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See detailHydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial
Knip, M.; Åkerblom, H.K.; Becker, D. et al

in JAMA : Journal of the American Medical Association (2014), 311(22), 2279-2287

Importance The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in ... [more ▼]

Importance The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. Objective To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. Design, Setting, and Participants A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows’ milk–based formula. The participants were observed to April 16, 2013. Interventions The participants received either a casein hydrolysate or a conventional cows’ milk formula supplemented with 20% of the casein hydrolysate. Main Outcomes and Measures Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated–2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). Results The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. Conclusions and Relevance Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. [less ▲]

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See detailUse of vitamin D supplements during infancy in an international feeding trial
Lehtonen, E.; Ormisson, A.; Nucci, A. et al

in Public Health Nutrition (2014), 17(4), 810-822

To examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial. Longitudinal study.

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See detailGrowth differences between North American and European children at risk for type 1 diabetes
Nucci, A.M.; Becker, D.J.; Virtanen, S.M. et al

in Pediatric Diabetes (2012)

AIM: To evaluate the relationships between early growth and regional variations in type 1 diabetes (T1D) incidence in an international cohort of children with familial and genetic risk for T1D. METHODS ... [more ▼]

AIM: To evaluate the relationships between early growth and regional variations in type 1 diabetes (T1D) incidence in an international cohort of children with familial and genetic risk for T1D. METHODS: Anthropometric indices between birth to 5 yr of age were compared among regions and T1D proband in 2160 children participating in the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk study. RESULTS: Children in Northern Europe had the highest weight z-score between birth to 12 months of age, while those in Southern Europe and U.S.A. had the lowest weight and length/height z-scores at most time points (p < 0.005 to p < 0.001). Few differences in z-score values for weight, height, and body mass index were found by maternal T1D status. Using International Obesity Task Force criteria, the obesity rates generally increased with age and at 5 yr were highest in males in Northern Europe (6.0%) and in females in Canada (12.8%). However, no statistically significance difference was found by geographic region. In Canada, the obesity rate for female children of mothers with and without T1D differed significantly at 4 and 5 yr (6.0 vs. 0.0% and 21.3 vs. 1.9%, respectively; p < 0.0125) but no differences by maternal T1D status were found in other regions. CONCLUSIONS: There are regional differences in early childhood growth that are consistent with the higher incidence of T1D in Northern Europe and Canada as compared to Southern Europe. Our prospective study from birth will allow evaluation of relationships between growth and the emerging development of autoimmunity and progression to T1D by region in this at-risk population of children [less ▲]

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See detailEarly feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR)
Knip, M; Virtanen, S.M.; Becker, D. et al

in American Journal of Clinical Nutrition (2011), 96(6), 1814-1820

Short-term breastfeeding and early exposure to complex dietary proteins, such as cow milk proteins and cereals, or to fruit, berries, and roots have been implicated as risk factors for β cell autoimmunity ... [more ▼]

Short-term breastfeeding and early exposure to complex dietary proteins, such as cow milk proteins and cereals, or to fruit, berries, and roots have been implicated as risk factors for β cell autoimmunity, clinical type 1 diabetes, or both. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) is an international, randomized, double-blind, controlled intervention trial designed to answer the question of whether weaning to an extensively hydrolyzed formula in infancy will decrease the risk of type 1 diabetes later in childhood. In our pilot study, weaning to a highly hydrolyzed formula decreased by ≈ 50% the cumulative incidence of one or more diabetes-associated autoantibodies by a mean age of 4.7 y. This finding was confirmed in a recent follow-up analysis to 10 y of age. Currently, the full-scale TRIGR takes place in 77 centers in 15 countries. The TRIGR initially recruited 5606 newborn infants with a family member affected by type 1 diabetes and enrolled 2159 eligible subjects who carried a risk-conferring HLA genotype. All recruited mothers were encouraged to breastfeed. The intervention lasted for 6-8 mo with a minimum study formula exposure time of 2 mo, and hydrolyzed casein and standard cow milk-based weaning formulas were compared. Eighty percent of the participants were exposed to the study formula. The overall retention rate over the first 5 y was 87%, and protocol compliance was 94%. The randomization code will be opened when the last recruited child turns 10 y of age (ie, in 2017). PMID: 21653795 [Pub [less ▲]

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See detailThe Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up.
Akerblom, H.K.; Krischer, J; Virtanen, SM et al

in Diabetologia (2011), 54(3), 627-633

AIMS/HYPOTHESIS: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study was designed to establish whether weaning to a highly hydrolysed formula in infancy subsequently reduces the risk of type ... [more ▼]

