Nutri-epigenetics: the effect of maternal diet and early nutrition on the pathogenesis of autoimmune diseases.

Autoimmune diseases comprise a wide group of diseases involving a self-response of the immune system against the host. The etiopathogenesis is very complex involving disease-specific factors but also environmental factors, among which the diet. Maternal diet during pregnancy as well as early nutrition recently attracted the interest of the scientists as contributing to the immune programming. In this paper, we reviewed the most recent literature on the effect of maternal diet and early nutrition in modulating the immune system in a selected subset of autoimmune diseases: type 1 diabetes, celiac disease, inflammatory bowel disease, juvenile idiopathic arthritis and rheumatoid arthritis. Particularly, we focused our narrative on the role of maternal and perinatal nutrition in the epigenetic mechanisms underlying the auto-immune response. Maternal diet during pregnancy as well as breastfeeding and early nutrition play a big role in many epigenetic mechanisms. Most of the nutrients consumed by the mother and the infant are known exerting epigenetic functions, such as folate, methionine, zinc, vitamins B12 and D, fibers, casein and gliadin, and they were linked to gene expression changes in the immune pathways. Despite the common role of maternal diet, breastfeeding and early nutrition in almost all the autoimmune diseases, each disease seems to have specific diet-driver epigenetic mechanisms that require further investigations. The research in this field is opening new routes to establishing a precision nutrition approach to the auto-immune diseases.

Vitamin D effects and endocrine diseases.

A lack of vitamin D has been linked to autoimmune diseases including type 1 diabetes, autoimmune thyroiditis and to obesity. The prevalence of vitamin D deficiency is higher in diabetic or obese children and patients with thyroiditis compared to healthy controls. Moreover, low vitamin D values seem to be associated with major complications and poor glycemic control, in particular in obese children. Supplementation with vitamin D, which has immune-regulatory properties, may support our therapies and improve the outcomes in different diseases. Although some studies suggest a possible role of vitamin D in the etiology of autoimmune diseases and obesity, data on supplementation benefits are inconclusive and further studies are needed. In this paper, we focus on the current evidence regarding vitamin D function in endocrine diseases and possible benefits of its supplementation in pediatric age.

Association between Bioactive Molecules in Breast Milk and Type 1 Diabetes Mellitus.

The association between breastfeeding and type 1 diabetes mellitus (T1DM) is controversial. However, several recent studies have established a link between these two factors, necessitating a need to review this subject to raise public awareness. Current research indicates that breast milk contains a variety of bioactive substances including immunoglobulins, oligosaccharides, insulin, lactoferrin, lysozyme, cytokines, epidermal growth factors, leukocytes, nucleotides, beneficial bacteria and vitamins. Such substances strengthen the breastfeeding infant's immune system, both directly, by increasing gut microbiota diversity and attacking harmful bacteria and pro-inflammatory molecules, and indirectly, by increasing thymus performance. Accordingly, a lack of or inadequate breastfeeding may predispose infants to several autoimmune disorders, including T1DM. Nursing mothers and caregivers are therefore advised to follow optimal breastfeeding practices prior to introducing complementary foods.

Serum 25-hydroxyvitamin D concentration in childhood and risk of islet autoimmunity and type 1 diabetes: the TRIGR nested case-control ancillary study.

AIMS/HYPOTHESIS: Our aim was to study the association between serum 25-hydroxyvitamin D (25OHD) concentration and islet autoimmunity and type 1 diabetes in children with an increased genetic risk of type 1 diabetes. METHODS: Serum samples for 25OHD measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children in 15 countries. Case children (n = 244) were defined as having positivity for at least two out of four diabetes-associated autoantibodies measured at any one sample. For each case child, two control children were selected matched for country and date of birth (±1 year) (n = 488). Of the case children, 144 developed type 1 diabetes. Serum 25OHD was measured repeatedly in infancy and childhood and was compared according to age at the first seroconversion (at 6, 12 and 18 months prior to and at seroconversion) and calendar age (0, 6, 12 and 18 months). RESULTS: In children with islet autoimmunity, mean serum 25OHD concentration was lower 18 months prior to the age of first seroconversion of the case children compared with the control children (57.7 vs 64.8 nmol/l, p = 0.007). In children with type 1 diabetes (n = 144), mean serum 25OHD concentration was lower 18 months prior to the age of the first seroconversion (58.0 vs 65.0 nmol/l, p = 0.018) and at the calendar age of 12 months (70.1 vs 75.9 nmol/l, p = 0.031) than in their control counterparts. Analyses were adjusted for month of sample collection, human leucocyte antigen genotype, maternal type 1 diabetes and sex. CONCLUSIONS/INTERPRETATION: The results suggest that early postnatal vitamin D may confer protection against the development of type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777.

