.44 (−12.72, −4.15) <0.001 −0.11 (−0.42, 0.21) 0.590 −0.81 (−1.49, −0.13) 0.019 —- —- —-
>3 m 32.61 (24.951, 40.271) <0.001 2.04 (-0.94, 5.02) 0.180 −0.12 (−0.54, 0.31) 0.509 0.01 (−0.45, 0.47) 0.961 —- —- —-
Baseline 25(OH)D
<50 nmol/L 31.65 (21.31, 41.99) <0.001 −5.77 (−10.48, −1.05) 0.017 −0.11 (−0.47, 0.26) 0.563 −0.81 (−1.51, −0.11) 0.024 —- —- —-
50–75 nmol/L 48.33 (29.46, 67.21) <0.001 3.37 (−1.81, 8.54) 0.202 −0.00 (−0.14, 0.14) 1.000 0.03 (−0.67, 0.72) 0.941 —- —- —-
>75 nmol/L 32.98 (−39.64, 105.06) 0.373 −18.00 (−43.24, 7.24) 0.162 −0.39 (−0.78, 0.00) 0.052 −0.08 (−0.55, 0.39) 0.737 —- —- —-
Baseline HbA1c 1
≤7% 45.27 (25.39, 65.15) <0.001 −4.09 (−15.44, 7.27) 0.481 −0.17 (−0.86, 0.52) 0.635 −0.27 (−0.65, 0.11) 0.160 0.55 (−1.49,2.59) 0.53
>7% 29.86 (18.22, 41.49) <0.001 −3.53 (−9.42, 2.35) 0.240 −0.08 (−0.34, 0.18) 0.548 −0.65 (−1.83, 0.54) 0.286 −2.57 (−3.27, −1.87) <0.001
Overall 33.98 (24.60, 43.37) <0.001 −3.59 (−7.94, 0.76) 0.105 −0.11 (−0.35, 0.13) 0.381 −0.58 (−1.11, −0.05) 0.033 −0.83 (−2.31, 0.64) 0.268
1 Abbreviations: WMD: weighted mean difference; SMD: standardized mean difference; FBG: fasting blood glucose; HbA1c: hemoglobin A1c; HOMA-IR: homeostatic model assessment of
insulin resistance; BMI: Body mass index. 2 normal: 18.5–24.9kg/m2 ; overweight: 25.0–29.9 kg/m2 ; obese: ≥30.0 kg/m2 . “—-”: subgroup inapplicable to this outcome.
Nutrients 2018, 10, x FOR PEER REVIEW 8 of 16
Nutrients 2018, 10, 375 7 of 15

Figure
Figure 2. Risk of
2. Risk of bias
bias assessment
assessment ofof the
the included
included studies
studies using
using the
the Cochrane
Cochrane Collaboration
Collaboration tool
tool across
across
seven
seven domains.
domains. Risk
Risk of
of bias
bias levels: low (green),
levels: low (green), unclear
unclear (yellow),
(yellow), high
high (red).
(red).

3.6. The Effect on HOMA-IR

The effect
effectofofvitamin
vitamin D supplementation
D supplementation on HOMA-IR
on HOMA-IR was evaluated
was evaluated in sevenintrials
seven
(n =trials
409)
(n = 409) [21,22,24,26,36–38].
[21,22,24,26,36–38]. We foundWe foundreduction
a larger a larger reduction
of HOMA-IRof HOMA-IR in intervention
in intervention groups than groups than
in placebo
in placebo
groups (SMDgroups (SMD
= −0.57; = −0.57;
95%CI: 95%CI: p−=1.09~
−1.09~−0.04; 0.03)−although
0.04; p = 0.03) although thewas
the heterogeneity heterogeneity
significant was
(p <
significant 2 = 83%) (Figure 3D). Similar results were demonstrated in subgroups of
0.001; I2 = 83%)
(p <(Figure
0.001; I3D). Similar results were demonstrated in subgroups of duration ≤ 3 months,
duration ≤ 3 months,
other Asians, normal BMI,
otherand baseline
Asians, vitamin
normal BMI, D
anddeficient
baseline(Table 2). D deficient (Table 2).
vitamin

