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1.
Diabetes Care ; 46(3): 526-534, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36730530

ABSTRACT

OBJECTIVE: Continuous glucose monitoring (CGM) parameters may identify individuals at risk for progression to overt type 1 diabetes. We aimed to determine whether CGM metrics provide additional insights into progression to clinical stage 3 type 1 diabetes. RESEARCH DESIGN AND METHODS: One hundred five relatives of individuals in type 1 diabetes probands (median age 16.8 years; 89% non-Hispanic White; 43.8% female) from the TrialNet Pathway to Prevention study underwent 7-day CGM assessments and oral glucose tolerance tests (OGTTs) at 6-month intervals. The baseline data are reported here. Three groups were evaluated: individuals with 1) stage 2 type 1 diabetes (n = 42) with two or more diabetes-related autoantibodies and abnormal OGTT; 2) stage 1 type 1 diabetes (n = 53) with two or more diabetes-related autoantibodies and normal OGTT; and 3) negative test for all diabetes-related autoantibodies and normal OGTT (n = 10). RESULTS: Multiple CGM metrics were associated with progression to stage 3 type 1 diabetes. Specifically, spending ≥5% time with glucose levels ≥140 mg/dL (P = 0.01), ≥8% time with glucose levels ≥140 mg/dL (P = 0.02), ≥5% time with glucose levels ≥160 mg/dL (P = 0.0001), and ≥8% time with glucose levels ≥160 mg/dL (P = 0.02) were all associated with progression to stage 3 disease. Stage 2 participants and those who progressed to stage 3 also exhibited higher mean daytime glucose values; spent more time with glucose values over 120, 140, and 160 mg/dL; and had greater variability. CONCLUSIONS: CGM could aid in the identification of individuals, including those with a normal OGTT, who are likely to rapidly progress to stage 3 type 1 diabetes.


Subject(s)
Diabetes Mellitus, Type 1 , Humans , Female , Adolescent , Male , Diabetes Mellitus, Type 1/drug therapy , Blood Glucose/metabolism , Blood Glucose Self-Monitoring , Glucose/therapeutic use , Autoantibodies
2.
Diabetes ; 68(9): 1819-1829, 2019 09.
Article in English | MEDLINE | ID: mdl-31167877

ABSTRACT

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 would identify high-risk subjects who would benefit from participation in prevention trials who have one islet antibody by traditional testing and otherwise would be misclassified as "low risk" relatives.


Subject(s)
Autoantibodies , Diabetes Mellitus, Type 1/diagnosis , HLA-DRB1 Chains/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 8/immunology , Adolescent , Adult , Child , Child, Preschool , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Female , Haplotypes , Humans , Infant , Male , Middle Aged , Young Adult
4.
JCI Insight ; 3(23)2018 12 06.
Article in English | MEDLINE | ID: mdl-30518692

ABSTRACT

We describe a protective effect on autoimmune diabetes and reduced destructive insulitis in NOD.scid recipients following splenocyte injections from diabetic NOD donors and sorted CD19+ cells compared with NOD.scid recipients receiving splenocytes alone. This protective effect was age specific (only CD19+ cells from young NOD donors exerted this effect; P < 0.001). We found that the CD19+IgM+ cell is the primary subpopulation of B cells that delayed transfer of diabetes mediated by diabetogenic T cells from NOD mice (P = 0.002). Removal of IgM+ cells from the CD19+ pool did not result in protection. Notably, protection conferred by CD19+IgM+ cotransfers were not dependent on the presence of Tregs, as their depletion did not affect their ability to delay onset of diabetes. Blockade of IL-10 with neutralizing antibodies at the time of CD19+ cell cotransfers also abrogated the therapeutic effect, suggesting that IL-10 secretion was an important component of protection. These results were strengthened by ex vivo incubation of CD19+ cells with IL-5, resulting in enhanced proliferation and IL-10 production and equivalently delayed diabetes progression (P = 0.0005). The potential to expand CD19+IgM+ cells, especially in response to IL-5 stimulation or by pharmacologic agents, may be a new therapeutic option for type 1 diabetes.


Subject(s)
Antigens, CD19/therapeutic use , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/therapy , Immunoglobulin M/therapeutic use , Animals , Antibodies, Neutralizing , B-Lymphocytes , Cell Proliferation , Female , Histocompatibility Antigens Class I , Interleukin-10/metabolism , Interleukin-5/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID
5.
Diabetes Care ; 41(12): 2637-2640, 2018 12.
Article in English | MEDLINE | ID: mdl-30327357

ABSTRACT

OBJECTIVE: Autoantibodies directed against tyrosine phosphatase IA-2 antibody (IA-2 Ab) are diagnostic for autoimmune type 1 diabetes. Conventional assays target the intracellular domain of IA-2. Among patients with ketosis-prone diabetes (KPD), characterized by presentation with diabetic ketoacidosis (DKA), >60% of adults lack three classic islet autoantibodies-IA-2, GAD65, and ZnT8 Abs-associated with type 1 diabetes. We aimed to determine whether apparently autoantibody-negative ("A-") KPD patients possess occult IA-2 Ab directed against full-length IA-2 (IA-2FL) or its extracellular domain (IA-2EC). RESEARCH DESIGN AND METHODS: We developed an assay that targets IA-2FL and IA-2EC and used it to analyze 288 subjects with A- KPD. RESULTS: Ten A- KPD patients were positive for IA-2EC Ab (3.5%), and three were also positive for IA-2FL Ab (1.0%), similar to frequencies in type 1 and type 2 diabetes. CONCLUSIONS: Measurement of IA-2FL Ab and IA-2EC Ab improves the accuracy of the Aß classification of KPD patients.


