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OBJECTIVE: Innate immune responses may be involved in the earliest phases of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: To test whether blocking innate immaune cells modulated progression of the disease, we randomly assigned 273 individuals with stage 1 T1D to treatment with hydroxychloroquine (n = 183; 5 mg/kg per day to a maximum of 400 mg) or placebo (n = 90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e., two or more islet autoantibodies with abnormal glucose tolerance). RESULTS: After a median follow-up of 23.3 months, the trial was stopped prematurely by the data safety monitoring board because of futility. There were no safety concerns in the hydroxychloroquine arm, including in annual ophthalmologic examinations. Preplanned secondary analyses showed a transient decrease in the glucose average area under the curve to oral glucose in the hydroxychloroquine-treated arm at month 6 and reduced titers of anti-GAD and anti-insulin autoantibodies and acquisition of positive autoantibodies in the hydroxychloroquine arm (P = 0.032). CONCLUSIONS: We conclude that hydroxychloroquine does not delay progression to stage 2 T1D in individuals with stage 1 disease. Drug treatment reduces the acquisition of additional autoantibodies and the titers of autoantibodies to GAD and insulin.
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Diabetes Mellitus Tipo 1 , Hidroxicloroquina , Humanos , Hidroxicloroquina/uso terapéutico , Autoanticuerpos , Insulina , GlucosaRESUMEN
The past 200 years have brought an understanding of diabetes and its pathogenesis, as well as the development of treatments that could not have been predicted when the disorder was first clinically described 2000 years ago. Beginning in the late 19th century, the initial descriptions of the microscopic anatomy of the pancreatic islets by Langerhans led to recognition of pancreatic endocrine function. Many investigators attempted to isolate the hypoglycemic factor produced by the pancreas, but Banting, Best, Macleod, and Collip were able to extract and purify "isletin" to treat human diabetes in 1921. Rapid scientific progress over the next 100 years led to an understanding of insulin synthesis, structure and function, production of modified synthetic insulins, and the physiopathology that permitted classification of diabetes subtypes. Improvements in control of diabetes have reduced the risks of complications. In less than two hundred years, we have gone from being unable to measure glucose in blood to being able to offer people with diabetes continuous blood glucose monitoring, linked to continuous subcutaneous insulin infusion. We come ever closer with new drugs and treatments to repair the biochemical defects in type 2 diabetes and to biologically replace islets and their function in type 1 diabetes. This review addresses the history of continuing progress in diabetes care.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Humanos , Automonitorización de la Glucosa Sanguínea , Glucemia , Insulina , Diabetes Mellitus Tipo 1/terapiaRESUMEN
OBJECTIVE: There is evidence that youth with type 1 diabetes are at risk for depression, and depression is a significant risk factor for subsequent psychological and physical health problems. However, it is not clear if/when this depression risk emerges. The goal of this study was to determine if there are differences in levels of depressive symptoms between youth with and without type 1 diabetes that develop over the course of emerging adulthood. We also examined whether adolescent psychosocial variables predicted depressive symptoms during emerging adulthood. METHODS: Youth with (n = 132) and without (n = 131) type 1 diabetes were enrolled in the study at average age 12 and followed for 14 years. Depressive symptoms were measured throughout the study. Psychosocial variables of interest were measured during adolescence. RESULTS: Group differences in depressive symptoms emerged by study end at average age 26. Depressive symptoms appeared to decline over time for youth without diabetes and to increase over time for youth with diabetes. Parent relationship difficulties increased over adolescence as did peer conflict for the entire cohort. Supportive relationships with parent and peers predicted fewer end of study depressive symptoms (controlling for baseline depressive symptoms)-equally so for both groups. CONCLUSIONS: This study provides evidence that those with type 1 diabetes may be at risk for depressive symptoms many years after diagnosis and after adolescence. Although relational difficulties with parents and peers increase during adolescence, supportive relationships over the course of adolescence may help to mitigate depressive symptoms during young adulthood.
