Invest Clin 62(2): 159 - 168, 2021 https://doi.org/10.22209/IC.v62n2a06

Corresponding author: Jiacong Xuan. Department of Pharmacy, Tongde Hospital of Zhejiang Province, Xihu Dis-

trict, Hangzhou City, Zhejiang Province, China. Email: wang.medical23@gmail.com

Effect of vitamin D drops combined with

conventional western medicine on children

with Type 1 diabetes mellitus.

Jinjun Xue

and Jiacong Xuan

Department of Paediatrics, Tongde Hospital of Zhejiang Province, Hangzhou City,

Zhejiang Province, China.

Department of Pharmacy, Tongde Hospital of Zhejiang Province, Xihu District,

Hangzhou City, Zhejiang Province, China.

Key words: vitamin D; Type 1 diabetes; helper T-Cells; children.

Abstract. We investigated the therapeutic effect of vitamin D (VitD) drops,

combined with conventional western medicine (insulin), on children with type

1 diabetes mellitus (T1DM). Eighty-four children with T1DM were divided into

a routine group and an observation group (42 cases in each group). The routine

group was treated with insulin; while the observation group was treated with

insulin plus VitD drops. The serum levels of 25-hydroxyvitamin D3 (25(OH)D3)

were compared between the two groups before and after treatment. The daily

dosage of insulin, time needed for glucose control, two-hour postprandial blood

sugar and frequency of episodes of hypoglycemia, were recorded. Flow cytometry

was used to detect and compare interferon gamma (INF-γ), interleukin 4 (IL4),

and INF-γ/IL-4 expression in CD4

T cells of peripheral blood before and after

treatment. Complication rates and readmission rates were documented dur-

ing the six-month follow-ups. VitD drops significantly improved serum vitamin

D levels in the routine group (P<0.05). Compared with this group, the daily

doses of insulin were lower, the time of blood sugar reaching normal ranges was

shorter and the frequency of hypoglycemia was lower in the observation group

(P<0.05). There were significant differences in the 2-hour postprandial blood

sugar levels, and flow cytometry results between the two groups (P<0.05). VitD

drops combined with insulin are beneficial for blood glucose control of children

with T1DM, effectively reducing the insulin utilization rate, reducing the fre-

quency of hypoglycemia, and helping to regulate the Th1/Th2 balance disorder.

Complementary treatment with this vitamin is safe and reliable, and can reduce

the incidence of complications and readmission rates.

160 Xue and Xuan

Investigación Clínica 62(2): 2021

Efecto de gotas de vitamina D, combinadas con la medicina

occidental convencional, en niños con diabetes mellitus Tipo 1.

Invest Clin 2021; 62 (2): 159-168

Palabras clave: vitamina D; diabetes tipo 1; células T auxiliares; niños.

Resumen. Investigamos el efecto terapéutico de gotas de vitamina D

(VitD), combinadas con la insulina de la medicina occidental convencional, en

niños con diabetes mellitus tipo 1 (TDM1). Se clasificaron 84 niños con TDM1

en un grupo de rutina y un grupo de observación (42 casos en cada grupo). El

grupo de rutina fue tratado con insulina; mientras que el grupo de observación

fue tratado con insulina más gotas de VitD. Se compararon los niveles séricos

de 25-hidroxivitamina D3 (25 (OH) D3) entre los dos grupos antes y después

del tratamiento. Se registraron la dosis diaria de insulina, el tiempo en que se

alcanzó el control de la glicemia dentro de rangos normales, la frecuencia de

episodios de hipoglicemia y la glicemia postprandial a las dos horas. Se utilizó

citometría de flujo para detectar y comparar la expresión de interferón gam-

ma (INF-γ), interleucina 4 (IL4) e INF-γ / IL-4 en células T CD4 + de sangre

periférica antes y después del tratamiento. Las tasas de complicaciones y las

tasas de reingreso se documentaron durante el seguimiento de seis meses. Las

gotas de VitD mejoraron significativamente los niveles de vitamina D en suero

en comparación con el otro grupo (P<0,05). En comparación con el grupo de

rutina, la dosis diaria de insulina fue menor, el tiempo en que la glucosa en

sangre alcanzó un rango normal fue más corto y la frecuencia de episodios de

hipoglicemia fue menor en el grupo de observación (P<0,05). Hubo diferencias

significativas en el nivel de glicemia posprandial a las dos horas y los resultados

