المؤلفون: Sims, Emily K., Besser, Rachel E.J., Dayan, Colin, Geno Rasmussen, Cristy, Greenbaum, Carla, Griffin, Kurt J., Hagopian, William, Knip, Mikael, Long, Anna E., Martin, Frank, Mathieu, Chantal, Rewers, Marian, Steck, Andrea K., Wentworth, John M., Rich, Stephen S., Kordonouri, Olga, Ziegler, Anette-Gabriele, Herold, Kevan C., NIDDK Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes; Apr2022, Vol. 71 Issue 4, p610-623, 14p

مصطلحات موضوعية: AUTOANTIBODIES, RESEARCH, RESEARCH methodology, TYPE 1 diabetes, MEDICAL screening, EVALUATION research, COMPARATIVE studies, QUESTIONNAIRES, RESEARCH funding

مستخلص: Most screening programs to identify individuals at risk for type 1 diabetes have targeted relatives of people living with the disease to improve yield and feasibility. However, ∼90% of those who develop type 1 diabetes do not have a family history. Recent successes in disease-modifying therapies to impact the course of early-stage disease have ignited the consideration of the need for and feasibility of population screening to identify those at increased risk. Existing population screening programs rely on genetic or autoantibody screening, and these have yielded significant information about disease progression and approaches for timing for screening in clinical practice. At the March 2021 Type 1 Diabetes TrialNet Steering Committee meeting, a session was held in which ongoing efforts for screening in the general population were discussed. This report reviews the background of these efforts and the details of those programs. Additionally, we present hurdles that need to be addressed for successful implementation of population screening and provide initial recommendations for individuals with positive screens so that standardized guidelines for monitoring and follow-up can be established. [ABSTRACT FROM AUTHOR]

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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., Geyer, Susan, Steck, Andrea K., Sosenko, Jay, Anderson, Mark, Antinozzi, Peter, Michels, Aaron, Wentworth, John, Ping Xu, Pugliese, Alberto, Xu, Ping, Type 1 Diabetes TrialNet Study Group

المصدر: Diabetes Care; Feb2018, Vol. 41 Issue 2, p311-317, 7p

مصطلحات موضوعية: PHENOTYPES, TYPE 1 diabetes, TRANSCRIPTION factors, SINGLE nucleotide polymorphisms, DIAGNOSIS of diabetes, ALLELES, COMPARATIVE studies, DISEASE susceptibility, GENETIC polymorphisms, GENETICS, LONGITUDINAL method, RESEARCH methodology, MEDICAL cooperation, PROTEINS, RESEARCH, EVALUATION research

مستخلص: Objective: The phenotypic diversity of type 1 diabetes suggests heterogeneous etiopathogenesis. We investigated the relationship of type 2 diabetes-associated transcription factor 7 like 2 (TCF7L2) single nucleotide polymorphisms (SNPs) with immunologic and metabolic characteristics at type 1 diabetes diagnosis.Research Design and Methods: We studied TrialNet participants with newly diagnosed autoimmune type 1 diabetes with available TCF7L2 rs4506565 and rs7901695 SNP data (n = 810; median age 13.6 years; range 3.3-58.6). We modeled the influence of carrying a TCF7L2 variant (i.e., having 1 or 2 minor alleles) on the number of islet autoantibodies and oral glucose tolerance test (OGTT)-stimulated C-peptide and glucose measures at diabetes diagnosis. All analyses were adjusted for known confounders.Results: The rs4506565 variant was a significant independent factor of expressing a single autoantibody, instead of multiple autoantibodies, at diagnosis (odds ratio [OR] 1.66 [95% CI 1.07, 2.57], P = 0.024). Interaction analysis demonstrated that this association was only significant in participants ≥12 years old (n = 504; OR 2.12 [1.29, 3.47], P = 0.003) but not younger ones (n = 306, P = 0.73). The rs4506565 variant was independently associated with higher C-peptide area under the curve (AUC) (P = 0.008) and lower mean glucose AUC (P = 0.0127). The results were similar for the rs7901695 SNP.Conclusions: In this cohort of individuals with new-onset type 1 diabetes, type 2 diabetes-linked TCF7L2 variants were associated with single autoantibody (among those ≥12 years old), higher C-peptide AUC, and lower glucose AUC levels during an OGTT. Thus, carriers of the TCF7L2 variant had a milder immunologic and metabolic phenotype at type 1 diabetes diagnosis, which could be partly driven by type 2 diabetes-like pathogenic mechanisms. [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: Wentworth, John M.¹, Fourlanos, Spiros¹, Harrison, Leonard C.¹ harrison@wehi.edu.au

المصدر: Nature Reviews Endocrinology. Sep2009, Vol. 5 Issue 9, p483-489. 7p. 1 Diagram, 1 Chart.

مصطلحات موضوعية: *NOSOLOGY, *DIABETES, *TYPE 2 diabetes, *INSULIN resistance, *DISEASE incidence, *RESEARCH, *RESEARCH methodology, *TYPE 1 diabetes, *MEDICAL cooperation, *EVALUATION research, *STEREOTYPES, *INSULIN, *COMPARATIVE studies, DEVELOPING countries

مستخلص: The prevailing concentration of blood glucose is a result of the integrated regulation of insulin secretion and insulin action. Nevertheless, the classic stereotypes of diabetes are dichotomous: type 1 diabetes mellitus (T1DM) is attributed to impaired insulin secretion, and type 2 diabetes mellitus (T2DM) is primarily attributed to impaired insulin action (insulin resistance). The available evidence indicates that this view is overly simplistic. Impaired insulin secretion (beta-cell dysfunction) is also a feature of T2DM, and insulin resistance is also a risk factor for the development of T1DM. Moreover, with the increasing incidence of T2DM and T1DM in both developed and developing countries, attributed to environmental factors, the existence of 'hybrid' diabetes types that have clinical and pathogenetic features of both conditions is becoming clearly evident. A common thread across the spectrum of diabetes might be the activation of innate immunological and inflammatory pathways by a proinflammatory environment, which leads to beta-cell dysfunction in T2DM, insulin resistance in both T2DM and T1DM, and enhanced adaptive immunity that kills beta cells in T1DM. Embracing a holistic view of the diabetes syndrome will help us to understand the environmental basis for the epidemic of diabetes and improve preventative strategies. [ABSTRACT FROM AUTHOR]

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.)