3.7. The Effect of Fasting Insulin

Only four (n = 364) out of 20 randomized controlled trials measured fasting insulin [21,25,26,38].
Results showed no significant effect of vitamin D supplementation on fasting insulin (SMD = −0.84;
Nutrients 2018, 10, 375 8 of 15

3.7. The Effect of Fasting Insulin

Only four (n = 364) out of 20 randomized controlled trials measured fasting insulin [21,25,26,38].
Nutrients 2018, 10, x FOR PEER REVIEW
Results showed no significant effect of vitamin D supplementation on fasting insulin (SMD =9− of 16
0.84;
95%CI: −2.27–0.60; p = 0.25) (Figure 3E). The heterogeneity was relatively high (p < 0.001;2 I = 93%). 2
95%CI: −2.27–0.60; p = 0.25) (Figure 3E). The heterogeneity was relatively high (p < 0.001; I = 93%).
However, preferred changes were manifested in the following subgroups: other Asians, normal BMI,
However, preferred changes were manifested in the following subgroups: other Asians, normal BMI,
vitamin
vitaminD dose
D dose ≤ 2000 IU/day
≤ 2000 IU/dayand
andbaseline
baseline HbA1c
HbA1c > 7%. In
> 7%. In contrast,
contrast,other
otherethnicities
ethnicitiesand
andobesity
obesity
subgroups
subgroups showed
showed preferred changes
preferred changesthat
thatwere
weresignificantly
significantly in
in favor
favor of the control
of the controlgroup
group(Table
(Table2).
2).

Figure
Figure 3. Effect
3. Effect of of vitamin
vitamin DDsupplementation
supplementationon on(A)
(A) serum vitamin
vitamin DDlevel;
level;(B)
(B)fasting
fastingblood
bloodglucose;
glucose;
(C) (C) hemoglobin
hemoglobin A1c;
A1c; (D)(D) homeostasismodel
homeostasis modelassessment
assessment of insulin
insulin resistance
resistanceandand(E)
(E)fasting
fastinginsulin.
insulin.
(The(The
sizesize
of of
boxbox representsthe
represents theweight
weightofofeach
each study,
study, and
and the
the lateral
lateral tips
tips of
of diamond
diamondshows showsthethe
confidence
confidence interval
interval of of
thethe pooled
pooled result.)
result.)
Nutrients 2018,
Nutrients 2018, 10,
10, 375
x FOR PEER REVIEW 10 of 15
9 of 16

