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1.
Sci Data ; 10(1): 323, 2023 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-37237059

RESUMEN

The Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, islet autoantibody positivity (AAb+), and without diabetes. nPOD recovers, processes, analyzes, and distributes high-quality biospecimens, collected using optimized standard operating procedures, and associated de-identified data/metadata to researchers around the world. Herein describes the release of high-parameter genotyping data from this collection. 372 donors were genotyped using a custom precision medicine single nucleotide polymorphism (SNP) microarray. Data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 donors were assessed for rare known and novel coding region variants via whole exome sequencing (WES). These data are publicly-available to enable genotype-specific sample requests and the study of novel genotype:phenotype associations, aiding in the mission of nPOD to enhance understanding of diabetes pathogenesis to promote the development of novel therapies.


Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Donantes de Tejidos , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Genómica , Páncreas
2.
Diabetologia ; 64(8): 1822-1833, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34003304

RESUMEN

AIMS/HYPOTHESIS: The circadian clock influences both diabetes and immunity. Our goal in this study was to characterise more thoroughly the circadian patterns of immune cell populations and cytokines that are particularly relevant to the immune pathology of type 1 diabetes and thus fill in a current gap in our understanding of this disease. METHODS: Ten individuals with established type 1 diabetes (mean disease duration 11 years, age 18-40 years, six female) participated in a circadian sampling protocol, each providing six blood samples over a 24 h period. RESULTS: Daily ranges of population frequencies were sometimes large and possibly clinically significant. Several immune populations, such as dendritic cells, CD4 and CD8 T cells and their effector memory subpopulations, CD4 regulatory T cells, B cells and cytokine IL-6, exhibited statistically significant circadian rhythmicity. In a comparison with historical healthy control individuals, but using shipped samples, we observed that participants with type 1 diabetes had statistically significant phase shifts occurring in the time of peak occurrence of B cells (+4.8 h), CD4 and CD8 T cells (~ +5 h) and their naive and effector memory subsets (~ +3.3 to +4.5 h), and regulatory T cells (+4.1 h). An independent streptozotocin murine experiment confirmed the phase shifting of CD8 T cells and suggests that circadian dysrhythmia in type 1 diabetes might be an effect and not a cause of the disease. CONCLUSIONS/INTERPRETATION: Future efforts investigating this newly described aspect of type 1 diabetes in human participants are warranted. Peripheral immune populations should be measured near the same time of day in order to reduce circadian-related variation.


Asunto(s)
Trastornos Cronobiológicos/inmunología , Ritmo Circadiano/inmunología , Diabetes Mellitus Tipo 1/inmunología , Sistema Inmunológico/fisiología , Adolescente , Adulto , Animales , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Relojes Circadianos/genética , Células Dendríticas/inmunología , Femenino , Citometría de Flujo , Humanos , Interleucina-6/sangre , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/inmunología , Adulto Joven
3.
Diabetes ; 70(4): 932-943, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33419759

RESUMEN

We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual ß-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA-2A), zinc transporter 8 autoantibody (ZnT8A), and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (median duration 4.5 years [range 0-60]). Indeed, a combined model with incorporation of disease duration, age at onset, GRS, and titers of IA-2A, ZnT8A, and GADA provided superior capacity to predict C-peptide detection (quasi-likelihood information criterion [QIC] = 334.6) compared with the capacity of disease duration, age at onset, and GRS as the sole parameters (QIC = 359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials where investigators are seeking to preserve or restore endogenous ß-cell function.


Asunto(s)
Autoanticuerpos/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/metabolismo , Autoanticuerpos/genética , Péptido C/genética , Péptido C/metabolismo , Estudios Transversales , Diabetes Mellitus Tipo 1/genética , Humanos , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/genética , Transportador 8 de Zinc/genética , Transportador 8 de Zinc/metabolismo
4.
Proc Natl Acad Sci U S A ; 114(38): 10196-10201, 2017 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-28874568

