scholarly journals Plasma metabolome and circulating vitamins stratified onset age of an initial islet autoantibody and progression to type 1 diabetes: the TEDDY study

2020 ◽  
Author(s):  
Ada Admin ◽  
Qian Li ◽  
Xiang Liu ◽  
Jimin Yang ◽  
Iris Erlund ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Type 1 Diabetes ◽  
Early Onset ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Differential Analysis ◽  
Plasma Ascorbic Acid ◽  
Hydroxyvitamin D ◽  
Plasma Metabolome

Children’s plasma metabolome, especially lipidome reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The TEDDY study enrolled 8676 newborns by screening HLA-DR-DQ genotypes at six clinical centers in four countries; profiled metabolome and measured concentrations of ascorbic acid, 25-hydroxyvitamin D (25(OH)D), erythrocyte membrane fatty acids following birth until IA seroconversion under nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or glutamic acid decarboxylase (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared to non-progressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA cases but not in matched controls, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.

scholarly journals Plasma metabolome and circulating vitamins stratified onset age of an initial islet autoantibody and progression to type 1 diabetes: the TEDDY study

2020 ◽  
Author(s):  
Ada Admin ◽  
Qian Li ◽  
Xiang Liu ◽  
Jimin Yang ◽  
Iris Erlund ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Type 1 Diabetes ◽  
Early Onset ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Differential Analysis ◽  
Plasma Ascorbic Acid ◽  
Hydroxyvitamin D ◽  
Plasma Metabolome

Children’s plasma metabolome, especially lipidome reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The TEDDY study enrolled 8676 newborns by screening HLA-DR-DQ genotypes at six clinical centers in four countries; profiled metabolome and measured concentrations of ascorbic acid, 25-hydroxyvitamin D (25(OH)D), erythrocyte membrane fatty acids following birth until IA seroconversion under nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or glutamic acid decarboxylase (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared to non-progressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA cases but not in matched controls, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.

scholarly journals Plasma ascorbic acid and the risk of islet autoimmunity and type 1 diabetes: the TEDDY study

Diabetologia ◽  
2019 ◽  
Vol 63 (2) ◽  
pp. 278-286 ◽  
Author(s):  
Markus Mattila ◽  
◽  
Iris Erlund ◽  
Hye-Seung Lee ◽  
Sari Niinistö ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Type 1 Diabetes ◽  
Vitamin C ◽  
Data Availability ◽  
Islet Autoimmunity ◽  
Plasma Ascorbic Acid ◽  
Background Population ◽  
Increased Risk ◽  
Nested Case Control

Abstract Aims/hypothesis We studied the association of plasma ascorbic acid with the risk of developing islet autoimmunity and type 1 diabetes and examined whether SNPs in vitamin C transport genes modify these associations. Furthermore, we aimed to determine whether the SNPs themselves are associated with the risk of islet autoimmunity or type 1 diabetes. Methods We used a risk set sampled nested case–control design within an ongoing international multicentre observational study: The Environmental Determinants of Diabetes in the Young (TEDDY). The TEDDY study followed children with increased genetic risk from birth to endpoints of islet autoantibodies (350 cases, 974 controls) and type 1 diabetes (102 cases, 282 controls) in six clinical centres. Control participants were matched for family history of type 1 diabetes, clinical centre and sex. Plasma ascorbic acid concentration was measured at ages 6 and 12 months and then annually up to age 6 years. SNPs in vitamin C transport genes were genotyped using the ImmunoChip custom microarray. Comparisons were adjusted for HLA genotypes and for background population stratification. Results Childhood plasma ascorbic acid (mean ± SD 10.76 ± 3.54 mg/l in controls) was inversely associated with islet autoimmunity risk (adjusted OR 0.96 [95% CI 0.92, 0.99] per +1 mg/l), particularly islet autoimmunity, starting with insulin autoantibodies (OR 0.94 [95% CI 0.88, 0.99]), but not with type 1 diabetes risk (OR 0.93 [95% Cl 0.86, 1.02]). The SLC2A2 rs5400 SNP was associated with increased risk of type 1 diabetes (OR 1.77 [95% CI 1.12, 2.80]), independent of plasma ascorbic acid (OR 0.92 [95% CI 0.84, 1.00]). Conclusions/interpretation Higher plasma ascorbic acid levels may protect against islet autoimmunity in children genetically at risk for type 1 diabetes. Further studies are warranted to confirm these findings. Data availability The datasets generated and analysed during the current study will be made available in the NIDDK Central Repository at https://www.niddkrepository.org/studies/teddy.

