LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
Institute of Physiology and Pharmacology
MASTER’S THESIS
Relationship of the vitamin D deficiency and the
prevalence of type 1 diabetes mellitus: Literature
Review
Thesis supervisor
Assoc. Prof. Dalia Akramiene
Author
Anton Gavrilov MF 6, group 38
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Table of content
1. SUMMARY ... 3 2. SANTRUKA ... 4 3. ACKNOWLEDGE……….…………...5 4. CONFLICT OF INTEREST... 65. CLEARANCE ISSUED BY THE ETHICS COMMITTEE ... 7
6. ABBREVIATION ... 8
7. TERMS ... 9
8. INTRODUCTION... 10
9. AIM AND OBJECTIVES OF THE THESIS ... 13
10. RESEARCH METHODOLOGY AND METHODS ... 14
11. RESULTS AND THEIR DISCUSSION ... 14
11.1- DOES Vit D3 DEFICIENCY CAN BE AS A RISK FACTOR FOR DEVELOPMENT OF T1DM?... 16
11.2- IS THERE ANY GENDER DIFFERENCE IN INCIDENCE OF T1DM IN RELATION TO VIT D3 DEFICIENCY?...22
11.3- WHAT POSSIBLE MECHANISM OF VIT D3 DEFICIENCY ON THE PATHOGENESIS OF T1DM?...25
12. CONCLUSION ... 28
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1. SUMMARY
Author: Anton Gavrilov
Title: Relationship of the vitamin D deficiency and the prevalence of type 1 diabetes mellitus.
Introduction: T1DM incidence has increased rapidly in few decades, and the lack of knowledge
of its development and the sudden increase leading to reveal other likely risk factors for development, one of them is a deficiency of Vit D. It was proven that Vit D has immune modulation properties, however, its role in the pathogenesis of T1DM remains unclear.
Research aim: To analyze and discuss the associations between T1DM and Vitamin D deficiency. Objectives:
This review will compile the available data presented in peer-reviewed published clinical studies to address the following questions:
1. Does Vit D deficiency can be as a risk factor for the development of T1DM?
2. Is there any gender difference in the incidence of T1DM in relation to Vit D deficiency? 3. What possible mechanism of Vit D deficiency on the pathogenesis of T1DM?
Methodology: studies were searched in the PubMed Medline database, were published in the last 10
years in the English language.
Results and conclusion:
In this study articles from the last 10 years were reviewed to study the correlation of Vit D deficiency. The studies showed that there is a tendency is of T1DM patients to have a lower level of Vit D compared to control. However, the studies couldn’t provide an answer if there is correlation between Vit D deficiency and T1DM or difference between genders. More studies need to be done to resolve the Vit D deficiency and T1DM correlation.
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2. SANTRUKA
Autorios: Anton Gavrilov
Pavadinimas: Ryšys tarp vitamino D trūkumo ir sergamumo 1 tipo cukriniu diabetu. Literatūros
apžvalga.
Įžanga: Sergamumas 1 tipo cukriniu diabetu greitai išaugo per kelis dešimtmečius. Vis dar trūksta
aiškių įrodymų dėl jo atsiradimo ir tokio sergamumo padidėjimo. Vienas iš galimų faktorių jo išsivytymui galėtų būti vitamino D trūkumas. Yra įrodymų, kad vitaminas D turi imuninę sistemą moduliuojančių savybių, tačiau vis dar lieka neiaiškus jo vaidmuo T1DM patogenezei.
Tyrimo tikslas: Išanalizuoti ir aptarti T1DM ir vitamino D trūkumo ryšius. Uždaviniai:
Šioje apžvalgoje bus pateikiami ir analizuojami duomenys, pateikti publikuotuose recenzuotuose klinikiniuose tyrimuose, siekiant atsakyti į šiuos klausimus:
1. Ar Vit D3 trūkumas gali būti 1 tipo cukrinio diabeto išsivystymo rizikos veiksnys?
2. Ar yra kokių nors lyčių skirtumų tarp 1 tipo cukrinio diabeto išsivystymo ir Vit D trūkumo? 3. Koks galimas Vit D trūkumo mechanizmas 1 tipo cukrinio diabeto patogenezėje?
Metodai: analizuoti ir palyginti per paskutinius 10 metų publikuoti tyrimai anglų kalba. Tyrimai
ieškoti PubMed Medline duomenų bazėje, taikant tam tikrus įtraukimo kriterijus.