de la citometría de flujo entre los grupos (P<0,05). Las gotas de VitD combina-

das con insulina son beneficiosas para el control de la glucosa en sangre de los

niños con DM1, reducen eficazmente la tasa de utilización de insulina, reducen

la frecuencia de episodios de hipoglicemia y ayudan a regular el trastorno del

equilibrio Th1 / Th2. El tratamiento combinado con esta vitamina es seguro,

confiable y puede reducir la incidencia de complicaciones así como la tasa de

reingreso.

Received: 16-02-2021 Accepted: 04-04-2021

INTRODUCTION

Type 1 diabetes mellitus (T1DM) is a

kind of autoimmune disease caused by the

pancreas islet B cell injury, and T1DM cases

take up nearly 5% to 10% of the prevalence

of DM. Currently, the increase rat of T1DM

prevalence has reached about 3.9% in the

world, mainly affecting the teenagers aged

between 10 and 14 years old, and bring-

ing about the severe burden on the mental

health of children and the family (1). So

far, insulin replacement therapy is the ma-

jor method for T1DM treatment, with exact

efficacy, yet still fails to control the blood

glucose for some children, or even results

in the occurrence of hypoglycemia (2). Evi-

dence from the clinical practice (3) suggests

Vit D drops combined with insulin in Type 1 diabetes 161

Vol. 62(2): 159 - 168, 2021

that vitamin D (VitD) deficiency is closely

correlated with T1DM and autoimmune dis-

ease, and VitD is found to regulate the in-

nate immune response and antigen present-

ing cells (APCs). Furthermore, existing data

have suggested that regular administration

of VitD is in a positive association with the

decreased prevalence of T1DM in children,

while there remains no adequate evidence

that suggests the efficacy of co-administra-

tion of VitD and insulin on the T1DM pe-

diatric patients. Thus, in this study, we put

forward the strategy of co-administration of

VitD and insulin in treatment of pediatric

T1DM, and compared the resulting efficacy,

immune regulation and safety evaluation

with the regular strategy, and the results are

reported as follows.

SUBJECTS AND METHODS

General data. A total of 84 children

with T1DM, who were admitted to our hos-

pital between January 2013 and April 2020,

were recruited into this study and divided

into the regular group and the observation

group, using a random digit table, with

42 patients in each group. In the regular

group, there were 16 boys and 26 girls,

aged between 1 and 12 years-old with an

average age of 5.90±1.12 years, and their

average body mass index (BMI) (5) was

21.04±2.05 kg/m

; 23 patients presented

positive responses to the antibody test, in-

cluding eight patients to the GAD65Ab, five

positive to the anti-islet cell antibody (ICA),

four positive to the anti-insulin antibody

(IAA), three positive to IA-2Ab and three

positive to GAD65Ab + IAA; 31 patients

had complications of diabetic ketosis; as for

the clinical manifestations, 22 patients had

polydipsia, polyuria, polyphagia and weight

loss, ten had fever, eight had vomiting, and

16 had abdominal pain. In the observation

group, there were 18 boys and 24 girls, aged

between 1 and 12 years-old with an average

age of 5.78±1.10 years. Their average BMI

(5) was 21.11±2.04 kg/m

; 24 patients

presented positive responses to the anti-

body test, including none patients to the

GAD65Ab, six positive to the anti-islet cell

antibody (ICA), three positive to the anti-

insulin antibody (IAA), three positive to IA-

2Ab and three positive to GAD65Ab + IAA;

29 patients had complications of diabetic

ketosis; as for the clinical manifestations,

24 patients had polydipsia, polyuria, poly-

phagia and weight loss, 11 had fever, 7 had

vomiting, and 14 had abdominal pain. Com-

parison of the general data between two

groups showed no significant difference (all

P > 0.05; Table I). This study had been ap-

proved by the Ethical Board of our Hospital.