Dilemmas in Vitamin D Management in Children and Adolescents.

The importance of vitamin D and its role in several biological processes has been a topic of interest in recent years. Vitamin D is an essential nutrient that is needed for metabolic bone health and for maintaining bone calcium homeostasis. It is primarily synthesized in the skin on exposure to sunlight. Of late, vitamin D deficiency has been associated with conditions such as obesity, poor control of asthma and other autoimmune diseases, which has led to questions about its potential role in causation and management of these conditions. Given the increase in data about this topic, providers may often have questions about whom to screen and what to tell patients. In this article, we address screening guidelines for vitamin D in children and adolescents, management of vitamin D deficiency, and current literature on the role of vitamin D in conditions such as obesity, asthma, and type 1 diabetes mellitus. [Pediatr Ann. 2019;48(8):e298-e303.].

Perinatal risk factors for type 1 diabetes revisited: a population-based register study.

AIMS/HYPOTHESIS: Single-centre studies and meta-analyses have found diverging results as to which early life factors affect the risk of type 1 diabetes during childhood. We wanted to use a large, nationwide, prospective database to further clarify and analyse the associations between perinatal factors and the subsequent risk for childhood-onset type 1 diabetes using a case-control design. METHODS: The Swedish Childhood Diabetes Register was linked to the Swedish Medical Birth Register and National Patient Register, and 14,949 cases with type 1 diabetes onset at ages 0-14 years were compared with 55,712 matched controls born from the start of the Medical Birth Register in 1973 to 2013. After excluding confounders (i.e. children multiple births, those whose mother had maternal diabetes and those with a non-Nordic mother), we used conditional logistic regression analyses to determine risk factors for childhood-onset type 1 diabetes. We used WHO ICD codes for child and maternal diagnoses. RESULTS: In multivariate analysis, there were small but statistically significant associations between higher birthweight z score (OR 1.08, 95% CI 1.06, 1.10), delivery by Caesarean section (OR 1.08, 95% CI 1.02, 1.15), premature rupture of membranes (OR 1.08, 95% CI 1.01, 1.16) and maternal urinary tract infection during pregnancy (OR 1.39, 95% CI 1.04, 1.86) and the subsequent risk of childhood-onset type 1 diabetes. Birth before 32 weeks of gestation was associated with a lower risk of childhood-onset type 1 diabetes compared with full-term infants (OR 0.54, 95% CI 0.38, 0.76), whereas birth between 32 and 36 weeks' gestation was associated with a higher risk (OR 1.24, 95% CI 1.14, 1.35). In subgroup analyses (birth years 1992-2013), maternal obesity was independently associated with subsequent type 1 diabetes in the children (OR 1.27, 95% CI 1.15, 1.41) and rendered the association with Caesarean section non-significant. In contrast to previous studies, we found no association of childhood-onset type 1 diabetes with maternal-child blood-group incompatibility, maternal pre-eclampsia, perinatal infections or treatment of the newborn with phototherapy for neonatal jaundice. The proportion of children with neonatal jaundice was significantly higher in the 1973-1982 birth cohort compared with later cohorts. CONCLUSIONS/INTERPRETATION: Perinatal factors make small but statistically significant contributions to the overall risk of childhood-onset type 1 diabetes. Some of these risk factors, such as maternal obesity, may be amendable with improved antenatal care. Better perinatal practices may have affected some previously noted risk factors over time.