Rezultatai ir išvados: Šiame tyrime buvo apžvelgti pastarųjų 10 metų straipsniai, siekiant ištirti Vit D
trūkumo ryšį su 1 tipo cukrinio diabeto (T1CD) išsivystymu. Tyrimai parodė, kad T1CD sergančių pacientų Vit D lygis yra mažesnis nei kontrolinės. Tačiau tyrimai negalėjo pateikti atsakymo, ar yra ryšys tarp Vit D trūkumo ir T1DM, ar yra skirtumų tarp lyčių. Reikia atlikti daugiau tyrimų, kad būtų nustatytas Vit D trūkumas ir T1DM koreliacija.
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3. ACKNOWLEDGE
I would like to express my gratitude to my supervisor for the gaudiness and the patient during the process of writing this work.
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4. CONFLICT OF INTEREST
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5. CLEARANCE ISSUED BY THE ETHICS COMMITTEE
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6. ABBREVIATION
• DM - Diabetes Mellitus.
• T1DM - Type 1 Diabetes Mellitus • Vit D3 -Vitamin D 3
• HLA - Human Leukocyte Antigen. • 7-DHC - 7-dehydrocholesterol.
• Clacidiol - 5-Hydroxy Vitamin D3 / 25(OH)D. • Treg - T regulation cell.
• Calcitriol - 1,25(OH)2D). • VDR - Vitamin D3 receptor. • RXR - Retinoid X Receptor. • IFN - Interferon.
• TNF – Tumor Necrosis Factor. • UAE - United Arab Emirates.
• SPrOO - seasonal pre-ovulatory over-ripeness ovopathy. • MHC class II - Major Histocompatibility Complex.
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7. TERMS
• Vitamin D sufficiency - Serum 25(OH)D > 30 ng/mL or > 75 nmol/ • Vitamin D insufficiency - Serum 25(OH)D 20-29 ng/mL or 50 -74 nmol/L • Vitamin D deficiency - Serum 25(OH)D < 19 ng/mL or < 49 nmol/L
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8. INTRODUCTION
Diabetes mellitus (DM) is an endocrine disorder that is disturbing the glucose level by affecting it concentration and utilization by defects in insulin synthesis or recognition. DM divided into different types; type 1 and 2, the latter is the most common type worldwide. Type 2 diabetes mellitus develops due to resistance to insulin, leading to the failure of beta cells because of increasing demand in the production of insulin. [1] Type 1 diabetes mellitus (T1DM), is an autoimmune condition the affects beta cells of the pancreas and causes their destruction and lifelong deficiency of insulin secretion and dependence on exogenous insulin. It can manifest in adults as in childhood Up to 50% can occur in adults causing it to be misdiagnosed and misclassified (e.g. adults can be misdiagnosed with T2DM). [2,3]
In 2014, 422 million people around the world suffered from DM, a raise of 304 million from 1980 promoting it to world-wide concern and problem. 5%-10% of the cases of DM are T1DM. [4] T1DM has been associated with decreased Vit D3 level at diagnosis point and with seasonal variation due to UVB exposure, as most of Vit D3 is created by the skin. T1DM pathophysiology is complicated and caused by interaction between multi factors; Environmental, genome, and immune systems factors.
Environmental factor–The sudden increase in incidence in the past couple of decades indicates that it is less likely to be contributed by genetics alone changes cannot happen that fast. Another argument to support the environmental factor is the variety of incidence between unique countries with similar geographical locations. Promote the hypothesis of associations with other factors such as; Diet, Vitamin D deficiency, Viruses in childhood (e.g. Enterovirus), and obesity. [3] Genetics–According to DiMeglio, L.A study the risk to develop T1DM in case of close family diagnosed with T1DM is; Identical twins 30-70%, sibling risk of 6-7%, and if one of the parents has DM 1-9%. Two HLA that were confirmed in the pathogenesis of T1DM are DR3 and DR4-DQ8, on the other hand, HLA DR15-DQ6 showed a reduction in risk to develop T1DM. [3] Immune system—Not completely understood, if the reason is trigger by a viral infection and followed by cross-reactivity and leading to develop antibodies against beta cells or if the autoimmune is random. [3,5]
T1DM patients possess antibodies to beta-pancreas cells and found in over 90% of patients. Antibodies can be to insulin, glutamate decarboxylase, islet antigen 2, zinc transporter 8, and
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tetraspanin-7. Being positive to the antibodies increases the risk to develop T1DM further up in life by 84% only if positive for two or more antibody types and it also until 18 years [17]
The dreadful complication of the disease and the rising awareness of the disease, still not enough as some populations still can’t afford to receive optimal treatment due to a variety of reasons such as; socioeconomically, geographical location, or lack of knowledge. As a result, patients develop Microvascular and Macrovascular complications.