Criteria for inclusion and exclusion

Inclusion criteria: 1) Patients con-

forming to the diagnostic criteria for T1DM

stipulated by the World Health Organiza-

tion (WHO) (6); 2) patients diagnosed for

the first time; 3) patients whose guardians

signed the written informed consents. Exclu-

sion criteria: 1) patients who had taken the

calcium supplements or related drugs, such

as VitD, within two months before admis-

sion; 2) patients complicated with infection,

trauma or with a surgery history; 3) patients

who had the complications of severe liver or

kidney dysfunction, hyperthyroidism or oth-

er diseases of the endocrine system; 4) pa-

tients with diseases that potentially affected

the levels of VitD in serum, blood glucose,

CD4+T cell quantity and Th1/Th2 levels.

Treatment

Treatment for T1DM complicated with

ketoacidosis was conducted as follows: Two

venous channels were used – one for rapid

infusion of insulin at dose of 0.05 to 1 U/

kg·h or adjusted according to the blood

glucose of patients, while the other was

used for fluid infusion to perform the com-

prehensive treatment; when blood glucose

was controlled within 8 to 12 mmol/L, 5%

glucose + insulin (2-4 g: 1 U) was infused

intravenously; for patients with obvious re-

covery and tolerance to the meals, regular

162 Xue and Xuan

Investigación Clínica 62(2): 2021

insulin was given subcutaneously prior to

meals or sleep, and the dose was adjusted

according to the blood glucose, diet or

exercise, so as to maintain the blood glu-

cose stable for three months: fasting blood

glucose between 4.1 and 7.0 mmol/L, and

2-hour postprandial blood glucose (2hPG)

between 7.0 and 10.0 mmol/L.

For patients without ketoacidosis in the

regular group, regular insulin was given once

prior to the meal or sleep at an initial dose of

0.5 to 1.0 U/kg·d adjusted by the diet, exer-

cise and blood glucose to maintain the blood

glucose stable for three months.

For those patients in the observation

group, they, in addition to the treatment

above, received VitD drops (Qingdao Dou-

ble Whale Pharmaceutical Co., Ltd; State

Food and Drug Administration Approval No.:

H20113033; Specification: 400 U * 12 cap-

sules * three plates) orally (two capsules per

day) until the blood glucose was maintained

stable for three months.

Observation indexes

Comparison of the levels of 25(OH)D3

in serum before and after treatment

Fasting venous blood (2mL) collected

from the patients, was left at room tempera-

ture and then subjected to centrifugation at

3000 rpm for 10 min, to collect the superna-

tant and to detect the level of 25(OH)D3 in se-

rum by using the chemiluminescence immune

analyzer and the corresponding kits provided

by Roche.

Comparison of the indicators of clinical

efficacy

Before the blood glucose was main-

tained stable, the daily dose of insulin, time

TABLE I

COMPARISON OF THE GENERAL DATA BETWEEN TWO GROUPS.

