We identified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three... more We identified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys27, Gly608, and Pro671) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (T1D) probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var–specific AAb in relatives was associated with accelerated progression to T1D in those positive for AAb to GAD65 and/or insulin but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1*04-DQB1*03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alters the three amino acids induces changes in the three-dimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb to IA-2var ...
An anergic phenotype has been observed in nonobese diabetic (NOD) mice and some autoreactive T ce... more An anergic phenotype has been observed in nonobese diabetic (NOD) mice and some autoreactive T cells from patients with type I diabetes. To better understand this phenomenon, we measured T cell proliferative responses to 10 diabetes-associated and up to 9 control Ags/peptides in 148 new diabetic children, 51 age- and MHC (DQ)-matched siblings (sibs), 31 patients with longstanding diabetes, and 40 healthy controls. Most (78–91%) patient and sib responses to glutamate decarboxylase of 65 kDa (GAD65), islet cell cytoplasmic autoantibody (ICA) 69, diabetes-associated T cell epitopes in ICA69 (Tep69), and heat shock protein (Hsp) 60 involved anergic T cells that required exogenous IL-2 to proliferate. Responses to proinsulin, IA-2 (and tetanus toxoid) required no IL-2 and generated sufficient cytokine to rescue anergic T cell responses. Most new patients (85%) had autoreactive T cells, three quarters targeting more than half of the diabetes Ags. Only 7.8% of the sibs and none of the cont...
The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) tested the hypothesis w... more The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) tested the hypothesis whether extensively hydrolyzed casein‐based versus regular cow's milk‐based infant formula reduces the risk of type 1 diabetes. We describe dietary compliance in the trial in terms of study formula intake, feeding of nonrecommended foods, and serum cow's milk antibody concentration reflecting intake of cow's milk protein among 2,159 eligible newborn infants with a biological first‐degree relative affected by type 1 diabetes and with HLA‐conferred susceptibility to type 1 diabetes. The participating infants were introduced to the study formula feeding at the median age of 15 days with a median duration of study formula use of 63 days. During the intervention, 80% of the infants received study formula. Of these, 57% received study formula for at least 2 months. On average, 45.5 l of study formula were used per infant. Only 13% of the population had received a nonrecommended food...
Aims/hypothesis The aim of this work was to examine the relationship between family history of ty... more Aims/hypothesis The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility. Methods In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member. Results Multiple autoantibodies (≥2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046, p < 0.001) and 0.81 (95% CI ...
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relative... more The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on gre...
Probiotics are linked to positive regulatory effects on the immune system. The aim of the study w... more Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (n = 1212) (HR 1.15; 95%CI 0.99, 1.35; p = 0.07) or celiac disease (n = 455) (HR 1.11; 95%CI 0.86, 1.43; p = 0.43) when adjusting for known risk factors. Intake of probiotic dietary supplements, however, was associated with a slightly increased risk of CDA (HR 1.18; 95%CI 1.00, 1.40; p = 0.043) compared to children who did not get probiotics. It was concluded that the overall exposure of probioti...
OBJECTIVE This study examined whether a history of diabetic ketoacidosis (DKA) is associated with... more OBJECTIVE This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes. RESEARCH DESIGN AND METHODS Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to <10 years, who participated in an observational study of the Diabetes Research in Children Network (DirecNet). Participants were grouped according to history of DKA severity (none/mild or moderate/severe). Each participant had unsedated MRI scans and cognitive testing at baseline and 18 months. RESULTS In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry. The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group. When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants w...
Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two ... more Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of 'slow progressors' (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Bart's Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed <5 years old from BOX) using th...
The Journal of clinical endocrinology and metabolism, Aug 22, 2017
Islet autoantibodies are markers of type 1 diabetes and an increase in number of autoantibodies d... more Islet autoantibodies are markers of type 1 diabetes and an increase in number of autoantibodies detected during the preclinical phase is predictive of progression to overt disease. To refine the impact of age in relation to islet antibody type on the progression from single to multiple autoantibodies in relatives of people with type 1 diabetes. We examined 994 relatives with normal glucose tolerance and positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention. Antibodies to GAD (GADA), insulin (IAA), IA-2 (IA-2A), zinc transporter 8 (ZnT8A) and ICA were tested every 6-12 months. The primary outcome was confirmed development of multiple autoantibodies. Age was categorized as <8yr; 8-11yr; 12-17yr; ≥18yr and optimal age breakpoints identified by recursive partitioning analysis. After median follow-up of 2 years, 141 relatives had developed ≥ 1 additional autoantibodies. Five-year risk was inversely related to age, but the pattern differed by ...
We aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes ... more We aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth. We studied 1,117 children in the TrialNet Pathway to Prevention cohort (autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index. Recursive partitioning and multivariate analyses yielded sex- and age- specific ceBMI thresholds for greatest type 1 diabetes risk. Higher ceBMI conferred significantly greater risk of progressing to type 1 diabetes. The increased diabetes risk occurred at lower ceBMI values in children <12 years of age compared with older subjects and in females versus males. Elevated BMI is associated with increased risk of diabetes progression in pediatric autoantibody-positive relatives, but the effect varies by sex and age.
The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from development of ty... more The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA-typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnorma...
We identified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three... more We identified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys27, Gly608, and Pro671) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (T1D) probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var–specific AAb in relatives was associated with accelerated progression to T1D in those positive for AAb to GAD65 and/or insulin but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1*04-DQB1*03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alters the three amino acids induces changes in the three-dimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb to IA-2var ...