scholarly journals Altered Systemic and Intestinal IgA Immune Responses in Individuals With Type 1 Diabetes

2020 ◽  
Vol 105 (12) ◽  
pp. e4616-e4625
Author(s):  
Juan Huang ◽  
Gan Huang ◽  
Xia Li ◽  
Fang Hu ◽  
Zhiguo Xie ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Immune Responses ◽  
Immunoglobulin A ◽  
Enzyme Linked Immunosorbent Assay ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Glutamic Acid Decarboxylase Autoantibody ◽  
Serum Iga ◽  
Healthy Control

Abstract Objective Increasing evidence supports the observation that immunoglobulin A (IgA) exerts a critical effect on the susceptibility to autoimmunity by modulating gut homeostasis and subsequent host immunity. We hypothesized that the IgA immunity is altered in individuals with type 1 diabetes. To test our hypothesis, we investigated intestinal, oral, and peripheral IgA immune responses in individuals with type 1 diabetes. Methods We collected stool, oral cavity, and blood samples from participants diagnosed with type 1 diabetes (within 1 year and more than 1 year) and healthy control individuals. Serum islet autoantibody titers were detected by radioligand assays. IgA-bound bacteria and IgA-expressing B cells were studied by flow cytometry. Oral free IgA level was measured by enzyme-linked immunosorbent assay. Serum and stool free IgA concentrations were determined by immune-turbidimetry method. Results Individuals diagnosed with type 1 diabetes within 1 year had an increased proportion of stool IgA-bound bacteria compared with healthy control individuals. The proportion of stool IgA-bound bacteria was positively associated with glutamic acid decarboxylase autoantibody titer. Moreover, individuals with a longer disease duration displayed a higher level of IgA-bound bacteria than those diagnosed within 1 year. In contrast to healthy control individuals, type 1 diabetes patients had increased serum IgA concentrations. Conclusions Individuals with type 1 diabetes display altered IgA immunity, especially increased stool IgA-bound bacteria, which is likely to contribute to β-cell autoimmunity and the disease development, and thus, might be considered as a novel therapeutic target for the treatment of type 1 diabetes.

scholarly journals Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children

2021 ◽  
Author(s):  
Kenney Ng ◽  
Harry Stavropoulos ◽  
Vibha Anand ◽  
Riitta Veijola ◽  
Jorma Toppari ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Familial Risk ◽  
Multivariable Analysis ◽  
Diabetes Risk ◽  
Islet Autoimmunity ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Surveillance Strategy ◽  
Risk Of Progression

OBJECTIVE: To utilize islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. <p>RESEARCH DESIGN AND METHODS: Prospective cohort studies in Finland, Germany, Sweden and the US followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonized for diabetes risk analyses.</p> <p>RESULTS: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n=909), GADA (n=1076) or IA-2A (n=714), when stratified by quartiles of titer, ranging from 19% (GADA 1<sup>st</sup> quartile) to 60% (IA-2A 4<sup>th</sup> quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6<sup>th</sup>, 52.4<sup>th</sup> and 10.2<sup>nd</sup> percentile of children specifically positive for each of IAA, GADA and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n=954) and multiple (n=527) autoantibodies could be stratified from 6% to 75% (p<0.0001). The thresholds effectively identified children with 50% or higher 5-year risk when considering age-specific autoantibody screening (57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy.</p> <p>CONCLUSIONS: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.</p>

scholarly journals Plasma Metabolome and Circulating Vitamins Stratified Onset Age of an Initial Islet Autoantibody and Progression to Type 1 Diabetes: The TEDDY Study