General data Observation group Regular group Statistics p

Sex (n, %)

Boys 18 (42.86) 16 (38.10) 0.198

0.657

Girls 24 (57.14) 26 (61.90)

Age (years) 5.78±1.10 5.90±1.12 0.495

0.622

BMI (kg/m

) 21.11±2.04 21.04±2.05 0.157

0.876

Autoantibody (n,%)

Positive to GAD65Ab 9 (21.43) 8 (19.05) 0.074

0.786

Positive to ICA 6 (14.29) 5 (11.90) 0.105

0.746

Positive to IAA 3 (7.14) 4 (9.52) 0.156

0.693

Positive to IA-2Ab 3 (7.14) 3 (7.14) 0.179

0.672

Positive to GAD65Ab+IAA 3 (7.14) 3 (7.14) 0.179

0.672

Positive to the autonomous antibodies 24 (57.14) 23 (54.76) 0.048

0.826

Clinical manifestations

Polydipsia, polyuria, polyphagia

and weight loss

24 (57.14) 22 (52.38) 0.192

0.661

Fever 11 (26.19) 10 (23.81) 0.063

0.801

Vomiting 7 (16.67) 8 (19.05) 0.081

0.776

Abdominal pains 14 (33.33) 16 (38.10) 0.207

0.649

for chi-square test;

for t test;

for calibrated chi-square test.

Vit D drops combined with insulin in Type 1 diabetes 163

Vol. 62(2): 159 - 168, 2021

needed for glucose control and frequency of

hypoglycemia attack were recorded. More-

over, we compared the 2hPG at the time

before treatment, one month later and after

treatment between the two groups.

Comparison of the positive rate of CD4+T

cells expressing INF-γ, IL-4 in peripheral

blood and the INF-γ/IL-4 ratio

Samples of venous blood (2.5 mL) were

drawn from patients before treatment, one

month later and after the treatment to isolate

the peripheral blood monocyte cells (PBMCs)

by using the density gradient centrifugation,

and the harvested PBMCs were diluted to a

density of 1.0×10

/mL with the RPMI1640

medium. PBMCs were then stimulated by

being incubated with the phorbol ester and

monensin, followed by fixation in paraformal-

dehyde. Surface antigens were labeled by con-

jugating with the anti-CD4+ antibody, and

holes were then made on the surface of cells

by the treatment of saponin-diosgenin com-

plex, where the monoclonal anti-INF-γ and

anti-IL-4 antibodies were added, followed by

the detection of positive rate of CD4+T cells

expressing INF-γ, IL-4 in peripheral blood by

using the flow cytometry.

Comparison of the incidence of adverse

reactions

Adverse reactions, including the dys-

function of liver or kidney, or anomalies in

the biochemical indicators of patients in two

groups were recorded during the treatment.

Comparison of the incidence of

complications and re-hospitalization rates

between two groups

Follow up was carried out within six

months after treatment to record the inci-

dence of retinal lesions, diabetic nephropa-

thy, skin lesions or other complications, and

the re-hospitalization rate.

Statistical analysis

SPSS 24.0 software was used to analyze

the data in this study. Measurement data

were expressed in form of mean ± standard

deviation (x±s). For repeated measure-

ments, the difference was validated by the

repeated measures analysis of variance, while

LSD-t test was adopted to validate the differ-

ence between two groups. Enumeration data

were described as n (%), and for the frequen-

cy ranging from 1 to 5, calibrated chi-square

test was carried out to detect the difference,

while for frequency > 5, chi-square test was

adopted. P<0.05 suggested that the differ-

ence had statistical significance.

RESULTS

Comparison of the levels of 25(OH)D3

in serum before and after treatment

Difference of the levels of 25(OH)D3

in serum before treatment showed no sta-

tistical significance (P>0.05), while after

treatment, the level of 25(OH)D3 in the

observation group surpassed that of the

regular group (P<0.05). Besides, in the

observation group, the level of 25(OH)

D3 after treatment experienced an obvi-

ous increase as compared to the level after

treatment (P<0.05), while in the regular

group, no significant change was found (P

> 0.05; Table II).