An anergic phenotype has been observed in nonobese diabetic (NOD) mice and some autoreactive T ce... more An anergic phenotype has been observed in nonobese diabetic (NOD) mice and some autoreactive T cells from patients with type I diabetes. To better understand this phenomenon, we measured T cell proliferative responses to 10 diabetes-associated and up to 9 control Ags/peptides in 148 new diabetic children, 51 age- and MHC (DQ)-matched siblings (sibs), 31 patients with longstanding diabetes, and 40 healthy controls. Most (78–91%) patient and sib responses to glutamate decarboxylase of 65 kDa (GAD65), islet cell cytoplasmic autoantibody (ICA) 69, diabetes-associated T cell epitopes in ICA69 (Tep69), and heat shock protein (Hsp) 60 involved anergic T cells that required exogenous IL-2 to proliferate. Responses to proinsulin, IA-2 (and tetanus toxoid) required no IL-2 and generated sufficient cytokine to rescue anergic T cell responses. Most new patients (85%) had autoreactive T cells, three quarters targeting more than half of the diabetes Ags. Only 7.8% of the sibs and none of the cont...
The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) tested the hypothesis w... more The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) tested the hypothesis whether extensively hydrolyzed casein‐based versus regular cow's milk‐based infant formula reduces the risk of type 1 diabetes. We describe dietary compliance in the trial in terms of study formula intake, feeding of nonrecommended foods, and serum cow's milk antibody concentration reflecting intake of cow's milk protein among 2,159 eligible newborn infants with a biological first‐degree relative affected by type 1 diabetes and with HLA‐conferred susceptibility to type 1 diabetes. The participating infants were introduced to the study formula feeding at the median age of 15 days with a median duration of study formula use of 63 days. During the intervention, 80% of the infants received study formula. Of these, 57% received study formula for at least 2 months. On average, 45.5 l of study formula were used per infant. Only 13% of the population had received a nonrecommended food...
Aims/hypothesis The aim of this work was to examine the relationship between family history of ty... more Aims/hypothesis The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility. Methods In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member. Results Multiple autoantibodies (≥2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046, p < 0.001) and 0.81 (95% CI ...
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relative... more The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on gre...
Probiotics are linked to positive regulatory effects on the immune system. The aim of the study w... more Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (n = 1212) (HR 1.15; 95%CI 0.99, 1.35; p = 0.07) or celiac disease (n = 455) (HR 1.11; 95%CI 0.86, 1.43; p = 0.43) when adjusting for known risk factors. Intake of probiotic dietary supplements, however, was associated with a slightly increased risk of CDA (HR 1.18; 95%CI 1.00, 1.40; p = 0.043) compared to children who did not get probiotics. It was concluded that the overall exposure of probioti...
OBJECTIVE This study examined whether a history of diabetic ketoacidosis (DKA) is associated with... more OBJECTIVE This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes. RESEARCH DESIGN AND METHODS Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to <10 years, who participated in an observational study of the Diabetes Research in Children Network (DirecNet). Participants were grouped according to history of DKA severity (none/mild or moderate/severe). Each participant had unsedated MRI scans and cognitive testing at baseline and 18 months. RESULTS In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry. The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group. When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants w...
Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two ... more Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of 'slow progressors' (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years. Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Bart's Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed <5 years old from BOX) using th...
The Journal of clinical endocrinology and metabolism, Aug 22, 2017
Islet autoantibodies are markers of type 1 diabetes and an increase in number of autoantibodies d... more Islet autoantibodies are markers of type 1 diabetes and an increase in number of autoantibodies detected during the preclinical phase is predictive of progression to overt disease. To refine the impact of age in relation to islet antibody type on the progression from single to multiple autoantibodies in relatives of people with type 1 diabetes. We examined 994 relatives with normal glucose tolerance and positive for a single autoantibody, followed prospectively in the TrialNet Pathway to Prevention. Antibodies to GAD (GADA), insulin (IAA), IA-2 (IA-2A), zinc transporter 8 (ZnT8A) and ICA were tested every 6-12 months. The primary outcome was confirmed development of multiple autoantibodies. Age was categorized as <8yr; 8-11yr; 12-17yr; ≥18yr and optimal age breakpoints identified by recursive partitioning analysis. After median follow-up of 2 years, 141 relatives had developed ≥ 1 additional autoantibodies. Five-year risk was inversely related to age, but the pattern differed by ...
We aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes ... more We aimed to determine the effect of elevated BMI over time on the progression to type 1 diabetes in youth. We studied 1,117 children in the TrialNet Pathway to Prevention cohort (autoantibody-positive relatives of patients with type 1 diabetes). Longitudinally accumulated BMI above the 85th age- and sex-adjusted percentile generated a cumulative excess BMI (ceBMI) index. Recursive partitioning and multivariate analyses yielded sex- and age- specific ceBMI thresholds for greatest type 1 diabetes risk. Higher ceBMI conferred significantly greater risk of progressing to type 1 diabetes. The increased diabetes risk occurred at lower ceBMI values in children <12 years of age compared with older subjects and in females versus males. Elevated BMI is associated with increased risk of diabetes progression in pediatric autoantibody-positive relatives, but the effect varies by sex and age.
The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from development of ty... more The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA-typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnorma...
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Papers by Dorothy Becker