RESUMEN

Identified as a major biomarker for type 1 diabetes (T1D) diagnosis, zinc transporter 8 autoantibody (ZnT8A) has shown promise for staging disease risk and disease diagnosis. However, existing assays for ZnT8 autoantibody (ZnT8A) are limited to detection by soluble domains of ZnT8, owing to difficulties in maintaining proper folding of a full-length ZnT8 protein outside its native membrane environment. Through a combined bioengineering and nanotechnology approach, we have developed a proteoliposome-based full-length ZnT8 self-antigen (full-length ZnT8 proteoliposomes; PLR-ZnT8) for efficient detection of ZnT8A on a plasmonic gold chip (pGOLD). The protective lipid matrix of proteoliposomes improved the proper folding and structural stability of full-length ZnT8, helping PLR-ZnT8 immobilized on pGOLD (PLR-ZnT8/pGOLD) achieve high-affinity capture of ZnT8A from T1D sera. Our PLR-ZnT8/pGOLD exhibited efficient ZnT8A detection for T1D diagnosis with ∼76% sensitivity and ∼97% specificity (n = 307), superior to assays based on detergent-solubilized full-length ZnT8 and the C-terminal domain of ZnT8. Multiplexed assays using pGOLD were also developed for simultaneous detection of ZnT8A, islet antigen 2 autoantibody, and glutamic acid decarboxylase autoantibody for diagnosing T1D.


Asunto(s)
Diabetes Mellitus Tipo 1/diagnóstico , Transportador 8 de Zinc/sangre , Células HEK293 , Humanos , Análisis por Matrices de Proteínas , Proteolípidos , Transportador 8 de Zinc/inmunología
5.
Diabetes Care ; 34(12): 2567-9, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22011412

RESUMEN

OBJECTIVE: We conducted an open-label, phase I study using autologous umbilical cord blood (UCB) infusion to ameliorate type 1 diabetes (T1D). Having previously reported on the first 15 patients reaching 1 year of follow-up, herein we report on the complete cohort after 2 years of follow-up. RESEARCH DESIGN AND METHODS: A total of 24 T1D patients (median age 5.1 years) received a single intravenous infusion of autologous UCB cells and underwent metabolic and immunologic assessments. RESULTS: No infusion-related adverse events were observed. ß-Cell function declined after UCB infusion. Area under the curve C-peptide was 24.3% of baseline 1 year postinfusion (P < 0.001) and 2% of baseline 2 years after infusion (P < 0.001). Flow cytometry revealed increased regulatory T cells (Tregs) (P = 0.04) and naive Tregs (P = 0.001) 6 and 9 months after infusion, respectively. CONCLUSIONS: Autologous UCB infusion in children with T1D is safe and induces changes in Treg frequency but fails to preserve C-peptide.


Asunto(s)
Transfusión de Sangre Autóloga , Diabetes Mellitus Tipo 1/terapia , Sangre Fetal/trasplante , Péptido C/sangre , Niño , Preescolar , Diabetes Mellitus Tipo 1/inmunología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Proyectos Piloto , Linfocitos T Reguladores/inmunología
6.
Diabetes Care ; 32(11): 2041-6, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19875605

RESUMEN

OBJECTIVE: Interest continues to grow regarding the therapeutic potential for umbilical cord blood therapies to modulate autoimmune disease. We conducted an open-label phase I study using autologous umbilical cord blood infusion to ameliorate type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifteen patients diagnosed with type 1 diabetes and for whom autologous umbilical cord blood was stored underwent a single intravenous infusion of autologous cells and completed 1 year of postinfusion follow-up. Intensive insulin regimens were used to optimize glycemic control. Metabolic and immunologic assessments were performed before infusion and at established time periods thereafter. RESULTS: Median (interquartile range [IQR]) age at infusion was 5.25 (3.1-7.3) years, with a median postdiagnosis time to infusion of 17.7 (10.9-26.5) weeks. No infusion-related adverse events were observed. Metabolic indexes 1 year postinfusion were peak C-peptide median 0.50 ng/ml (IQR 0.26-1.30), P = 0.002; A1C 7.0% (IQR 6.5-7.7), P = 0.97; and insulin dose 0.67 units * kg(-1) * day(-1) (IQR 0.55-0.77), P = 0.009. One year postinfusion, no changes were observed in autoantibody titers, regulatory T-cell numbers, CD4-to-CD8 ratio, or other T-cell phenotypes. CONCLUSIONS: Autologous umbilical cord blood transfusion in children with type 1 diabetes is safe but has yet to demonstrate efficacy in preserving C-peptide. Larger randomized studies as well as 2-year postinfusion follow-up of this cohort are needed to determine whether autologous cord blood-based approaches can be used to slow the decline of endogenous insulin production in children with type 1 diabetes.


Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 1/terapia , Sangre Fetal/trasplante , Transfusión de Sangre Autóloga/métodos , Péptido C/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Niño , Preescolar , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/inmunología , Estudios de Seguimiento , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Lactante , Infusiones Intravenosas , Insulina/uso terapéutico , Recuento de Leucocitos , Factores de Tiempo
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