Diabetes ◽  
2020 ◽  
Vol 70 (1) ◽  
pp. 282-292
Author(s):  
Qian Li ◽  
Xiang Liu ◽  
Jimin Yang ◽  
Iris Erlund ◽  
Åke Lernmark ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Islet Autoantibody ◽  
Onset Age ◽  
Plasma Metabolome

scholarly journals Evaluating the Prognostic Value of Islet Autoantibody Monitoring in Islet Transplant Recipients with Long-Standing Type 1 Diabetes Mellitus

2021 ◽  
Vol 10 (12) ◽  
pp. 2708
Author(s):  
Roi Anteby ◽  
Aaron Lucander ◽  
Piotr J. Bachul ◽  
Jordan Pyda ◽  
Damian Grybowski ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Severe Hypoglycemia ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Diabetic Patients ◽  
Prognostic Utility ◽  
Hla Haplotypes

(1) Background: The correlation between titers of islet autoantibodies (IAbs) and the loss of transplanted islets remains controversial. We sought to evaluate the prognostic utility of monitoring IAbs in diabetic patients after islet transplantation (ITx); (2) Methods: Twelve patients with Type 1 diabetes mellitus and severe hypoglycemia underwent ITx. Serum concentration of glutamic acid decarboxylase (GAD), insulinoma antigen 2 (IA-2), and zinc transport 8 (ZnT8) autoantibodies was assessed before ITx and 0, 7, and 75 days and every 3 months post-operatively; (3) Results: IA-2A (IA-2 antibody) and ZnT8A (ZnT8 antibody) levels were not detectable before or after ITx in all patients (median follow-up of 53 months (range 24–61)). Prior to ITx, GAD antibody (GADA) was undetectable in 67% (8/12) of patients. Of those, 75% (6/8) converted to GADA+ after ITx. In 67% (4/6) of patients with GADA+ seroconversion, GADA level peaked within 3 months after ITx and subsequently declined. All patients with GADA+ seroconversion maintained long-term partial or complete islet function (insulin independence) after 1 or 2 ITx. There was no correlation between the presence of IAb-associated HLA haplotypes and the presence of IAbs before or after ITx; (4) Conclusions: There is no association between serum GADA trends and ITx outcomes. IA-2A and ZnT8A were not detectable in any of our patients before or after ITx.

scholarly journals Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children

2021 ◽  
Author(s):  
Kenney Ng ◽  
Harry Stavropoulos ◽  
Vibha Anand ◽  
Riitta Veijola ◽  
Jorma Toppari ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Familial Risk ◽  
Multivariable Analysis ◽  
Diabetes Risk ◽  
Islet Autoimmunity ◽  
Acid Decarboxylase ◽  
Islet Autoantibody ◽  
Surveillance Strategy ◽  
Risk Of Progression

OBJECTIVE: To utilize islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. <p>RESEARCH DESIGN AND METHODS: Prospective cohort studies in Finland, Germany, Sweden and the US followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonized for diabetes risk analyses.</p> <p>RESULTS: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n=909), GADA (n=1076) or IA-2A (n=714), when stratified by quartiles of titer, ranging from 19% (GADA 1<sup>st</sup> quartile) to 60% (IA-2A 4<sup>th</sup> quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6<sup>th</sup>, 52.4<sup>th</sup> and 10.2<sup>nd</sup> percentile of children specifically positive for each of IAA, GADA and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n=954) and multiple (n=527) autoantibodies could be stratified from 6% to 75% (p<0.0001). The thresholds effectively identified children with 50% or higher 5-year risk when considering age-specific autoantibody screening (57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy.</p> <p>CONCLUSIONS: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.</p>

Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes

2019 ◽  
Vol 15 (3) ◽  
pp. 199-204 ◽  
Author(s):  
Elin Pettersen Sørgjerd
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Acid Decarboxylase ◽  
Adult Onset ◽  
Latent Autoimmune Diabetes ◽  
Childhood Type 1 Diabetes ◽  
Childhood Type

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

scholarly journals Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

2020 ◽  
Vol 21 (5) ◽  
pp. 1598 ◽  
Author(s):  
Johnny Ludvigsson
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Human Subjects ◽  
Subcutaneous Administration ◽  
Acid Decarboxylase ◽  
Recent Onset ◽  
Prevention Trials

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

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