Microvascular–Retinopathy, Neuropathy, Nephropathy, also can affect cognitive function, heart, and other organs.
Macrovascular–Atherosclerosis and thrombosis and peripheral arteries. [3,5]
Due to being a worldwide problem, many studies were done to reveal and uncover the effect of environmental factors on the pathogenesis. Leading us to learn more effect of Vit D3 deficiency on T1DM.
Vitamin D 3(Vit D3) can be produced by our body or be consumed from unique food sources (e.g. fish, liver). Vit D3 can lead to multiple functions in the body such as; bone modulation, calcium hemostasis, and immunomodulation. The deficiency state of Vit D3 can lead to increased risk for autoimmune diseases. The effects are seen mostly on CD8+ T cell, macrophage, CD+4 T cell, B cell and plasma cell, all cells have a role in T1DM development [6,8]
The first step in the synthesis of Vit D3 starts in the skin, with 7-dehydrocholesterol and ultraviolet B (UVB), conversion occurs and the first product that is made is precalciferol (known as previtaminD3). Precalciferol with the help to the heat undergoes isomerization to cholecalciferol (known as Vitamin D3). Sunlight is necessary for the endogenous production of Vit D3, especially as the majority of Vit D3 in the human body is from an endogenous source. An alternative pathway to get Vit D3 is from consuming food; animals or plants. 7-dehydrocholesterol from animals and ergosterol from the plants. Both of them are activated and forming ergocalciferol (known as vitamin D2). The next step in the pathway, occurs in the liver, and is true for both Vit D2 and Vit D3, hydroxylation to form calcidiol (also known as 5-hydroxy vitamin D3 {25(OH) D}. calcidiol is an indicator of Vit D3 status, due it being major circulating form and its half-life of three weeks. [5]. After that calcidiol is hydroxylated to the active metabolite in the kidney, mostly but not only, to calcitriol {1,25(OH) 2D)}. As the majority of our body Vit D3 is from UVB source, simple things as sunscreen, less time outside, long cloth indoor living and environmental condition as season and altitude can lower our UVB exposure and decrease Vit D3. [6,8-10] Interestingly, countries with abundant sun (e.g. Kuwait) or high
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altitude still have Vit D3 deficiency, and even different locations that have common geographical parameters, have different levels of Vit D3 levels (e.g. Russia and Finland). [6,7]
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9. AIM AND OBJECTIVES OF THE THESIS
Research aim: To analyze and discuss the associations between T1DM and Vitamin D deficiency. Objectives: This review will compile the available data presented in peer-reviewed published clinical
studies to address the following questions:
1. Does Vit D3 deficiency can be as a risk factor for the development of T1DM?
2. Is there any gender difference in the incidence of T1DM in relation to Vit D3 deficiency?
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10. RESEARCH METHODOLOGY AND METHODS
Data collection and search strategy:
The main search engine was MEDLINE PubMed that yielded about 291 research works. Randomized clinical trials, retrospective studies, literature reviews were used. Inclusion and exclusion criteria navigated which works should or shouldn’t be used.
Information source:
MEDLINE PubMed online research engine
Inclusion criteria:
Terms used: Diabetes mellites type 1, Vitamin D, UVB, Climate, Sun. Sentences used:
- Sun exposure diabetes type 1.
- Climate diabetes mellitus type 1 incidence.
- Vitamin D deficiency and diabetes mellitus type 1 incidence population. - Vitamin D.
- Vitamin D and diabetes mellitus type 1 incidence. - Diabetes Mellitus type 1.
Exclusion criteria
- Research work that wasn’t published in the last 10 years. - Works written not in the English language.
- Not relevant title or abstract. -Animals studies.
Data collection process:
The initial search in PubMed yielded 291 results, which were reduced to 173 after using filters such as published in the last ten years, only the English language and Human studies. Using the best match function in PubMed helped review the title and abstract of each work and select the most appropriate once which were 89 overall. After a full review of the text 23 research works were included in this literature review. The data that was collected from the studies included the number of participants in studies, Vit D3 concentration, location of the subjects, gender, Sun index, and the P values. The influence of Vit D3 on the immune system and its modulation.