Fas/FasL-mediated cell death in rat's diabetic hearts involves activation of calcineurin/NFAT4 and is potentiated by a high-fat diet rich in corn oil.

This study investigated if calcineurin/nuclear factor of activated T cells (NFAT) axis mediates the cardiac apoptosis in rats with type 1 diabetes mellitus (T1DM)-induced rats or administered chronically high-fat diet rich in corn oil (CO-HFD). Also, it investigated the impact of chronic administration of CO-HFD on Fas/Fas ligand (Fas/FasL)-induced apoptosis in the hearts of T1DM-induced rats. Adult male Wistar rats (140-160 g) were classified as control: (10% fat) CO-HFD: (40% fat), T1DM, and T1DM + CO-HFD (n=20/each). In vitro, cardiomyocytes were cultured in either low glucose (LG) or high glucose (HG) media in the presence or absence of linoleic acid (LA) and other inhibitors. Compared to the control, increased reactive oxygen species (ROS), protein levels of cytochrome C, cleaved caspase-8 and caspase-3, myocardial damage and impeded left ventricular (LV) function were observed in the hearts of all treated groups and maximally in T1DM + CO-HFD-treated rats. mRNA of all NFAT members (NFAT1-4) were not affected by any treatment. CO-HFD or LA significantly up-regulated Fas levels in both LVs and cultured cardiomyocytes in a ROS dependent mechanism and independent of modulating intracellular Ca2+ levels or calcineurin activity. T1DM or hyperglycemia significant up-regulated mRNA and protein levels of Fas and FasL by activating Ca2+/calcineurin/NFAT-4 axis. Furthermore, Fas/FasL cell death induced by recombinant FasL (rFasL) or HG media was enhanced by pre-incubating the cells with LA. In conclusion, activation of the Ca2+/calcineurin/NFAT4 axis is indispensable for hyperglycemia-induced Fas/FasL cell death in the cardiomyocytes and CO-HFD sensitizes this by up-regulation of Fas.

Maternal and Early Life Iron Intake and Risk of Childhood Type 1 Diabetes: A Danish Case-Cohort Study.

BACKGROUND: Iron overload has been associated with diabetes. Studies on iron exposure during pregnancy and in early life and risk of childhood type 1 diabetes (T1D) are sparse. We investigated whether iron supplementation during pregnancy and early in life were associated with risk of childhood T1D. METHODS: In a case-cohort design, we identified up to 257 children with T1D (prevalence 0.37%) from the Danish National Birth Cohort through linkage with the Danish Childhood Diabetes Register. The primary exposure was maternal pure iron supplementation (yes/no) during pregnancy as reported in interview two at 30 weeks of gestation (n = 68,497 with iron supplement data). We estimated hazard ratios (HRs) using weighted Cox regression adjusting for multiple confounders. We also examined if offspring supplementation during the first 18 months of life was associated with later risk of T1D. RESULTS: Maternal iron supplementation was not associated with later risk of T1D in the offspring HR 1.05 (95% CI: 0.76⁻1.45). Offspring intake of iron droplets during the first 18 months of life was inversely associated with risk of T1D HR 0.74 (95% CI: 0.55⁻1.00) (ptrend = 0.03). CONCLUSIONS: Our large-scale prospective study demonstrated no harmful effects of iron supplementation during pregnancy and in early life in regard to later risk of childhood T1D in the offspring.

