RESUMEN
AIMS: To investigate whether the N-terminal truncated glutamic acid decarboxylase 65 (GAD65) isoform is as well recognized by people with stiff person syndrome as it is by people with Type 1 diabetes, and whether conformational GAD65 antibody epitopes are displayed properly by the isoform. METHODS: GAD65 antibody-positive healthy individuals (n=13), people with stiff-person syndrome (n=15) and children with new-onset Type 1 diabetes (n=654) were analysed to determine binding to full-length GAD65 and the N-terminal truncated GAD65 isoform in each of these settings. GAD65 autoantibody epitope specificity was correlated with binding ratios of full-length GAD65/N-terminal truncated GAD65. RESULTS: The N-terminal truncated GAD65 isoform was significantly less recognized in GAD65Ab-positive people with stiff-person syndrome (P=0.002) and in healthy individuals (P=0.0001) than in people with Type 1 diabetes. Moreover, at least two specific conformational GAD65Ab epitopes were not, or were only partially, presented by the N-terminal truncated GAD65 isoform compared to full-length GAD65. Finally, an N-terminal conformational GAD65Ab epitope was significantly less recognized in DQ8/8 positive individuals with Type 1 diabetes (P=0.02). CONCLUSIONS: In people with stiff person syndrome preferred binding to the full-length GAD65 isoform over the N-terminal truncated molecule was observed. This binding characteristic is probably attributable to reduced presentation of two conformational epitopes by the N-terminal truncated molecule. These findings support the notion of disease-specific GAD65Ab epitope specificities and emphasize the need to evaluate the applicability of novel assays for different medical conditions.
Asunto(s)
Autoantígenos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Epítopos/inmunología , Glutamato Descarboxilasa/sangre , Fragmentos de Péptidos/sangre , Síndrome de la Persona Rígida/inmunología , Adolescente , Adulto , Anciano , Análisis de Varianza , Especificidad de Anticuerpos , Autoanticuerpos/sangre , Autoantígenos/sangre , Biomarcadores/sangre , Niño , Preescolar , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Encuestas Epidemiológicas , Voluntarios Sanos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Isoformas de Proteínas/sangre , Síndrome de la Persona Rígida/sangre , Síndrome de la Persona Rígida/genética , Síndrome de la Persona Rígida/fisiopatología , SueciaRESUMEN
The incidence of type 1 diabetes (T1D) in Sweden is one of the highest in the world. However, the possibility of other types of diabetes must also be considered. In addition, individuals with T1D constitute a heterogeneous group. A precise classification of diabetes is a prerequisite for optimal outcome. For precise classification, knowledge on the distribution of genetic factors, biochemical markers and clinical features in individuals with new onset of diabetes is needed. The Better Diabetes Diagnosis (BDD), is a nationwide study in Sweden with the primary aim to facilitate a more precise classification and diagnosis of diabetes in order to enable the most adequate treatment for each patient. Secondary aims include identification of risk factors for diabetes-related co-morbidities. Since 2005, data on almost all children and adolescents with newly diagnosed diabetes in Sweden are prospectively collected and including heredity of diabetes, clinical symptoms, levels of C peptide, genetic analyses and detection of autoantibodies. Since 2011, analyses of HLA profile, autoantibodies and C peptide levels are part of clinical routine in Sweden for all pediatric patients with suspected diagnosis of diabetes. In this review, we present the methods and main results of the BDD study so far and discuss future aspects.
Asunto(s)
Diabetes Mellitus/diagnóstico , Adolescente , Niño , Preescolar , Estudios de Cohortes , Diabetes Mellitus/patología , Femenino , Humanos , Incidencia , Masculino , Estudios Prospectivos , Factores de Riesgo , Suecia/epidemiologíaRESUMEN
AIMS: People with Type 1 diabetes have smaller pancreases than healthy individuals. Several diseases causing pancreatic atrophy are associated with pancreatic steatosis, but pancreatic fat in Type 1 diabetes has not been measured. This cross-sectional study aimed to compare pancreas size and fat fraction in children with Type 1 diabetes and controls. METHODS: The volume and fat fraction of the pancreases of 22 children with Type 1 diabetes and 29 controls were determined using magnetic resonance imaging. RESULTS: Pancreas volume was 27% smaller in children with diabetes (median 34.9 cm(3) ) than in controls (47.8 cm(3) ; P < 0.001). Pancreas volume correlated positively with age in controls (P = 0.033), but not in children with diabetes (P = 0.649). Pancreas volume did not correlate with diabetes duration, but it did correlate positively with units of insulin/kg body weight/day (P = 0.048). A linear model of pancreas volume as influenced by age, body surface area and insulin units/kg body weight/day found that insulin dosage correlated with pancreas volume after controlling for both age and body surface area (P = 0.009). Pancreatic fat fraction was not significantly different between the two groups (1.34% vs. 1.57%; P = 0.891). CONCLUSIONS: Our findings do not indicate that pancreatic atrophy in Type 1 diabetes is associated with an increased pancreatic fat fraction, unlike some other diseases featuring reduced pancreatic volume. We speculate that our results may support the hypotheses that much of pancreatic atrophy in Type 1 diabetes occurs before the clinical onset of the disease and that exogenous insulin administration decelerates pancreatic atrophy after diabetes onset.