AIMS/HYPOTHESIS: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study was designed to establish whether weaning to a highly hydrolysed formula in infancy subsequently reduces the risk of type 1 diabetes. METHODS: The study population comprises newborn infants who have first-degree relatives with type 1 diabetes and meet the increased risk HLA inclusion, but not exclusion criteria. The study is being performed in 15 countries in three continents. First-degree relatives of patients with type 1 diabetes were identified from diabetes clinics, diabetes registries, and from other endocrinology or obstetrics offices and websites. HLA typing was performed at birth from cord or heel stick blood, and the results sent to the study's Data Management Unit within 2 weeks for communication of eligibility to the clinical study centre. All mothers recruited were encouraged to breastfeed. The intervention lasted for 6 to 8 months, and weaning formulas based on hydrolysed casein and standard cow's milk were compared. RESULTS: TRIGR recruited 5,606 infants, of whom 2,160 were enrolled as eligible participants, 6% more than the target of 2,032. Of those enrolled, 80% were exposed to the study formula. The overall retention rate over the first 5 years is 87%, with protocol compliance at 94%. The randomisation code will be opened when the last recruited child turns 10 years of age, i.e. in 2017. CONCLUSIONS/INTERPRETATION: The TRIGR experience demonstrates the feasibility and successful implementation of an international dietary intervention study. TRIGR is the first ever primary prevention trial for type 1 diabetes and, if completed successfully, will provide a definite answer to the research question. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777 FUNDING: The study was funded by the National Institute of Child Health and Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (grant numbers HD040364, HD042444 and HD051997), Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation International and the Commission of the European Communities (specific RTD programme 'Quality of Life and Management of Living Resources', contract number QLK1-2002-00372 'Diabetes Prevention'. Other funding came from the EFSD/JDRF/Novo Nordisk Focused Research Grant, Academy of Finland, Dutch Diabetes Research Foundation and Finnish Diabetes Research Foundation). [less ▲]

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See detailMultinational study in children and adolescents with newly diagnosed type 1 diabetes: Association of age, ketoacidosis, HLA status, and autoantibodies on residual beta-cell function and glycemic control 12 months after diagnosis
Mortensen, H. B.; Swift, P. G.; Holl, R. W. et al

in Pediatric Diabetes (2010), 11(4), 218-226

Objective: To identify predictors of residual beta-cell function and glycemic control during the first 12 months after the diagnosis of type 1 diabetes (T1D).Subjects and Methods: Clinical information and ... [more ▼]

Objective: To identify predictors of residual beta-cell function and glycemic control during the first 12 months after the diagnosis of type 1 diabetes (T1D).Subjects and Methods: Clinical information and blood samples were collected from 275 children. HbA1c, antibodies, HLA typing and mixed meal-stimulated C-peptide levels 1, 6, and 12 months after diagnosis were analyzed centrally.Results: Mean age at diagnosis was 9.1 yr. DKA with standard bicarbonate <15 mmol/L was associated with significantly poorer residual beta-cell function 1 (p = 0.004) and 12 months (p = 0.0003) after diagnosis. At 12 months, the decline in stimulated C-peptide levels compared with the levels at 1 month was 69% in the youngest age group and 50% in patients 10 yr and above (p < 0.001). Stimulated C-peptide at 12 months was predicted by younger age (p < 0.02) and bicarbonate levels at diagnosis (p = 0.005), and by stimulated C-peptide (p < 0.0001), postmeal blood glucose (p = 0.0004), insulin antibodies (IA; p = 0.02) and glutamic acid decarboxylase antibodies (GADA; p = 0.0004) at 1 month. HbA1c at 12 months was predicted by HbA1c at diagnosis (p < 0.0001), GADA at 1 month (p = 0.01), and non-white Caucasian ethnicity (p = 0.002).Conclusions: Younger age, ketoacidosis at diagnosis, and IA and GADA 1 month after diagnosis were the strongest explanatory factors for residual beta-cell function at 12 months. Glycemic control at 12 months was influenced predominantly by ethnicity, HbA1c at diagnosis, and GADA at 1 month. © 2009 John Wiley & Sons A/S. [less ▲]

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See detailDisease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies
Pörksen, S.; Laborie, L. B.; Nielsen, L. et al

in BMC Endocrine Disorders (2010), 10

Background: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA ... [more ▼]

Background: To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes.Materials and methods: In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation.Results: Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c(P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide.Conclusion: GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes. © 2010 Pörksen et al; licensee BioMed Central Ltd. [less ▲]

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See detailThe TRIGR Trial: Testing the Potential Link between Weaning Diet and Type 1 Diabetes
Akerblom, H.K.; Knip, M.; Becker, D. et al

in Immunology, Endocrine & Metabolic Agents - Medicinal Chemistry (2007), 7

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See detailImpact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: Reduced insulin antibody titres and preserved beta cell function
Nielsen, L. B.; Mortensen, H. B.; Chiarelli, F. et al

in Diabetologia (2006), 49(1), 71-74

Aims/hypothesis: The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin ... [more ▼]

Aims/hypothesis: The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin gene (INS). We investigated the association between INS VNTR class III alleles (-23HphIA/T) and both insulin antibody presentation and residual beta cell function during the first year after diagnosis in 257 children with type 1 diabetes. Materials and methods: To estimate C-peptide levels and autoantibody presentation, patients underwent a meal-stimulated C-peptide test 1, 6, and 12 months after diagnosis. The insulin -23HphIA/T variant was used as a marker of class III alleles and genotyped by PCR-RFLP. Results: The insulin antibody titres at 1 and 6 months were significantly lower in the class III/III and class I/III genotype groups than in the class I/I genotype group (p = 0.01). Class III alleles were also associated with residual beta cell function 12 months after diagnosis and independently of age, sex, BMI, insulin antibody titres, and HLA-risk genotype group (p = 0.03). The C-peptide level was twice as high among class III/III genotypes as in class I/I and class I/III genotypes (319 vs 131 and 166 pmol/l, p=0.01). Furthermore, the class III/III genotype had a 1.1% reduction in HbA1c after adjustment for insulin dose (p = 0.04). Conclusions/interpretation: These findings suggest a direct connection in vivo between INS VNTR class III alleles, a decreased humoral immune response to insulin, and preservation of beta cell function in recent-onset type 1 diabetes. © Springer-Verlag 2005. [less ▲]

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