Intake of polyunsaturated fatty acids and risk of preclinical and clinical type 1 diabetes in children-a systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: The association between the intake of polyunsaturated fatty acids (PUFAs) and the risk of preclinical and clinical type 1 diabetes (T1D) in children has generated conflicting results. Thus, we aimed to evaluate the definite effects of PUFAs on the risk of preclinical and clinical T1D. SUBJECTS/METHODS: Three databases were systematically searched up to July 18, 2017 to identify relevant observational studies, without language restriction. Any study included should report the risk of preclinical or clinical T1D in children with PUFAs supplementation compared with the controls, and report relative risks (RRs) or odds ratios (ORs) or provide data for estimation. Pooled RRs (or ORs) with 95% confidence intervals (CI) were calculated using random-effects models irrespective of statistical heterogeneity assessed by I2 statistic. RESULTS: We identified seven studies (three prospective cohort studies and four case-control studies) on PUFAs intake during pregnancy or during early life in children. The pooled RR between the risk of preclinical T1D and n-3 PUFAs supplementation against controls was 0.98 (95%CI, 0.85-1.13), with no heterogeneity. The results were similar after the intake during pregnancy, but not during early life in children (pooled RR, 0.45; 95%CI, 0.21-0.96; P = 0.039). N-3 PUFAs supplementation was not associated with a significant reduction in the risk of clinical T1D in children (pooled RR, 0.87; 95%CI, 0.71-1.08), with substantial heterogeneity(I2 = 64.7%). No association was also found between n-6 PUFAs intake and the risk of preclinical (1.07; 0.97-1.017) or clinical T1D (1.05; 0.92-1.20) in children. CONCLUSIONS: The result of the meta-analysis does not support that n-3 or n-6 PUFAs supplementation in children affects the overall risk of preclinical or clinical T1D. However, n-3 PUFAs intake in early life might reduce the risk of preclinical T1D. Therefore, this finding should be verified by more and well-designed prospective research in the future.

The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: a narrative review.

Diabetes mellitus, a metabolic disorder associated with chronic complications, is traditionally classified into two main subtypes. Type 1 diabetes mellitus (T1DM) results from gradual pancreatic islet ß cell autoimmune destruction, extending over months or years. Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder, with both insulin resistance and impairment in insulin secretion contributing to its pathogenesis. Vitamin D is a fat-soluble vitamin with an established role in calcium metabolism. Recently, several studies have provided evidence suggesting a role for it in various non-skeletal metabolic conditions, including both types of diabetes mellitus. Preclinical studies of vitamin D action on insulin secretion, insulin action, inflammatory processes, and immune regulation, along with evidence of an increase of hypovitaminosis D worldwide, have prompted several epidemiological, observational, and supplementation clinical studies investigating a potential biological interaction between hypovitaminosis D and diabetes. This narrative review aims to summarize current knowledge on the effect of vitamin D on T1DM and T2DM pathogenesis, prevention, and treatment, as well as on micro- and macrovascular complications of the disease. Furthermore, on the basis of current existing evidence, we aim to highlight areas for potential future research.

Dietary Cows' Milk Protein A1 Beta-Casein Increases the Incidence of T1D in NOD Mice.

The contribution of cows' milk containing beta-casein protein A1 variant to the development of type 1 diabetes (T1D) has been controversial for decades. Despite epidemiological data demonstrating a relationship between A1 beta-casein consumption and T1D incidence, direct evidence is limited. We demonstrate that early life exposure to A1 beta-casein through the diet can modify progression to diabetes in non-obese diabetic (NOD) mice, with the effect apparent in later generations. Adult NOD mice from the F0 generation and all subsequent generations (F1 to F4) were fed either A1 or A2 beta-casein supplemented diets. Diabetes incidence in F0⁻F2 generations was similar in both cohorts of mice. However, diabetes incidence doubled in the F3 generation NOD mice fed an A1 beta-casein supplemented diet. In F4 NOD mice, subclinical insulitis and altered glucose handling was evident as early as 10 weeks of age in A1 fed mice only. A significant decrease in the proportion of non-conventional regulatory T cell subset defined as CD4⁺CD25-FoxP3⁺ was evident in the F4 generation of A1 fed mice. This feeding intervention study demonstrates that dietary A1 beta-casein may affect glucose homeostasis and T1D progression, although this effect takes generations to manifest.

Prenatal iron exposure and childhood type 1 diabetes.

