المؤلفون: Redondo, Maria J, Steck, Andrea K, Sosenko, Jay, Anderson, Mark, Antinozzi, Peter, Michels, Aaron, Wentworth, John M, Atkinson, Mark A, Pugliese, Alberto, Geyer, Susan, Group, the Type 1 Diabetes TrialNet Study

المصدر: Diabetes Care. 41(12)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Health Sciences, Prevention, Genetics, Autoimmune Disease, Nutrition, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adolescent, Adult, Antibody Specificity, Autoantibodies, Autoimmunity, Child, Child, Preschool, Cohort Studies, Diabetes Mellitus, Type 1, Disease Progression, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Infant, Male, Middle Aged, Obesity, Overweight, Polymorphism, Single Nucleotide, Risk Factors, Transcription Factor 7-Like 2 Protein, Young Adult, Type 1 Diabetes TrialNet Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences

الوصف: ObjectiveThe type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes.Research design and methodsWe evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used.ResultsDuring follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age.ConclusionsThe type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8qs5877sTest

المؤلفون: Bediaga, Naiara G., Li-Wai-Suen, Connie S.N., Haller, Michael J., Gitelman, Stephen E., Evans-Molina, Carmella, Gottlieb, Peter A., Hippich, Markus, Ziegler, Anette-Gabriele, Lernmark, Ake, DiMeglio, Linda A., Wherrett, Diane K., Colman, Peter G., Harrison, Leonard C., Wentworth, John M.

المساهمون: Pediatrics, School of Medicine

المصدر: PMC

مصطلحات موضوعية: Disease progression, OGTT, Prediction, Prevention, Risk stratification, Type 1 diabetes

الوصف: Aims/hypothesis: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. Methods: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. Results: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. Conclusions/interpretation: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.

وصف الملف: application/pdf

العلاقة: Diabetologia; Bediaga NG, Li-Wai-Suen CSN, Haller MJ, et al. Simplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample. Diabetologia. 2021;64(11):2432-2444. doi:10.1007/s00125-021-05523-2; https://hdl.handle.net/1805/31992Test

الإتاحة: https://doi.org/10.1007/s00125-021-05523-2Test
https://hdl.handle.net/1805/31992Test

المؤلفون: Bediaga, Naiara G., Garnham, Alexandra L., Naselli, Gaetano, Bandala-Sanchez, Esther, Stone, Natalie L., Cobb, Joanna, Harbison, Jessica E., Wentworth, John M., Ziegler, Annette-G., Couper, Jennifer J., Smyth, Gordon K., Harrison, Leonard C.

المصدر: Diabetes; Mar2022, Vol. 71 Issue 3, p566-577, 12p

مصطلحات موضوعية: TYPE 1 diabetes, T cells, GENE expression, CYTOTOXIC T cells, DIABETES in children, DISEASE progression, CHROMOSOMES, RESEARCH, SEQUENCE analysis, B cells, KILLER cells, EVALUATION research, ISLANDS of Langerhans, COMPARATIVE studies, GENES, IMMUNITY, DISEASE susceptibility

مستخلص: Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4+ T cells, in five genetically at risk children with islet autoantibodies who progressed to diabetes over a median of 3 years ("progressors") compared with five children matched for sex, age, and HLA-DR who had not progressed ("nonprogressors"). In progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 progressors and 11 nonprogressors. Flow cytometry confirmed that progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Ferrara, Christine T., Geyer, Susan M., Evans-Molina, Carmella, Libman, Ingrid M., Becker, Dorothy J., Wentworth, John M., Moran, Antoinette, Gitelman, Stephen E., Redondo, Maria J.

المساهمون: Medicine, School of Medicine

المصدر: PMC

مصطلحات موضوعية: Aging, Autoantibodies, Body Mass Index, Diabetes Mellitus -- Type 1, Disease progression, Insulin antibodies, Obesity

الوصف: Background: Given the global rise in both type 1 diabetes incidence and obesity, the role of body mass index (BMI) on type 1 diabetes pathophysiology has gained great interest. Sustained excess BMI in pediatric participants of the TrialNet Pathway to Prevention (PTP) cohort increased risk for progression to type 1 diabetes, but the effects of age and obesity in adults remain largely unknown. Objective: To determine the effect of age and sustained obesity on the risk for type 1 diabetes in adult participants in the TrialNet PTP cohort (i.e., nondiabetic autoantibody-positive relatives of patients with type 1 diabetes). Research Design and Methods: Longitudinally accumulated BMI >25 kg/m2 was calculated to generate a cumulative excess BMI (ceBMI) for each participant, with ceBMI values ≥0 kg/m2 and ≥5 kg/m2 representing sustained overweight or obese status, respectively. Recursive partitioning analysis yielded sex- and age-specific thresholds for ceBMI that confer the greatest risk for type 1 diabetes progression. Results: In this cohort of 665 adults (age 20 to 50 years; median follow-up, 3.9 years), 49 participants developed type 1 diabetes. Age was an independent protective factor for type 1 diabetes progression (hazard ratio, 0.95; P = 0.008), with a threshold of >35 years that reduced risk for type 1 diabetes. In men age >35 years and women age <35 years, sustained obesity (ceBMI ≥5 kg/m2) increased the risk for type 1 diabetes. Conclusions: Age is an important factor for type 1 diabetes progression in adults and influences the impact of elevated BMI, indicating an interplay of excess weight, age, and sex in adult type 1 diabetes pathophysiology.