15 Figure 2. Inclusion and exclusion flow chart that describes the data collection process
The data that was collected from the studies included the number of participants in studies, Vit D3 concentration, location of the subjects, gender, and Sun index. The influence of Vit D3 on the immune system and its modulation.
173 titles and abstract were reviewed
89 full review was preformed
13 studies were used in the literature review to answer the
question. Addition 10 systematic reviews and
meta-analysis were used for introduction and additional
information.
118 studies were excluded based on
exclusion criteria
84 studies were excluded based on title and abstract
review
66 studies were excluded based on irrelevance 291 studies were
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11. RESULTS AND THEIR DISCUSSION
11.1 Does Vit D3 deficiency can be as a risk factor for the
development of T1DM?
Table 1. Summary of studies of T1DM and Vit D3 deficiency
Author Type country Patients with T1DM (Controls) Percentage with Vit D3 deficiency P-value A. Sinha (2012) cross-sectional United Kingdom a563(44) 73% of the patients had deficiency, 18% insufficiency P< 0.0001
Nasser M Al-Daghri (2014) cross-sectional
Saudi 60(60) 100% of the DM
P=0.03
Bruna Franchi (2014) Case-control Italy 58(166) 67% of the patients had deficiency,
24% insufficiency
P =0.046
Mona Hafez (2016) prospective cohort Egypt 50 70% of the patients had deficiency, 24% had insufficiency P = 0.009
Asal Ataie-Jafari (2012) cross-sectional Iran 53 77% of the patients had deficiency, 23% insufficiency P = 0.003
Seham FA Azab (2013) Case-control Egypt 80(40) 55% of the patients had a deficiency
P > 0.05
Borkar VV (2010) Cross-sectional
North India 50(50) 14% of the patients had deficiency,
28% insufficiency
P = 0.009
Fatima Ahmed Al-Haddad (2016) Case-control Bahrain 18 11% of the patients had a deficiency, 61% insufficiency P = 0.048 Rasoul, M. A (2016) Cross-sectional Kuwait 216(204) 84% of the patients had P = 0.027
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deficiency, 15% insufficiency Greer RM (2012) Case-control Australia 56(56) 9% of the
patients had a deficiency
P = 0.73
Limitations:
• The reason for Vit D3 deficiency remains vague. The sun index was measured in some studies. However, the diet was hard to determine. The majority of the patients filled a questionnaire regarding diet and sun exposure. The results could be biased due to recall.
• The measured Vit D3 was not in incidence time lap but prevalence. It is difficult to know when patients will develop T1DM due to environmental factors, genetic factors, and viral such as. It is difficult to screen all populations for genetic predisposition beforehand and even if we screen Risk populations we will still won’t know their Vit D3 status in the future and possible viral infection.
• No follow up was made after the diagnosis regarding the concentrations of Vit D3, if the deficiency resolved later in life or it became permanent.
• Not all studies reported the duration of disease at the point of the studies.
To approach the question, studies worldwide tried to compare Vit D3 concentration levels at diagnosis point with controls by variable parameters, season, temperature, and climate. As the majority of Vit D3 in our body is produced by the UVB, some studies focused more on the climate effect on Vit D3 and T1DM incidence. The results were that some studies reported that even though their countries have abundant sun exposure, the sampled population with T1DM had Vit D3 either deficiency or insufficiency, and even control groups have under optimal Vit D3 concentrations.
The contradiction of having high exposure to UVB had Vit D3 deficiency can be seen in few of the reviewed studies. Borkar V.V. et al. study in North India included 100 children to the T1DM group and 50 in control. The study noted that in Vit D3 levels were significantly lower in the T1DM group compared to control (P= 0.009). [20] Majedah A. R et al. research study of 420 children in Kuwait, 204 control group, and 216 T1DM group. Out from 216 T1DM group 213 (99%) and out from 204 controls group 187 (92%) had Vit D3 levels below the cutoff value (< 29 ng/mL or < 74 nmol/L) with
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significant difference (P=0.027). In Saudi Arabia deficiency Vit D3 levels were measured in 66.7% T1DM patients compared to 41.7% in the control group. Another report from Saudi Arabia measured Vit D3 deficiency in 84% Saudi T1DM children compared to 59% in the controls [1]. Spanish cohort research done by Enric S. Pet al. with 193 participants, 145 T1DM patients, and 48 controls, had a significant difference between the control group and T1DM 43.2% of patients with T1DM had Vit D3 deficiency while only 21.7% in control (p = 0.018). [13] In Egypt two case-control studies reported different results, in one there was a significant difference in the other there was not. However, both agreed that the prevalence of Vit D3 deficiency or insufficiency was high. [18,14] Another study is reporting Vit D3 deficiency in abundant UVB country is Al-Haddad, F. A et al. from Bahrain. Investigated 18 patients with T1DM and 50% had insufficiency or deficiency of Vit D3. [15]
In non-necessary high exposure countries to UVB such as United Kingdom, Sinha A. et al. study, reported that from 563 DM participants 91% (511) had Vit D3 insufficiency. [19] Franchi B. et al. published a study in Italy, where 224 children participated, 166 controls, and 58 T1DM patients. There was a significant difference (p =0.010) between controls and T1DM groups. [16]
The reviewed studies above focused on determining that the level of Vit D3 is lower at the study time without researching the possible cause. Population in countries with abundant UVB exposure should have high levels of Vit D3 due to UVB, however, the opposite was recorded. Other studies tried to figure out the reason, some concluded that there may be more of genetic factors influencing then environmental.