Iron overload due to environmental or genetic causes have been associated diabetes. We hypothesized that prenatal iron exposure is associated with higher risk of childhood type 1 diabetes. In the Norwegian Mother and Child cohort study (n = 94,209 pregnancies, n = 373 developed type 1 diabetes) the incidence of type 1 diabetes was higher in children exposed to maternal iron supplementation than unexposed (36.8/100,000/year compared to 28.6/100,000/year, adjusted hazard ratio 1.33, 95%CI: 1.06-1.67). Cord plasma biomarkers of high iron status were non-significantly associated with higher risk of type 1 diabetes (ferritin OR = 1.05 [95%CI: 0.99-1.13] per 50 mg/L increase; soluble transferrin receptor: OR = 0.91 [95%CI: 0.81-1.01] per 0.5 mg/L increase). Maternal but not fetal HFE genotypes causing high/intermediate iron stores were associated with offspring diabetes (odds ratio: 1.45, 95%CI: 1.04, 2.02). Maternal anaemia or non-iron dietary supplements did not significantly predict type 1 diabetes. Perinatal iron exposures were not associated with cord blood DNA genome-wide methylation, but fetal HFE genotype was associated with differential fetal methylation near HFE. Maternal cytokines in mid-pregnancy of the pro-inflammatory M1 pathway differed by maternal iron supplements and HFE genotype. Our results suggest that exposure to iron during pregnancy may be a risk factor for type 1 diabetes in the offspring.

Metabolomic analysis and biochemical changes in the urine and serum of streptozotocin-induced normal- and obese-diabetic rats.

Diabetes mellitus (DM) is a chronic disease that can affect metabolism of glucose and other metabolites. In this study, the normal- and obese-diabetic rats were compared to understand the diabetes disorders of type 1 and 2 diabetes mellitus. This was done by evaluating their urine metabolites using proton nuclear magnetic resonance (1H NMR)-based metabolomics and comparing with controls at different time points, considering the induction periods of obesity and diabetes. The biochemical parameters of the serum were also investigated. The obese-diabetic model was developed by feeding the rats a high-fat diet and inducing diabetic conditions with a low dose of streptozotocin (STZ) (25 mg/kg bw). However, the normal rats were induced by a high dose of STZ (55 mg/kg bw). A partial least squares discriminant analysis (PLS-DA) model showed the biomarkers of both DM types compared to control. The synthesis and degradation of ketone bodies, tricarboxylic (TCA) cycles, and amino acid pathways were the ones most involved in the variation with the highest impact. The diabetic groups also exhibited a noticeable increase in the plasma glucose level and lipid profile disorders compared to the control. There was also an increase in the plasma cholesterol and low-density lipoprotein (LDL) levels and a decline in the high-density lipoprotein (HDL) of diabetic rats. The normal-diabetic rats exhibited the highest effect of all parameters compared to the obese-diabetic rats in the advancement of the DM period. This finding can build a platform to understand the metabolic and biochemical complications of both types of DM and can generate ideas for finding targeted drugs.

Vitamin D deficiency in childhood: old lessons and current challenges.

Hypovitaminosis D in childhood is a re-emerging public health problem in developed countries. New life style habits, current "epidemics" of obesity in children and adolescents worldwide, and other preventable risk factors may play a role in favoring the occurrence of vitamin D deficiency. In addition to skeletal consequences, hypovitaminosis D has been found to be involved in the development of serious health extra-skeletal problems in childhood, including atopy and autoimmunity. The increasing concerns about the global health impact of vitamin D deficiency make further research necessary to fill the gaps of knowledge in this field, and particularly to establish universally accepted "normal" serum 25(OH)D levels in the pediatric population, and to improve strategies for the screening, prevention and treatment of hypovitaminosis D. This review discusses the key points of hypovitaminosis D in childhood in the light of new knowledge, and highlights the limitations of current strategies to control this condition.

[Sustained serum 25-hydroxyvitamin D concentrations for one year with cholecalciferol supplementation improves glycaemic control and slows the decline of residual ß cell function in children with type 1 diabetes].