3.8. Meta-Regression
3.8. Meta-Regression
The univariate meta-regression suggested that a higher baseline FBG was associated with a
The
better univariate
effect meta-regression
of vitamin suggested
D supplementation that (p
in FBG a higher
= 0.04).baseline
However, FBG was
this associatedvanished
association with a better
after
effect of vitamin D supplementation in FBG (p = 0.04). However, this
adjusting for % female, BMI, baseline serum vitamin D and HbA1c in the multivariate meta-association vanished after
adjusting
regressionfor(p% female, BMI, baseline serum vitamin D and HbA1c in the multivariate meta-regression
= 0.10).
(p = 0.10).
3.9. Sensitivity Analyses
3.9. Sensitivity Analyses
Findings regarding serum vitamin D levels and glycemic indices basically remained robust in
the sensitivityregarding
Findings serum vitamin
analysis. However, D levels and
the significant effectglycemic indices
of vitamin basically remained
D supplementation robust in
on HOMA-IR
the sensitivity analysis. However, the significant effect of vitamin D supplementation
disappeared when excluding Baziar et al. [21], Yousefi et al. [38], Kim et al. [26] and trials carrying aon HOMA-IR
disappeared
high risk of when excluding On
bias [24,26,36]. Baziar
the etcontrary,
al. [21], Yousefi et al. [38], Kim
the improvement et al.became
of FBG [26] andsignificant
trials carrying
after
aKampmann
high risk of et bias [24,26,36].
al. and Krul-Poel On
et the contrary,
al. were the improvement
excluded of FBG
and an alternative becamestatistic
summary significant
was after
used
Kampmann et al. and
[25,27]. In addition, Krul-Poel
excluding et al.et were
Yousefi excluded
al. from and an alternative
the meta-analysis summary
of FBG resulted in astatistic
decrease was
in
used [25,27]. In addition, excluding
heterogeneity from 57% to 33% [38]. Yousefi et al. from the meta-analysis of FBG resulted in a decrease
in heterogeneity from 57% to 33% [38].
3.10. Publication Bias
3.10. Publication Bias
The funnel plot and statistical test showed no evidence of a publication bias (Figure 4; Egger’s
The funnel plot and statistical test showed no evidence of a publication bias (Figure 4; Egger’s
test: p = 0.81; 95%CI: −5.39–6.77).
test: p = 0.81; 95%CI: −5.39–6.77).
3.11. Quality
3.11. Quality of
of Evidence
Evidence
Table33 presents
Table presentsthe
the quality
quality of
of evidence
evidence by
by outcome,
outcome, assessed
assessed with
with the
the GRADE
GRADE system.
system. Evidence
Evidence
quality was classified as low for serum vitamin D level and HOMA-IR, and very low for FBG,
quality was classified as low for serum vitamin D level and HOMA-IR, and very low for FBG, HbA1c HbA1c
and fasting insulin.
and fasting insulin.

Figure 4. Funnel
Figure 4. Funnel plot
plot of
of serum
serum vitamin
vitamin D D changes
changes in
in patients
patients with
with type
type 22 diabetes
diabetes receiving
receiving vitamin
vitamin
D
D supplementation
supplementation based treatment
treatment versus controls
controls in
in 16
16 randomized
randomized controlled
controlled trials
trials (Each
(Each circle
circle
represents
representsaa study,
study,with
withthe
they-axis
y-axisrepresenting
representingthethestandard
standarderror
errorof
ofthe
the study
study and
and the
the x-axis
x-axis meaning
meaning
the
the weighted
weighted mean
mean difference
difference ofof it.
it. The
The funnel-shaped
funnel-shaped distribution is created by by studies
studies with
with high
high
precision
precision plotted near the average, and studies with low precision spread evenly on both sides of the
plotted near the average, and studies with low precision spread evenly on both sides of the
average.
average. Deviation
Deviation from
from this
this shape
shape indicates
indicates publication
publication bias).
bias).
Nutrients 2018, 10, 375 10 of 15

Table 3. Evidence quality rated using the GRADE approach.

Outcomes No. of Studies Limitations Inconsistency Indirectness Imprecision Publication Bias Evidence Quality
Serum vitamin D levels 16 Serious 2,3,4 Serious 5 Not serious Not serious Not found ⊕⊕ Low
FBG 1 13 Serious 2,3,4 Serious 5 Not serious Serious 6 Not found ⊕ Very low
HbA1c 1 15 Serious 3,4 Serious 5 Not serious Serious 6 Not found ⊕ Very low
HOMA-IR 1 7 Serious 3,4 Serious 5 Not serious Not serious Not assessed 7 ⊕⊕ Low
Fasting serum insulin 4 Serious 4 Serious 5 Not serious Serious 6 Not assessed 7 ⊕ Very low
1Abbreviations: FBG: fasting blood glucose; HbA1c: hemoglobin A1c; HOMA-IR: homeostasis model assessment of insulin resistance. 2 Had single-blind randomized controlled trial
design; 3 had reporting bias; 4 had attrition bias. 5 A significant heterogeneity was observed in this meta-analysis. 6 Wide confidence interval, including values in favour of the experimental
group and values in favour of the control group. 7 Not assessed because a limited number of studies were included in the meta-analyses on HOMA-IR and fasting serum insulin.
Nutrients 2018, 10, 375 11 of 15