Subject(s)
Autoantibodies/blood , Diabetic Ketoacidosis/classification , Diabetic Ketoacidosis/diagnosis , Receptor-Like Protein Tyrosine Phosphatases, Class 8/chemistry , Receptor-Like Protein Tyrosine Phosphatases, Class 8/immunology , Adolescent , Adult , Biomarkers/blood , Child , Cohort Studies , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetic Ketoacidosis/blood , Diagnosis, Differential , Female , Humans , Immunoassay/methods , Male , Middle Aged , Protein Domains/immunology , Reproducibility of Results , Sensitivity and Specificity , Young Adult
6.
Diabetes Care ; 40(4): 561-568, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28174261

ABSTRACT

OBJECTIVE: The characterization of diverse subtypes of diabetes is a dynamic field of clinical research and an active area of discussion. The objective of this study was to identify new antigenic determinants in the neuroendocrine autoantigen IA-2 (ICA512) and assess whether circulating autoantibodies directed to new IA-2 epitopes identify autoimmune diabetes in young and adult populations with diabetes. RESEARCH DESIGN AND METHODS: Clinically diagnosed patients with type 2 diabetes (n = 258; diabetes duration: 0.01-31 years) were evaluated using a new biomarker detecting autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2 (IA-2ec). The proportion of IA-2ec autoantibodies was also evaluated in newly diagnosed patients with type 1 diabetes (n = 150; diabetes duration: 0.04-0.49 years). In addition, IA-2 (intracellular domain), GAD65, and zinc transporter 8 autoantibodies were assayed. RESULTS: IA-2ec autoantibodies were detected in patients with type 1 diabetes and, surprisingly, in 5% of patients with type 2 diabetes without serologic responses to other IA-2 antigenic epitopes or other islet autoantigens. We also assessed the ability of IA-2ec-derived peptides to elicit CD4+ T-cell responses by stimulating peripheral blood mononuclear cells from patients with type 1 diabetes (n = 18) and HLA-matched healthy subjects (n = 13) with peptides and staining with the peptide/DQ8-specific tetramers, observing disease-associated responses to previously unreported epitopes within IA-2ec. CONCLUSIONS: We developed a new antibody biomarker identifying novel antigenic determinants within the N terminus of IA-2. IA-2ec autoantibodies can be detected in patients with type 1 diabetes and in a subgroup of adult autoimmune patients with type 2 diabetes phenotype negative for conventional islet autoantibody testing. These observations suggest that islet autoimmunity may be more common in clinically diagnosed type 2 diabetes than previously observed.


Subject(s)
Diabetes Mellitus, Type 1/immunology , Epitopes/immunology , Receptor-Like Protein Tyrosine Phosphatases, Class 8/immunology , Adolescent , Adult , Autoantibodies/immunology , Autoantigens/immunology , Biomarkers/analysis , Child , Child, Preschool , Diabetes Mellitus, Type 2/immunology , Female , Glutamate Decarboxylase/immunology , Humans , Leukocytes, Mononuclear/immunology , Male , Middle Aged , T-Lymphocytes/immunology , Young Adult
7.
Nephrol Dial Transplant ; 27(3): 1231-8, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21810767

ABSTRACT

BACKGROUND: Clinical relevance of donor-specific antibodies (DSAs) detected by a single antigen Luminex virtual crossmatch in pre-transplant serum samples from patients with a negative cytotoxicity-dependent complement crossmatch is controversial. The aim of this study was to analyse the influence of a pre-transplant positive virtual crossmatch in the outcome of kidney transplantation. METHODS: A total of 892 patients who received a graft from deceased donors after a negative cytotoxicity crossmatch were included. Presence of anti-human leucocyte antigen (HLA) antibodies was investigated using a Luminex screening assay and anti-HLA specificities were assigned performing a Luminex single antigen assay. RESULTS: Graft survival was significantly worse among patients with anti-HLA DSA compared to both patients with anti-HLA with no DSA (P = 0.001) and patients without HLA antibodies (P < 0.001) using a log-rank test. No graft survival differences between anti-HLA with no DSA and no HLA antibodies patient groups were observed (P = 0.595). Influence of both anti-Class I and anti-Class II DSA was detected (P < 0.0001 in both cases). When the fluorescence values were stratified in four groups, no significant differences in graft survival were observed among the groups with fluorescence levels >1500 (global P > 0.05). CONCLUSIONS: The presence of preformed HLA DSA in transplanted patients with a negative cytotoxicity crossmatch is associated with a lower allograft survival. The detection of anti-HLA with no DSA has no influence in the graft outcome. Finally, there were no demonstrable effects of mean fluorescence intensity (MFI) values >1500 on graft survival.


Subject(s)
Graft Rejection/immunology , Graft Survival/immunology , HLA Antigens/immunology , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class I/immunology , Isoantibodies/blood , Kidney Transplantation/immunology , Adolescent , Adult , Aged , Antibody Specificity , Child , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Histocompatibility Testing , Humans , Male , Middle Aged , Predictive Value of Tests , Tissue Donors , Transplantation, Homologous , Young Adult
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