INTRODUCTION: Studies using vitamin D for preservation of residual b-cell function (RBCF) and improvement of glycaemic control in type 1 diabetes (T1D) have shown inconsistent results. The possible causes of the discrepancies in the results are related to the dosage, type, and duration of vitamin D supplementation, C-peptide concentration at entry into the study, and the influence of glycaemic control on RBCF during supplementation. AIM OF THE STUDY: To evaluate the effect of cholecalciferol supplementation on RBCF and glycaemic control in children with T1D. MATERIAL AND METHODS: Forty-two children aged 6-12 years and within 1-2 years of diagnosis of T1D received cholecalciferol 3000 IU/day for one year (Group A). Thirty patients were recruited as controls (Group B). The mean changes in stimulated C-peptide levels, HbA1c, fasting blood glucose (FBG), mean blood glucose (MBG), and mean total daily insulin (TDI) dose from baseline to the study endpoint were calculated. RESULTS: Children in Group A showed lower mean FBG, MBG, HbA1c, and lesser TDI as compared to Group B at all follow-up visits. However, the differences in these parameters between the two groups reached statistical significance towards the study endpoint. Within group A, the decline in C-peptide levels from baseline to the endpoint was minor (-0.13 ±0.11, p-value = 0.16) as compared to a substantial decline in Group B (-0.41 ±0.07, p-value = 0.00). Comparison of the mean decrease in stimulated C-peptide levels from baseline to the endpoint between the two groups was also statistically significant (-0.13 ±0.11 vs. -0.41 ±0.07, p-value = 0.00). The mean decrease in FBG and MBG in Group A were greater, whereas the comparison of the mean decrease in HbA1c between the groups reached statistical significance at the study endpoint (p-value = 0.04). The decrease in the TDI was, however, similar in the two groups (p-value = 0.10). CONCLUSIONS: Sustained serum 25-(OH)D concentrations with cholecalciferol supplementation for one year improves metabolic control and slows the decline of RBCF in children with T1D. Larger studies with longer duration and cholecalciferol dosage stratification are suggested.

Environmental Factors Associated with Type 1 Diabetes Development: A Case Control Study in Egypt.

Uncertainty still exists regarding the role of some environmental risk in the development of type 1 diabetes mellitus (T1DM) both globally and in Egypt. The objective here was to explore the potential environmental risk factors associated with the development of T1DM among children in Egypt. A case-controlled study of 204 T1DM children and an equal number of age and sex-matched controls was conducted in Assiut, Egypt. Data regarding the parental, gestational, neonatal, and childhood possible risk factors for T1DM were evaluated. The final sex adjusted multivariable logistic regression model revealed that the risk for T1DM was significantly higher among rural residents (aOR = 2.03, 95% CI: 1.30-4.25), those with parental history of T1DM (aOR = 9.03, 95% CI: 1.02-83.32), birth through cesarean section (aOR = 2.13, 95% CI: 1.09-5.03), and having history of early introduction of cow milk in the first year of life (aOR = 19.49, 95% CI: 8.73-45.53). On the other hand, a protective effect was observed between at least six months' breastfeeding, vitamin D supplementation in the first year of life, high physical activity, and the development of T1DM. Educational programs should be adopted to improve awareness and knowledge of the parents to avoid the increased risk factors and encourage protective practices.

Vitamin D deficiency and diabetes.

Vitamin D deficiency has been linked to the onset of diabetes. This review summarizes the role of Vitamin D in maintaining the normal release of insulin by the pancreatic beta cells (ß-cells). Diabetes is initiated by the onset of insulin resistance. The ß-cells can overcome this resistance by releasing more insulin, thus preventing hyperglycaemia. However, as this hyperactivity increases, the ß-cells experience excessive Ca2+ and reactive oxygen species (ROS) signalling that results in cell death and the onset of diabetes. Vitamin D deficiency contributes to both the initial insulin resistance and the subsequent onset of diabetes caused by ß-cell death. Vitamin D acts to reduce inflammation, which is a major process in inducing insulin resistance. Vitamin D maintains the normal resting levels of both Ca2+ and ROS that are elevated in the ß-cells during diabetes. Vitamin D also has a very significant role in maintaining the epigenome. Epigenetic alterations are a feature of diabetes by which many diabetes-related genes are inactivated by hypermethylation. Vitamin D acts to prevent such hypermethylation by increasing the expression of the DNA demethylases that prevent hypermethylation of multiple gene promoter regions of many diabetes-related genes. What is remarkable is just how many cellular processes are maintained by Vitamin D. When Vitamin D is deficient, many of these processes begin to decline and this sets the stage for the onset of diseases such as diabetes.