One of the studies that help us think about greater influence of genetic variation is an Australian study by Greer R.M. et al. 112 children were divided by 56 controls and 46 T1DM patients, Vit D3 was lower in the group with T1DM than control (p=0.01). UV Index was not significant (p=0.90) and no differences between genders. Another parameter the study checked the difference between newly established T1DM with relation with control and established T1DM in regarding of Vit D3 levels. It was revealed that Vit D3 levels were lower in newly diagnosed T1DM compared with controls (p=0.03) and established T1DM (p=0.01). [12]
Another study, by L. Reinert-Hartwall et al. on Finnish and Estonian children discovered variation in expression of FOXP3. 83 children from Finland and 32 children from Estonia were chosen,
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due to similar geographic the variation in sun exposure were none or minimal. 25(OH) D levels were compared between them. Finnish children had significantly higher levels of Vit D3 compared to Estonian (p<0.001) and no significant difference in 1,25(OH) 2D. The Estonian children have lower Vit D3 levels and despite that, the incidence of T1DM is lower than in Finland. {Finland (61/100 000 children) and Estonia (17.2/100 000 children)}. The research investigated FOXP3(Protein, FOXP3 helps in the regulation of CD+4 T cell, lower the immune reaction and expression in CD+4 memory cell) levels in both groups and realized that there was a difference in favor of Estonian people (median, 56.2 vs 42.8 respectively, p<0.01). [11]
To further investigate the impact of Vit D3 deficiency as a risk factor to develop T1DM, M. Simpson et al. conducted a cross-sectional study was concluded with two groups. Intending to reveal the risks for the development of T1DM; the first group, participants with first-degree family history of T1DM. The second group had a genetic predisposition with confirmed alleles. Two studies were conducted, The first study with the first group didn’t show any significant difference (p= 0.58) in developing autoantibodies to a beta cell in participants with lower Vit D3 levels; Second study with the second group, focused on antibody-positive participants and the risk to develop T1DM and revealed no significant difference (p= 0.54) to develop T1DM, with consumption or deficiency of Vit D3. [21]
The result from the Simpson et al., L. Reinert-Hartwall et al. and Greer R.M. et al. showing that Vit D3 is not the only risk factor, but it may be even irrelevant as a risk factor. However, we cannot ignore the fact that at point of the study patients have a lower concentration of Vit D3 compared with controls, possible hypothesis that is arising is the T1DM influencing Vit D3 levels and not vice versa. In support of this hypothesis a study conducted in Sweden, reported that Calcifediol levels were low at diagnosis, and with to improvement in the next eight years. [20] Data from an Indian study revealed that they have a high prevalence of Vit D3 deficiency but a lower incidence of T1DM compared to other countries that have a lower prevalence of hypovitaminosis but higher rates of incidence. [20] On the other hand, as the genetic predisposition cannot explain the sudden rise in incidence, for example, increased incidence of T1DM from 3.96/100,000 to 40.1/100,000 in the last 40 years in Kuwait [1] and the season variation that was reported Enric S. Pet al. there was reported significant difference with climate, with positive correlation obtained between the UVB exposure and 25OHD levels (p = 0.023). [13]. Franchi B. et al study from Italy calculated the odds ratio and discovered that with low Vit D3 level the odd increase (OR=3.45), inverse correlation. The study also mentioned that according to previous publications intake of Vit D3 supplements lowered the odds ratio to develop T1DM and add a dose-dependent effect (OR 0.71). [16]
