Breastfeeding and circulating immunological markers during the first 3 years of life : the DIABIMMUNE study

Aims/hypothesis Our aim was to study the association between duration of breastfeeding and circulating immunological markers during the first 3 years of life in children with HLA-conferred susceptibility to type 1 diabetes. Methods We performed a longitudinal analysis of 38 circulating immunological markers (cytokines, chemokines and growth factors) in serum samples from Finnish (56 individuals, 147 samples), Estonian (56 individuals 148 samples) and Russian Karelian children (62 individuals, 149 samples) at 3, 6, 12, 18, 24 and 36 months of age. We also analysed gut inflammation markers (calprotectin and human beta defensin-2) at 3 (n = 96) and 6 months (n = 153) of age. Comparisons of immunological marker medians were performed between children who were breastfed for 6 months or longer vs children who were breastfed for less than 6 months. Results Breastfeeding for 6 months or longer vs less than 6 months was associated with lower median of serum immunological markers at 6 months (granulocyte-macrophage colony-stimulating factor [GMCSF], macrophage inflammatory protein [MIP-3 alpha]), 12 months (IFN-alpha 2, vascular endothelial growth factor, GMCSF, IFN-gamma, IL-21), 18 months (FGF-2, IFN-alpha 2) and 24 months of age (CCL11 [eotaxin], monocyte chemoattractant protein-1, TGF alpha, soluble CD40 ligand, IL-13, IL-21, IL-5, MIP-1 alpha) (all p < 0.01) but not at 36 months of age. Breastfeeding was not associated with gut inflammation markers at 3 and 6 months of age. Conclusions/interpretation Children who were breastfed for 6 months or longer had lower medians for 14 immunological markers at one or more age points during the first 2 years of life compared with children who were breastfed for less than 6 months. The clinical meaning of the findings is not clear. However, the present study contributes to the understanding of immunological differences in children that have been breastfed longer, and thus provides a mechanistic suggestion for the previously observed associations between breastfeeding and risk of type 1 diabetes.Peer reviewe

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.Peer reviewe

Ultraviolet B radiation modifies circadian time in epidermal skin and in subcutaneous adipose tissue

Background Recent findings suggest that circadian time regulates cellular functions in the skin and may affect protection against ultraviolet radiation (UVR). It is not known, however, whether UVR through skin directly affects the expression of circadian genes. We investigated the effect of ultraviolet B (UVB) exposure on cryptochrome circadian clock 1 (CRY1), cryptochrome circadian clock 2 (CRY2), and circadian associated repressor of transcription (CIART) genes. Methods Healthy volunteers (n = 12) were exposed to narrow-band UVB radiation of four standard erythemal dose (SED). Epidermal/dermal and subcutaneous adipose tissue samples were obtained by punch biopsies from irradiated and non-irradiated skin 10 cm away from the irradiated site 24 hours after UVB exposure. Gene expression of CRY1, CRY2, and CIART was measured using RT-PCR (TaqMan). Results Ultraviolet B radiation affected mRNA expression in the epidermal/dermal skin and in the subcutaneous adipose tissue. It down-regulated expression of CRY2 gene in the epidermal/dermal skin, whereas it up-regulated expression of CRY1 and CIART genes in the subcutaneous adipose tissue. Conclusion We showed for the first time that UVB radiation affects expression of circadian genes in the subcutaneous adipose tissue. Further studies are warranted to understand the mechanisms in detail.Peer reviewe

Serum fatty acids and risk of developing islet autoimmunity : A nested case-control study within the TRIGR birth cohort