Vitamin D and diabetes mellitus: Causal or casual association?

The incidence of both type 2 and type 1 diabetes mellitus has been increasing worldwide. Vitamin D deficiency, or the awareness of its prevalence, has also been increasing. Vitamin D may have a role in the pathogenic mechanisms predisposing to type 2 diabetes by modulating insulin resistance and/or pancreatic ß-cell function. Vitamin D status or elements involved in its activation or transport may also be involved in the development of type 1 diabetes mellitus through immunomodulatory role . Based on these observations a potential association between vitamin D and diabetes has been hypothesized. In this review we discuss up to date evidence linking vitamin D with the development of diabetes. Moreover, the role of vitamin D supplementation in the prevention of both types of diabetes is analysed together with its role in improving glycemic control in diabetic patients. We also address the potential role of vitamin D deficiency in the development of macro- and microvascular complications in diabetes. Finally, we provide recommendation for Vitamin D therapy in diabetes in view of current evidence and highlight areas for potential future research in this area.

Low perinatal zinc status is not associated with the risk of type 1 diabetes in children.

AIM: Immunologic events during fetal life may play a part in the pathogenesis of type 1 diabetes (T1D). As zinc is involved in immunologic processes, the purpose was to investigate perinatal zinc status and the later risk of developing T1D and association to age at onset. METHODS: A population-based case-control study based on data from Danish Childhood Diabetes Register and the Danish Newborn Screening Biobank. Cases and controls were matched by birth year and month. Zinc status was analyzed in dried blood spots collected 5 to 7 days after birth. Logistic regression model was used to test the influence of zinc on risk of T1D. Linear regression modeling was used to examine the association between zinc status and covariates as well as age at onset. Zinc status was adjusted for HLA-DQB1 genotype, birth data and maternal age. RESULTS: Each doubling in perinatal zinc status was not associated with T1D risk; odds ratio (OR) = 1.06 (95% confidence interval [CI] 0.84, 1.32) ( P = 0.62), adjusted for birth year and season. This finding persisted after adjustment for possible confounders; OR = 1.01 (95% CI 0.77, 1.34) ( P = 0.93). In none of the cohorts there were significant associations to age at onset. CONCLUSION: The risk of developing T1D in Danish children was not associated with perinatal zinc status nor age at onset.

Standardized bovine colostrum derivative impedes development of type 1 diabetes in rodents.

Bovine colostrum is a rich source of nutrients and immunologically active components that play a role in conveying passive immunity to the offspring, protection and maturation of new-born's gastrointestinal tract. Colostrum has exerted positive effects in diseases affecting gastrointestinal tract, as well as type 2 diabetes (T2D). However, health-promoting effects in type 1 diabetes have not been reported. The aim of this study was to investigate therapeutic value of oral administration of standardized bovine colostrum derivative (SBCD) in three models of type 1 diabetes (T1D): spontaneously developed T1D in NOD mice and BB-DP rats, and in chemically induced T1D in C57BL/6 mice with multiple low doses of streptozotocin (MLDS). SBCD was administered per os and the disease development was evaluated by weekly measurement of blood glucose and by histological analyses of the pancreas. SBCD administration prevented diabetes development in all three models, as indicated by euglicaemia. Ex vivo analysis of cytokine expression and production in the spleen and mesenteric lymph nodes (MLN) in MLDS challenged mice revealed a strong modulation of the immune response. In the MLN cells SBCD disrupted harmful Th17 response induced by MLDS. Expression of Th1 signature cytokine IFN-γ was down-regulated in MLN cells of SBCD-treated mice, while IL-4 secretion (Th2 cytokine) was up-regulated in comparison to diabetic group. Modulation of the immune response seen in the MLN protruded to the spleen, giving overall less infiltration of immune cells to the pancreas. SBCD acted on immune cells and halted (auto) aggression towards pancreatic beta cells. Moreover, SBCD induced beta cell proliferation. Hence, this derivative could be tested in diabetes and other similar diseases with aberrant immune response.