Comparison of the clinical indicators

between two groups

In comparison with the regular group,

patients in the observation group excelled

in the lower daily doses of insulin, shorter

time needed to control the blood glucose

and a lower frequency of hypoglycemia (all

P< 0.05); for 2hPG, the differences between

two groups, different time points and inter-

actions showed statistical significance (all

P< 0.05), while no significant difference

was identified in the 2hPG between the two

groups before treatment (P>0.05). One

month later and after treatment, 2hPG in

the observation group was lower than that

in the regular group (P<0.05), and particu-

larly, 2hPG in two groups was all lower than

that before treatment (P<0.05; Table III).

164 Xue and Xuan

Investigación Clínica 62(2): 2021

Comparison of the positive rates of

CD4+T cells expressing INF-γ, IL-4 and

the INF-γ/IL-4 ratios in peripheral blood

Statistical significance was indicated

in the differences of the positive rates of

CD4+T cells expressing INF-γ, IL-4 and those

of the INF-γ/IL-4 ratios between groups, dif-

ferent time points and interactions (all P <

0.05). Prior to the treatment, no significant

difference was reported in comparing the

positive rates and INF-γ/IL-4 ratios (all P >

0.05); one month later, in the observation

group, positive rates of CD4+T cells express-

ing INF-γ and INF-γ/IL-4 ratio were all lower

than those in the regular group, with a higher

positive rate of CD4+T cells expressing IL-4

(all P<0.05); as the treatment went on, posi-

tive rates of CD4+T cells expressing INF-γ

and INF-γ/IL-4 ratio continued decreasing in

two groups (all P<0.05), while positive rates

of CD4+T cells expressing IL-4 increased (P

< 0.05; Table IV).

Comparison of the incidence of adverse

reactions

During the treatment, patients in the

two groups had no severe adverse reactions, or

anomalies in the functions of liver or kidney.

Comparison of the incidence of

complications and re-hospitalization rates

There were no reported cases of com-

plications during the follow up in the ob-

servation group, but one patient was re-

hospitalized due to the fluctuation of blood

glucose; patients in the regular group had

seven cases of complications, including two

cases of retinal lesion, two cases of diabetic

TABLE II

COMPARISON OF THE LEVELS OF 25(OH)D3 IN SERUM BEFORE

AND AFTER TREATMENT ( (x±s), ng/mL).

Group N Before treatment After treatment t p

Observation group 42 21.26±2.14 29.35±3.12 13.858 0.000

Regular group 42 21.11±2.17 21.46±2.96 0.618 0.538

t 0.319 11.889 —— ——

p 0.751 0.000 —— ——

TABLE III

COMPARISON OF THE CLINICAL INDICATORS BETWEEN TWO GROUPS

(x±s)

Group Observation

group

Regular

group

t/F p

N 42 42

Daily dose of insulin (U/kg) 1.20±0.21 1.49±0.32 4.91 0

Time needed to control

the blood glucose (d)

5.20±0.80 6.41±1.20 5.437 0

Hypoglycemia

frequency

(times/d) 0.35±0.06 0.65±0.12 14.491 0

2hPG

(mmol/L)

Before treatment 7.98±0.80 7.93±0.82 F

intergroup

=7.028; F

time

=21.289;

interaction

=17.615

intergroup

=0.000;

time

=0.000;

interaction

=0.000

One month later 4.79±0.53

5.52±0.55

After treatment 4.81±0.49

5.54±0.51

p<0.05 vs. the regular group;

p < 0.05 vs. the level before treatment in the same group.

Vit D drops combined with insulin in Type 1 diabetes 165

Vol. 62(2): 159 - 168, 2021

nephropathy and three cases of skin lesions,

and eight patients were re-hospitalized due

to the fluctuation of blood glucose. Thus,

the total incidence rate of complications in

the observation group was lower than that in

the regular group (P<0.05; Table V).