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Nevertheless, not all studies reported significant difference with climate, like in Australian study where no significant difference between Vit D3 levels and different seasons was reported, and they concluded that Vit D3 concentration is constant all year. Similar conclusion was seen in Borkar V.V. et al study, no significant between the season was observed in North India (p=0.25). [20]
The understanding of the causes is still lacking, as some studies reported contradicted results of the studies weren’t done without flaws, such as not paying attention to the local diet, background diseases, or even genetic analysis of all individuals that were participants in the study. Further studies recommended such as a prospective cohort so we will be able to truly see the effect of Vit D3 on the development. 0 100 200 300 400 500 600 700 800 "Sufficiency "Serum 25(OH)D > 30 ng/mL "Insufficiency" Serum 25(OH)D 20-29 ng/mL "Deficiency" Serum 25(OH)D < 19 ng/mL Numbe r of pe ople
Summary of Vit D3 deficiency concentrations
Control T1DM
a- In part of reviewed studies there were no control groups Graph 1. Summary of Vit D3 concentrations
21 0 10 20 30 40 50 60 70 80 90 0.2 >1 1.4 >5 17 49.3 V it D3 le ve ls i n nmol \l Duration of T1DM in months
Vit D3 concentration in relativeness to duration from diagnosis
Number of patients
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50 53 60 80 50
Graph 2. Vit D3 concentration with duration form diagnosis
a- In part of the reviewed studies there was no mentioning of duration.
b- part of the studies described duration as more than one month of five months.
0 10 20 30 40 50 60 70 80 90 0 2 4 6 8 10 12 V it D3 le ve ls at di ag nosi s (nmol/ L ) Mean age
Vit D3 concentration according to age of T1DM patients used
in the studies
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11.2 Is there any gender difference in the incidence of T1DM in relation
to Vit D3 deficiency?
Limitation:
• The reviewed articles didn’t compare men to females on age base or Vit D3 levels • The number of studies that researched the questions is limited.
• Limited number of studies that were found to answer the question.
Author Number of T1DM patients (total number of participants)
country Men with
T1DM and Vit D3 deficiency (total number of Men) Women with T1DM and Vit D3 deficiency (total number of Women) P-value A. Sinha (2012) 563(607) United Kingdom Not mentioned Not mentioned
No comparison was done
Borkar VV (2010) 50(100) North
India
(29) (21) No comparison was done
Nasser M Al-Daghri (2014)
60(120) Saudi (34) (26) No comparison was done
Fatima Ahmed Al-Haddad (2016)
18 Bahrain (9) (9) No comparison was done
Rasoul, M. A (2016) 216(420) Kuwait (104a) (112a) No comparison was done
Bruna Franchi
(2014)
58 (224) Italy (32b) (26b) P =1.000
Mona Hafez (2016) 50 Egypt 14(27) 21(23) P = 0.009
Asal Ataie-Jafari (2012) 53 Iran (14c) (39c) P = 0.063 Greer RM (2012) 56(112) Australia (28) (28) P = 0.40 Seham FA Azab (2013) 80(120) Egypt (34d) (46d) P > 0.05
a- Not mentioned the status of gender. Only general statement, 84% of the patients had Vit D3 deficiency and,
15% insufficiency
b- No comparison was made. Only general statement 24% of the patients had Vit D3 insufficiency, 67% had a
deficiency
c- Not mentioned the status of gender. Only a general statement that all patients were Vit D3 deficient (77%)
or insufficient (23%).
d- Not mentioned the status of gender. Only general statement 44(55%) diabetic cases had Vit D3 deficient
Table 2. Summary of studies of T1DM and Vit D3 deficiency in gender
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A limited number of studies tried to answer this question, the majority of them only reported a general number of participants and the gender division. Even though the articles did mention that females had lower levels of Vit D3. Not always the studies studied the gender as risk factor in Vit D3 deficiency and T1DM, some just reported the lower levels of Vit D3 in population, as we have seen in the first question there was found a correlation between them.