Asunto(s)
Adiposidad/fisiología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Páncreas/metabolismo , Páncreas/patología , Adiposidad/efectos de los fármacos , Adolescente , Atrofia , Estudios de Casos y Controles , Niño , Estudios Transversales , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/patología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Humanos , Insulina/farmacología , Trastornos del Metabolismo de los Lípidos/metabolismo , Trastornos del Metabolismo de los Lípidos/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Páncreas/efectos de los fármacos , Enfermedades Pancreáticas/metabolismo , Enfermedades Pancreáticas/patologíaRESUMEN
The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.
Asunto(s)
Autoanticuerpos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Antígenos HLA-DQ/inmunología , Proteínas Mutantes Quiméricas/inmunología , Adolescente , Adulto , Autoantígenos/inmunología , Autoinmunidad/genética , Autoinmunidad/inmunología , Niño , Preescolar , Diabetes Mellitus Tipo 1/diagnóstico , Femenino , Antígenos HLA-DQ/genética , Humanos , Lactante , Insulina/inmunología , Masculino , Unión Proteica/inmunología , Adulto JovenRESUMEN
Exposure to Ljungan virus (LV) is implicated in the risk of autoimmune (type 1) diabetes but possible contribution by other parechoviruses is not ruled out. The aim was to compare children diagnosed with type 1 diabetes in 2005-2011 (n = 69) with healthy controls (n = 294), all from the Jämtland County in Sweden, using an exploratory suspension multiplex immunoassay for IgM and IgG against 26 peptides of LV, human parechoviruses (HPeV), Aichi virus and poliovirus in relation to a radiobinding assay (RBA) for antibodies against LV and InfluenzaA/H1N1pdm09. Islet autoantibodies and HLA-DQ genotypes were also determined. 1) All five LV-peptide antibodies correlated to each other (P < 0.001) in the suspension multiplex IgM- and IgG-antibody assay; 2) The LV-VP1_31-60-IgG correlated with insulin autoantibodies alone (P = 0.007) and in combination with HLA-DQ8 overall (P = 0.022) as well as with HLA-DQ 8/8 and 8/X subjects (P = 0.013); 3) RBA detected LV antibodies correlated with young age at diagnosis (P < 0.001) and with insulin autoantibodies (P < 0.001) especially in young HLA-DQ8 subjects (P = 0.004); 4) LV-peptide-VP1_31-60-IgG correlated to RBA LV antibodies (P = 0.009); 5) HPeV3-peptide-IgM and -IgG showed inter-peptide correlations (P < 0.001) but only HPeV3-VP1_1-30-IgG (P < 0.001) and VP1_95-124-IgG (P = 0.009) were related to RBA LV antibodies without relation to insulin autoantibody positivity (P = 0.072 and P = 0.486, respectively). Both exploratory suspension multiplex IgG to LV-peptide VP1_31-60 and RBA detected LV antibodies correlated with insulin autoantibodies and HLA-DQ8 suggesting possible role in type 1 diabetes. It remains to be determined if cross-reactivity or concomitant exposure to LV and HPeV3 contributes to the seroprevalence.
Asunto(s)
Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/etiología , Parechovirus/inmunología , Infecciones por Picornaviridae/complicaciones , Infecciones por Picornaviridae/epidemiología , Adolescente , Alelos , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Genotipo , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Lactante , Masculino , Péptidos/química , Péptidos/inmunología , Infecciones por Picornaviridae/inmunología , Estudios Seroepidemiológicos , Suecia/epidemiologíaRESUMEN
We determined A/H1N1-hemagglutinin (HA) antibodies in relation to HLA-DQ genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7-to 18-year-old type 1 diabetes patients diagnosed April 2009-December 2010. Antibodies to (35) S-methionine-labelled A/H1N1 hemagglutinin were determined in a radiobinding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009-March 2010 Swedish A(H1N1)pdm09 vaccination campaign, along with HLA-DQ genotypes and autoantibodies against GAD, insulin, IA-2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1-HA antibodies compared with 40% during and 27% after vaccination (P < 0.0001). In children <3 years of age, A/H1N1-HA antibodies were found only during vaccination. The frequency of A/H1N1-HA antibodies during vaccination decreased after vaccination among the 3 < 6 (P = 0.006) and 13 < 18 (P = 0.001), but not among the 6 < 13-year-olds. HLA-DQ2/8 positive children <3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1-HA antibodies compared with non-DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (<3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix(®) . As the proportion of DQ2/8 patients <3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.
Asunto(s)
Anticuerpos Antivirales/sangre , Diabetes Mellitus Tipo 1/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Vacunación , Adolescente , Autoanticuerpos/sangre , Proteínas de Transporte de Catión/genética , Niño , Preescolar , Glutamato Descarboxilasa/metabolismo , Antígenos HLA-DQ/genética , Humanos , Modelos Logísticos , Transportador 8 de ZincRESUMEN
AIMS: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative. METHODS: A total of 686 patients diagnosed in 1996-2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes. RESULTS: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%-a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1(*)X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA. CONCLUSIONS: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1(*)X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.