DISCUSSION

T1DM is a highly complicated T cell-

dominated autoimmune dysregulation,

generally caused by the interaction be-

tween environmental factors and genetic

factors (7-8). T1DM progression involves

two stages – inflammation of pancreas and

overt diabetes: Inflammation of pancreas

is predominantly the persistent injury and

apoptosis of pancreas islet β cells caused

by the infiltration of macrophages and

lymphocytes, and when the apoptotic rate

of pancreas islet β cells surpasses 90%,

disease progresses into the overt diabetes

with clinical manifestations of polydipsia,

polyuria, polyphagia and weight loss, se-

verely devastating the mental health and

life quality of children (9). Previous data

(10) support that VitD plays a key role in

T1DM pathogenesis via binding to VitD re-

ceptor (VDR) which is mainly distributed

in the pancreas and T lymphocytes. VitD,

at a low level, can induce the long-term

inflammation of pancreas islet β cells,

thereby affecting the functions to synthe-

size and secret insulins, or triggering the

intolerance to glucose, or decreasing the

sensitivity of insulin, eventually contribut-

ing to the development of diabetes mel-

litus.

Results of this study indicated that af-

ter treatment, the level of 25(OH)D3 in se-

rum of patients was higher than that in the

regular group, and the such an increase was

TABLE IV

COMPARISON OF THE POSITIVE RATES OF CD4

T CELLS EXPRESSING INF-Γ, IL-4

AND THE INF-Γ/IL-4 RATIOS IN PERIPHERAL BLOOD (x±s, n=27).

Group Observation group Regular group t/F p

INF-γ (%) Before

treatment

22.51±2.83 22.47±2.59 F

intergroup

=10.186;

time

=22.261;

interaction

=16.526

intergroup

=0.000;

time

=0.000;

interaction

=0.000

One month

later

17.54±2.09

19.36±2.13

After

treatment

14.32±1.59

abc

17.12±1.86

IL-4 (%) Before

treatment

3.52±0.31 3.64±0.33 F

intergroup

=13.516;

time

=8.516;

interaction

=11.869

intergroup

=0.000;

time

=0.000;

pinteraction

=0.000

One month

later

4.23±0.49

3.85±0.55

After

treatment

5.22±0.45

abc

4.61±0.46

INF-γ/IL-4 Before

treatment

6.37±1.06 6.25±1.12 F

intergroup

=11.896;

time

=25.296;

interaction

=18.417

intergroup

=0.000;

time

=0.000;

interaction

=0.000

One month

later

4.12±0.44

5.25±0.46

After

treatment

2.85±0.51

abc

4.12±0.55

p <0.05 vs. the regular group;

p <0.05 vs. the level before treatment in the same group;

p < 0.05 vs. the level one

month later in the same group.

166 Xue and Xuan

Investigación Clínica 62(2): 2021

only found in the observation, instead of

the regular group; besides, patients in the

observation group excelled in the lower dos-

age of insulin, shorter time needed to con-

trol the blood glucose and a lower frequency

of hypoglycemia; one month later and after

treatment, 2hPG of patients in the observa-

tion group was lower than that in the regu-

lar group, but the positive rate of CD4+T

cells expressing IL-4 were higher than that

in the regular group. Furthermore, as the

treatment went on, 2hPG in two groups

continued to decrease, suggesting that VitD

drops in combination with the regular insu-

lin treatment is conducive to the control of

blood glucose and reducing the dose of insu-

lin and frequency of hypoglycemia in T1DM

patients. As an essential vitamin, VitD is a

kind of steroid hormone that is metabolized

into the active 25(OH)D3 which is a major

ligand of VDR that is involved in a variety of

biological events, including the metabolism

of calcium and phosphorus of multiple or-

gans and tissues as well as the cell differen-

tiation and growth (11).

A retrospective analysis of Wu M et

al. (12) found that VitD supplementation

is critical to the T1DM patients. Thus, in

their study, regular insulin replacement

therapy was combined with the use of VitD

drops, and as well as us, found that T1DM

patients had a significant reduction in the

daily dose of insulin, time needed to con-

trol the blood glucose and the frequency

of hypoglycemia.