Jacobsen, R et al. Danish study, reported decreased Vit D3 levels were measured in male infants born from October to May, with higher T1DM incidence and especially with positive correlation to gestation in darker months of the year and not in girls, Not the first time this result was reported. Due to the sun exposure being low in the third semester and some of the second semester. The importance of the Vit D3 in pregnancy is the only way for the fetus to receive Vit D3 is from the placenta, meaning the level can fluctuate depending on the mother's diet or sun exposure. Seasonal pre-ovulatory over-ripeness ovopathy (SPrOO) hypothesis was considered. SPrOO phenomenon defect in ripping of the ovary in darker months, this phenomenon more common in males, and leading to early defects. UVB or its product Vit D3 can help in optimizing the ripping process. However, in Jacobsen, R et al. study, an association was found in late-stage gestation and not in the beginning. Which disproves the hypothesis for this study [23] An additional likely explanation is the protective function of Vit D3 by influencing the immune system. Viral infection in infancy can increase the likelihood of T1DM, Vit D3 can protect from infection and lowers the incidence of viral infection in neonates. This supports the results that third semester Vit D3 protects from T1DM. interestingly, sun exposure in the first year of life decreases the risk in boys but increases risk in girls until age 5 years according to the Danish study, not known why. [23]
The other studies that mentioned and compared genders were mostly in the middle east, so the result is biased and cannot be reflected worldwide, only local. Alyahya, K. O. et al. article in the Middle East reported differences in gender, in terms of Vit D3. In United Arab Emirates 293 girls were studied and resulted in 78.8% of them with deficiency. Similar results were reported in other studies that were conducted in the Middle East; In Iranian children, 29% of boys and 66.6% of girls had Vit D3 deficiency. Alyahya, K. O et al. researched the topic in Kuwait and reported that from 199 children, 106 girls and 93 boys, boys had 34.0 vs. 27.0 median Vit D3 value and Sufficient level was Found only in 32.2% boys and 15.1% girls (P= 0.001). The study also reported that only 38.7% of the boys vs. 22.6% of the girls were exposed to the sun for up to 30 minutes.
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The basis for the difference suspected to be sun exposure and religion. In middle east countries, females tend to be less time outside, and the extreme heat also playing a part in more indoor activities additionally, they wear more covering cloths, less exposed skin for the synthesis of Vit D3. [22]. Ataie-Jafari, A. et al. research preformed in Iran supports the arguments by showing similar results. Sun index was higher in boys than girls (11.0 vs. 9.4 P < 0.001) boys were spending more time outside than girls (3.08 vs. 2.22, P = 0.004), and the clothes they wore (1.87 vs.1.33, P < 0.001) [17]. A potential reason for the difference in Vit D3 levels is the physiology of females, as the synthesis of Vit D3 depends on estradiol and estrogen. teen girls have an immature GnRH axis and it can take a few tears to mature.
There is none or slight variation in gender in European countries. However, in middle east countries it is different. The causes are due to lifestyle in countries. Girls less go out and more dressed than men. Objectively, it is harder to see if the correlation is due to gender differences in physiology or lifestyle. 29 9 32 28 27 14 34 34 21 9 26 28 23 39 46 26 0 10 20 30 40 50 60 70 80 90 9 9 9.2 10.2 10.24 10.3 11.4 25.9
Total patients number
Me an ag e in y ea rs
T1DM distribution according to gender
Male Female 33 nmol/l 28.11 nmol/l 26.57 nmol/l 36.2 nmol/l 44.6 nmol/l 78.7 nmol/l 28.1 nmo/l 24.7 nmol/l Graph 4. T1DM gender distribution
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11.3 What possible mechanism of Vit D3 deficiency on the pathogenesis
of T1DM?
Limitation:• Wasn’t able to find the answer to the question researched in the reviews and clinical trials that were used in this literature review.
• No cut-off values were mentioned, not knowing that basic levels of T cell, interleukins, cytokines, and the levels after the incidence of T1DM in Vit D3 deficiency.
• Not enough data about the exact value of Vit D3 concentration and its correlation to increased or decreased levels of immune system interleukins or cells.
The answer to this question was not answered in our studies. However, the potential answer to this question was studied in vitro in systematic studies and meta-analysis.
According to them, the pathway of Vit D3 production is complicated and involving multiple organs, so the dysfunction of any of the organs on its pathway can lead to deficiency. However, as the majority of the patients with T1DM diagnosed at an early age, even teenagers, the assumption that the function of their organs is normal.