4. Discussion
This meta-analysis found that compared with placebo, oral vitamin D supplementation yielded
better effects on HOMA-IR in T2D patients, although the result was not very robust when excluding
studies one by one, and it was subject to substantial heterogeneity partially from the diversity between
durations, ethnicities, BMIs and baseline vitamin D statuses across the studies. In contrast, we observed
no benefit of vitamin D supplementation in regard to improving FBG, HbA1c and fasting insulin.
However, despite the overall null finding, characteristics of the intervention and population greatly
influenced the effects, and significant positive effects emerged in several subgroups.
In terms of the intervention, daily doses of more than 2000 IU/day were consistently associated
with a higher post-test vitamin D status and larger improvement of glycemic indices. The appropriate
dose of vitamin D to achieve non-skeletal benefits still remains unclear. Some observational studies
indicated that supraphysiological dosing of vitamin D could be harmful; however, the most common
dosing of supplementation, 2000 IU/day, was much lower than that, as well as than the debated
dosing required for efficacy, 4000 to 5000 IU/day [13,40]. Under these conditions, the benefits of higher
doses seemed reasonable since high doses increased the chances of correcting vitamin D deficiency or
achieving favorable levels of serum 25(OH)D, confirmed by relatively higher 25(OH)D levels in the
high dose subgroup after intervention (78.52 versus 75.01 nmol/L in the low dose subgroup).
The impact of intervention duration was more ambiguous. Contrary to the findings of Lee et al.
and Mirhosseini et al. that longer durations of supplementation were associated with larger reductions
in glycemic control, which was possibly due to the 2–3 month lifespan of HbA1c [11,13], our results
were in line with Krul-Poel et al. and suggested the effects of vitamin D supplementation were mainly
manifested in durations shorter than 3 months [10]. A potential explanation was the difference in
doses. Actually, the average dose of studies included in the short-term subgroup was much higher
than that in the long-term subgroups (3000 versus 1833 IU/day). In addition, the worsening of diabetic
conditions over time could also attenuate the effects of a long-term intervention.
Apart from intervention features, several characteristics of participants also played important
roles in modifying the efficacy of supplementation. First, significant reductions in FBG and HOMA-IR
were observed in patients with vitamin D deficiency but not in patients with vitamin D insufficiency
or sufficiency. Similarly, we found that even though 25(OH)D increased significantly in all subgroups,
the highest improvement came in vitamin D deficient patients. This might be responsible for
advantages in FBG and HOMA-IR shown in the vitamin D deficient group and could be because in the
sufficient group the excess vitamin D from supplementation was stored in adipose tissue rather than
triggering a further increase in serum level.
Second, vitamin D supplementation produced different effects among various ethnicities with
a similar trend: Middle Easterners showed the biggest reduction, the other Asians the second, and
other ethnicities had the smallest preferred changes. Incongruent results in subgroup analyses of
HOMA-IR and fasting insulin were due to the limited number of studies that measured these variables.
As Wang et al. demonstrated that vitamin D-binding protein polymorphism was associated with
increased susceptibility to T2D in Asians, but not in Caucasians; this might explain the heterogeneous
responses between Asians and the other groups [41]. In addition, studies found that populations with
darker skin color and cultural preferences toward less exposure to the sun, which matched the profile
of Middle Easterners, were at a higher risk of vitamin D deficiency, and that, in turn, was associated
with better effects from supplementation [42,43]. However, none of the studies we included in the
analysis were based on American participants’ data. Thus, the supplementation effect of vitamin D in
this population warrants further investigation in the future.
Third, better glycemic parameters appeared in non-obese patients. This observation is somewhat
opposite to previous studies that suggested that BMI was negatively associated with serum 25(OH)D
concentration and that supplementation would be especially helpful in obese patients [44]; however,
a recent meta-analysis supports our finding that the obese population, even with an inadequate
vitamin D status, does not benefit more from supplementation beacause of doses trapped in their
Nutrients 2018, 10, 375 12 of 15