Background Circulating fatty acids have been linked to development of type 1 diabetes. Objectives To study the prospective associations of serum fatty acids with the risk of islet autoimmunity in high-risk children. Methods A nested case-control selection was carried out within the TRIGR cohort, which included infants with HLA (DQB1 or DQA1)-conferred disease susceptibility and a first-degree relative with type 1 diabetes, born between 2002 and 2007 in 15 countries and followed-up until 2017. The present study included 244 case children positive for at least two islet autoantibodies (ICA, IAA, GADA, and IA-2A) and two control children were matched for country and age. Proportions of 26 serum fatty acids at cord blood and at 6, 12, and 18 months of age were assessed using gas-chromatography. Results The average proportions of the following fatty acids were associated with an increased risk of islet autoimmunity, adjusted for sex, HLA risk, and maternal type 1 diabetes: pentadecanoic acid (15:0) (OR 3.41: 95% CI 1.70, 6.85), heptadecanoic acid (iso 17:0) (2.64: 1.62, 4.28) and (anteiso 17:0) (2.27: 1.39, 3.70), stearic acid (18:0) (23.8: 2.32, 244.6), and conjugated linoleic acid (18:2n-7) (2.60: 1.47, 4.59). Breastfeeding and not having maternal type 1 diabetes were positively associated with levels of the above-mentioned fatty acids. N-3 fatty acids were not consistently associated with islet autoimmunity. Conclusions We found direct associations of pentadecanoic acid, heptadecanoic acid, stearic acid, and conjugated linoleic acid with the risk of islet autoimmunity. Further studies are needed to understand the complex role of fatty acids in the development of type 1 diabetes.Peer reviewe

Associations Between Serum Fatty Acids and Immunological Markers in Children Developing Islet Autoimmunity-The TRIGR Nested Case-Control Study

AimsAltered immune functions as well as fatty acid intake and status have been associated with the development of type 1 diabetes. We aimed to study the relationship between fatty acids and immunological markers in young children with increased genetic risk for type 1 diabetes in order to define putative mechanisms related to development of islet autoimmunity. MethodsSerum samples for fatty acid and immunological marker measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children born between 2002 and 2007 in 15 countries. Case children (n = 95) were defined as having repeated positivity for at least two out of four diabetes-associated autoantibodies. For each case child, control children were selected matched for country and date of birth (n = 173). Serum fatty acids and immunological markers were measured from cord serum and at the age of 6 and 12 months. Spearman correlation coefficients were calculated between fatty acids and immunological markers. ResultsCorrelations between circulating fatty acids and immunological markers were different in case children who developed islet autoimmunity than in control children already at birth continuing across the first year of life. In case children, saturated fatty acids (SFAs) showed stronger correlations with immunological markers, while in controls, polyunsaturated fatty acids (PUFAs) showed stronger correlations. ConclusionsIn cases, SFAs were associated with several immunological markers (CXCL10, IL-6, IL-9, IL-17, and CM-CSF) previously linked to the type 1 diabetes disease process. Findings indicate that fatty acids could have immunomodulatory potential in the early phase of the disease development, although causality between fatty acids and the immunological pathways remains to be explored. Trial registry numberNCT00179777Peer reviewe

Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI

Purpose: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. Methods: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 106 CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7–12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. Results: In BMC-treated patients, there was a decrease in [11C]-HED defect size (−4.9 ± 4.0 vs. −1.6 ± 2.2%, p = 0.08) and an increase in [18F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. −0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (−4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m2, p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (−0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. −5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). Conclusion: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo

Maternal VDR variants rather than 25-hydroxyvitamin D concentration during early pregnancy are associated with type 1 diabetes in the offspring

This study was supported by the Finnish Academy (grant 127219), the European Foundation for the Study of Diabetes, the Novo Nordisk Foundation, the Diabetes Research Foundation, the EVO funding of the South Ostrobothnia Central Hospital from the Ministry ofHealthand SocialAffairs (EVO1107), the BiomedicumHelsinki Foun- dation, the Jalmari and Rauha Ahokas Foundation, the Yrjö Jahnsson Foundation, the Suoma Loimaranta-Airila Fund, the Onni and Hilja Tuovinen Foundation and the Juho Vainio Foundation