Vit D3 can have a direct effect on beta cells and indirectly through immunomodulation. Both of the possible actions were further investigated. For what is known until now, the immunomodulation process occurs when calcitriol binds to Vit D3 receptor (VDR), followed by heterodimerization with retinoid x receptor (RXR), the result is a starting of transcription that can be increased or inhibited. In Vitro studies were done on both beta cells of pancreases and immune cells. [6,8-10]
In vitro study, on Human immune cells in a high dose of Vit D3 solution was performed. Following results were observed; monocytes didn’t differentiate to dendritic cells, stopped at intermediate cells, leading to a rise in its population. Intermediate cells can activate Treg cells. Optimize macrophages by increasing their maturation, cytokines, secretion, and phagocytosis. T-helpers were also affected by high dose Vit D3. In K. M. Miller et al. was also mentioned lower expression of VDR in T-helper cells of T1DM patients compared with healthy, moreover, they had a decreased number of CD+4 cells in case of receiving Vit D3, although, only in a patient with FF genome [10]. Other effects of Vit D3 including lowering the production of IL-2, interferon (IFN)- γ,
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and tumor necrosis, all of which are pro-inflammatory cytokines, produced by Th1 CD+4. As well as, 1,25(OH) 2D also inhibits T cell proliferation, production of cytokines, and their expression, the possible reason may be due to VDR-RXR heterodimer. Have been reported that 1,25(OH) 2D promoted the expression of FOXP3 by VDR-VDRE. Th2 increased production of cytokines such as IL-4, IL-5, and IL-10 due to Vit D3, leading to a shift to a more regulated immune response and less active, in other words, lower autoimmunity. Additional, positive effect on regulatory (Treg) cells function, suppression of Th17, and Decreasing MHC class II (can be found on monocytes, help stimulate T cells) leading to decreasing stimulation of T cells. Vit D3 had a positive effect on T killer cells by developing and production of cytokines, which can suggest that Vit D3 may be necessary for human immune system development. [6,8-10]
According to Yang, C. Y et al. Previous studies, done on Vit D3, demonstrated a direct effect on beta cells. Protection of beta cells of the pancreas, and lowering the needed dose of therapy for insulin, though temporally and had to consume Vit D3 supplements. [8] In vitro study by Miller, K.M. et al. reported that beta cells of the pancreas had increased expression of VDR and 1α-hydroxylase, besides Vit D3 response was found in the insulin gene promoter. Rat beta-cell showed response {1,25(OH) D} by increasing calcium [9]. The result of the study revealing the direct effect of Vit D3 on beta cells and possible deficiency of calcium, lowers the physiological function because of decreased calcium. However, there was no conclusive answer on the protection factor of Vit D3 as mentioned in Yang C. Y et al. One study showed that exposure of beta-cell supplied by Vit D3 to inflammatory cytokines didn’t show protection on beta cells, on the other hand, a different study in vitro reported that beta cells surrounded by proinflammatory cytokines were supplied with Vit D3 and that lead to lower CD+8 activity. [9] It is difficult to clarify the indirect effect as not much research was done on this topic.
Taken into consideration that people with Vit D3 deficiency may have malnutrition and possible other deficiency in electrolytes or vitamins. One of the important electrolytes that are needed for insulin secretion is Calcium. The function of beta cells includes the conversion of proinsulin to insulin, insulin exocytosis, and all of them are have calcium-dependent enzymes. Vit D3 has an important function in calcium hemostasis by absorption from GI, bones, and kidney. Vit D3 deficiency leads to a decrease in insulin secretion. According to Wolden-Kirk, H et al. study on rats to observe the importance of calcium deficiency compared to Vit D3 deficiency on insulin secretion. Rats that had relative Vit D3 deficiency and hypocalcemia secreted the normal amount of insulin 21 to 63 days after birth. Another study that was mentioned reported an elevation in T1DM incidence in rats with Vit D3 deficiency, even though the calcium was in range. [10] The study tried to break the relationship
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between calcium and Vit D3 to understand if hypocalcemia may lead to T1DM. According to the result, calcium rule is insignificant and not as thought to be.
Figure 4. Function of immune cell and the effect of Vit D3 on them [4] Figure 3. The immunomodulatory effects of Vit D3 on immune cells [8]
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12. CONCLUSION
In this literature review, I analyzed and researched works done in the last ten years to present the most updated information about T1DM incidence in Vit D3 deficiency Several conclusions were drawn from the research done:
• The majority of diagnosed patients with T1DM had some kind of Vit D3 deficiency. However, it is not proven if a lack of proper plasma levels of Vit D3 can lead to T1DM.
• Most of the reviewed studies didn’t study the genders as a risk factor.
• According to studies that were revised couldn’t be answered. Possible mechanism of Vit D3 deficiency on the pathogenesis of T1DM is immunomodulation, by lowering and regulating hyperimmune reaction. But more studies are needed to answer this question, should be proved in other studies.
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