This suggest that VitD level in T1DM

patients contributes to the control of blood

glucose, which may attribute to the increase

of VitD that promotes 25(OH)D3 to bind to

the VDR on the surface of pancreas islet β

cells, thereby regulating the relevant signal

pathways to improve the secretion of pancre-

as islet β cells. However, the specific regula-

tion mechanism remains to be validated by

the future work.

In addition, we found that one month

later and after treatment, positive rate of

CD4+T cells expressing INF-γ and INF-γ/

IL-4 ratio were all lower than those in the

regular group, with a higher positive rate of

CD4+T cells expressing IL-4; as the treat-

ment went on, positive rates of CD4+T cells

expressing INF-γ and INF-γ/IL-4 ratio contin-

ued decreasing in both groups, while posi-

tive rates of CD4+T cells expressing IL-4

increased in the observation group; during

the treatment, patients in the two groups

had no severe adverse reactions, and during

the follow-up, the incidence of complica-

tions and re-hospitalization rate in the ob-

servation group were lower than those in the

regular group. Thus, VitD drops in combina-

tion with the insulin replacement therapy

is conducive to the regulation of Th1/Th2

imbalance in T1DM patients, which is safe

and reliable, with the remarkable decreases

in the incidence rate of complications and

re-hospitalization rate.

Since T1DM is an autoimmune dis-

ease, we infer that the effect of VitD on the

function of pancreatic islet β cells may be

realized by the immune regulation, instead

of the calcium/phosphorus metabolism.

Current evidence (13-14) shows that infil-

TABLE V

COMPARISON OF THE INCIDENCE OF COMPLICATIONS AND RE-HOSPITALIZATION RATES.

Group N Incidence of complications

n(%)

Re-hospitalization

n(%)

Observation group 42 0 (0.00) 1 (2.38)

Regular group 42 7 (16.67) 8 (19.05)

Calibrated χ

— 4.480

p 0.018 0.034

Vit D drops combined with insulin in Type 1 diabetes 167

Vol. 62(2): 159 - 168, 2021

trations of monocytes and cytotoxic lym-

phocytes are the pathological landmarks

of T1DM. T lymphocyte-mediated immune

dysregulation causes the left shift in the

equilibrium of Th1/Th2, representing the

enhancement of Th1 immune response that

further increases the secretion of INF-γ and

antigen presentation, thus strengthening

the sensibility of pancreas islet β cells to

the cytotoxicity and advancing the progres-

sion of T1DM. In this study, in addition

to the regular supplementation of exog-

enous insulin, VitD was also taken to regu-

late the balance of Th1/Th2. According to

our analysis, 25(OH)D3 is able to bind to

the VDR on the surface of T lymphocytes,

which, therefore, transfers the complex to

the VitD reaction element in the promotor

of IFN-γ to affect the transcription of IFN-γ

in Th1 cells, thus inhibiting the response

of Th1 (15). Moreover, increased 25(OH)D3

contributes to the synthesis and secretion

of IL-4, which results in the right shift of

Th1/Th2 balance and improves the immune

dysregulation of pancreas islet β cells. Ad-

ditionally, patients who underwent the

combined strategy had no severe adverse

reactions, suggesting that appropriate sup-

plementation of VitD is safe and reliable in

treatment of T1DM, and also contributes to

the stable control of blood glucose (16).

In conclusion, for pediatric T1DM pa-

tients, VitD drops in combination with the

regular insulin replacement therapy im-

proves the control of blood glucose, reduc-

es the dose of insulin and the frequency

of hypoglycemia, and restore the dysregu-

lated Th1/Th2 balance. Besides, it is safe

and reliable in the treatment of T1DM,

with a low incidence rate of complications

and re-hospitalization rates. However, the

conclusion of this study is still limited due

to the small sample size that may increase

the statistical bias. Thus, in future work,

we will expand the sample size and pro-

long the follow-up to validate the accuracy

of this conclusion.

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