وصف الملف: application/pdf

العلاقة: The Journal of Clinical Endocrinology and Metabolism; Ferrara, C. T., Geyer, S. M., Evans-Molina, C., Libman, I. M., Becker, D. J., Wentworth, J. M., … Type 1 Diabetes TrialNet Study Group (). The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults. The Journal of clinical endocrinology and metabolism, 102(12), 4596–4603. doi:10.1210/jc.2017-01490; https://hdl.handle.net/1805/19526Test

الإتاحة: https://doi.org/10.1210/jc.2017-01490Test
https://hdl.handle.net/1805/19526Test

المؤلفون: Harbison, Jessica E., Roth‐Schulze, Alexandra J., Giles, Lynne C., Tran, Cuong D., Ngui, Katrina M., Penno, Megan A., Thomson, Rebecca L., Wentworth, John M., Colman, Peter G., Craig, Maria E., Morahan, Grant, Papenfuss, Anthony T., Barry, Simon C., Harrison, Leonard C., Couper, Jennifer J.

المصدر: Pediatric Diabetes; Aug2019, Vol. 20 Issue 5, p574-583, 10p, 2 Charts, 2 Graphs

مصطلحات موضوعية: AUTOANTIBODY analysis, AGE factors in disease, CONFIDENCE intervals, DEOXY sugars, DISACCHARIDES, INGESTION, TYPE 1 diabetes, INTESTINAL mucosa, ISLANDS of Langerhans, LONGITUDINAL method, PEDIATRICS, PERMEABILITY, REGRESSION analysis, GUT microbiome, DISEASE progression, GRAM-negative anaerobic bacteria, SHORT-chain fatty acids

مستخلص: Aims/hypothesis: To investigate the longitudinal relationship between the gut microbiome, circulating short chain fatty acids (SCFAs) and intestinal permeability in children with islet autoimmunity or type 1 diabetes and controls. Methods: We analyzed the gut bacterial microbiome, plasma SCFAs, small intestinal permeability and dietary intake in 47 children with islet autoimmunity or recent‐onset type 1 diabetes and in 41 unrelated or sibling controls over a median (range) of 13 (2‐34) months follow‐up. Results: Children with multiple islet autoantibodies (≥2 IA) or type 1 diabetes had gut microbiome dysbiosis. Anti‐inflammatory Prevotella and Butyricimonas genera were less abundant and these changes were not explained by differences in diet. Small intestinal permeability measured by blood lactulose:rhamnose ratio was higher in type 1 diabetes. Children with ≥2 IA who progressed to type 1 diabetes (progressors), compared to those who did not progress, had higher intestinal permeability (mean [SE] difference +5.14 [2.0], 95% confidence interval [CI] 1.21, 9.07, P =.006), lower within‐sample (alpha) microbial diversity (31.3 [11.2], 95% CI 9.3, 53.3, P =.005), and lower abundance of SCFA‐producing bacteria. Alpha diversity (observed richness) correlated with plasma acetate levels in all groups combined (regression coefficient [SE] 0.57 [0.21], 95% CI 0.15, 0.99 P =.008). Conclusions/Interpretation: Children with ≥2 IA who progress to diabetes, like those with recent‐onset diabetes, have gut microbiome dysbiosis associated with increased intestinal permeability. Interventions that expand gut microbial diversity, in particular SCFA‐producing bacteria, may have a role to decrease progression to diabetes in children at‐risk. [ABSTRACT FROM AUTHOR]

: Copyright of Pediatric Diabetes is the property of Hindawi Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Redondo, Maria J., Geyer, Susan, Steck, Andrea K., Sharp, Seth, Wentworth, John M., Weedon, Michael N., Antinozzi, Peter, Sosenko, Jay, Atkinson, Mark, Pugliese, Alberto, Oram, Richard A., Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes Care; Sep2018, Vol. 41 Issue 9, p1887-1894, 8p

مصطلحات موضوعية: DIABETES complications, AUTOANTIBODIES, COMPARATIVE studies, DISEASE susceptibility, GENETIC polymorphisms, IMMUNITY, ISLANDS of Langerhans, TYPE 1 diabetes, RESEARCH methodology, MEDICAL cooperation, PROGNOSIS, RESEARCH, HLA-B27 antigen, EVALUATION research, DISEASE progression, GENOTYPES, DISEASE complications, DIAGNOSIS

مستخلص: Objective: We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.Research Design and Methods: We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients' relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2-51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial-Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.Results: Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06-1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47-3.51; P = 0.0002).Conclusions: The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes Care is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Redondo, Maria J, Steck, Andrea K, Sosenko, Jay, Anderson, Mark, Antinozzi, Peter, Michels, Aaron, Wentworth, John M, Atkinson, Mark A, Pugliese, Alberto, Geyer, Susan, Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes Care; Oct2018, Vol. 41 Issue 10, pN.PAG-N.PAG, 1p

مصطلحات موضوعية: OBESITY complications, AUTOANTIBODIES, COMPARATIVE studies, DISEASE susceptibility, GENES, GENETIC polymorphisms, IMMUNITY, TYPE 1 diabetes, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, OBESITY, PROTEINS, RESEARCH, EVALUATION research, DISEASE progression, DISEASE complications

مستخلص: Objective: The type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes.Research Design and Methods: We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used.Results: During follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age.Conclusions: The type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes Care is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)