fat mass [12,13]. However, our data suggest a different mechanism because although the entry level
baseline vitamin D status of the obese subgroup was slightly lower than the non-obese subjects’
baseline status (40.14 vs. 45.05 nmol/L), the relationship was reversed in the post-test analysis (obese
89.96 versus non-obese 75.96 nmol/L), in contrast to the previously published hypothesis.
Finally, optimal baseline glycemic control, HbA1c ≤ 7% to be specific, was associated with
preferred effects of vitamin D supplementation on serum 25(OH)D levels, FBG and HbA1c.
The HOMA-IR and fasting insulin data did not support this finding, but the fact that they were
based on a small number of studies reduced their credibility. Nevertheless, Krul-Poel et al. and Soric et al.
reported that significant improvements in glucose metabolism were only manifested in patients with
poor glycemic control at baseline [10,45]. While they used different cutoffs (HbA1c ≥ 8% and 9%
respectively), applying alternative cutoffs did not change the results in this meta-analysis. Further
investigations are required to clarify this association and explore the underlying explanation for it.
To our knowledge, this meta-analysis is unique because it evaluates the effects of vitamin D
supplementation on beta cell function as measured by fasting insulin. In addition, our analysis takes
into account the most recent years of publications on vitamin D and type 2 diabetes, thereby expanding
our appreciation of fasting blood glucose, hemoglobin A1c and HOMAR-IR by encompassing the
evidence base related to type 2 diabetes. We also used the GRADE system to assess the quality of the
evidence. In addition, we conducted a comprehensive exploration of the influential factors on the
supplementation effects and identified some important ones, like ethnicity, BMI, baseline vitamin D
status and HbA1c. This might encourage further studies to confirm the influence and mechanisms of
these factors and allow the provision of supplementation with appropriate timing and in appropriate
subpopulations. Moreover, the other strength of our study is that we only included randomized
controlled trials with oral vitamin D supplementation, mainly cholecalciferol; thus, the relative
uniformity of the study design and formulation of vitamin D reduced the overall heterogeneity.
However, heterogeneity was still significant owing to the various lengths, doses, and participants
involved in the studies. Other limitations include the fact that most studies did not assess effects of
sun exposure, dietary intake and physical exercise, which may also have influenced vitamin D status.
In addition, the use of antidiabetic medication or insulin therapy might also mask the benefits of
vitamin D, especially in studies that allowed medication adjustment during the intervention period.
Last, some trials included had relatively small sample sizes and short intervention durations.

5. Conclusions
Oral vitamin D supplementation has shown better effects in enhancing serum 25(OH)D levels and
reducing insulin resistance compared with placebos among type 2 diabetes patients. However, it did
not appear to influence FBG, HbA1c and fasting insulin levels. Large dosage, short-term vitamin D
supplementation was most likely to yield preferred changes in vitamin D deficient, non-obese
groups, Asians, especially Middle Easterners, and patients with optimal glycemic control at baseline.
Additional large well-designed studies with longer duration are required to further clarify the impacts
of BMI and baseline HbA1c.

Acknowledgments: This work was supported by the National Natural Science Foundation of China under grant
No. 81573429 and by the Major Programs of Ministry of Science and Technology of China during the 13th Five-Year
Plan Period under grant No. 2017YFD0400602.
Author Contributions: X.L. and Y.L. conducted the literature selection, interpreted the data and wrote the papaer;
Yi.Z. contributed to the data analysis; P.W. and Yu.Z. conceived the study.
Conflicts of Interest: The authors declare no conflict of interest. The founding sponsors had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the
decision to publish the results.
Nutrients 2018, 10, 375 13 of 15

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