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Conducta del Adolescente , Diabetes Mellitus Tipo 1 , Adolescente , Humanos , Adulto Joven , Adulto , Niño , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/psicología , Depresión/psicología , Grupo Paritario , Conducta del Adolescente/psicología , Estudios de Cohortes , Estudios LongitudinalesRESUMEN
The international Trial to Reduce IDDM in the Genetically at Risk (TRIGR) tested the hypothesis whether extensively hydrolyzed casein-based versus regular cow's milk-based infant formula reduces the risk of type 1 diabetes. We describe dietary compliance in the trial in terms of study formula intake, feeding of nonrecommended foods, and serum cow's milk antibody concentration reflecting intake of cow's milk protein among 2,159 eligible newborn infants with a biological first-degree relative affected by type 1 diabetes and with HLA-conferred susceptibility to type 1 diabetes. The participating infants were introduced to the study formula feeding at the median age of 15 days with a median duration of study formula use of 63 days. During the intervention, 80% of the infants received study formula. Of these, 57% received study formula for at least 2 months. On average, 45.5 l of study formula were used per infant. Only 13% of the population had received a nonrecommended food by the age of 6 months. The dietary compliance was similar in the intervention and control arm. The reported cow's milk consumption by the families matched very well with measured serum casein IgA and IgG antibody concentration. To conclude, good compliance was observed in this randomized infant feeding trial. Compliance varied between the regions and those infants who were breastfed for a longer period of time had a shorter exposure to the study formula. High dietary compliance in infant feeding trial is necessary to allow accurate interpretation of study results.
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OBJECTIVE: The ß-cell stress hypothesis suggests that increased insulin demand contributes to the development of type 1 diabetes. In the TRIGR trial we set out to assess the profile of plasma glucose and HbA1c before the diagnosis of clinical diabetes compared to nondiabetic children. RESEARCH DESIGN AND METHODS: A cohort of children (N = 2159) with an affected first-degree relative and increased HLA risk were recruited 2002-2007 and followed until 2017. To study the relationship between plasma glucose/HbA1c and the development of autoantibodies or clinical disease Kaplan-Meir curves were developed. Mixed models were constructed for plasma glucose and HbA1c separately. RESULTS: A family history of type 2 diabetes was related to an increase in plasma glucose (p < 0.001). An increase in glucose from the previous sample predicted clinical diabetes (p < 0.001) but not autoantibodies. An increase of HbA1c of 20% or 30% from the previous sample predicted the development of any autoantibody (p < 0.003 resp <0.001) and the development of diabetes (p < 0.002 resp <0.001. Participants without autoantibodies had lower HbA1c (mean 5.18%, STD 0.24; mean 33.08 mmol/mol, STD 2.85) than those who progressed to clinical disease (5.31%, 0.42; 34.46 mmol/mol, 4.68; p < 0.001) but higher than those who developed any autoantibody (5.10%, 0.30; 32.21 mmol/mol, 3.49; p < 0.001), or multiple autoantibodies (5.11%, 0.35; 32.26 mmol/mol, 3.92; p < 0.003). CONCLUSIONS: A pronounced increase in plasma glucose and HbA1c precedes development of clinical diabetes, while the association between plasma glucose or HbA1c and development of autoantibodies is complex. Increased insulin demand may contribute to development of type 1 diabetes.
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Glucemia/análisis , Diabetes Mellitus Tipo 1/sangre , Autoanticuerpos/sangre , Estudios de Cohortes , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Hemoglobina Glucada/análisis , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Lactante , Insulina/fisiología , Resistencia a la Insulina/fisiología , Células Secretoras de Insulina/inmunología , Masculino , Estrés Fisiológico/inmunologíaRESUMEN
OBJECTIVE: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant. RESULTS: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/IF]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/IF), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. CONCLUSIONS: In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Adolescente , Péptido C , Diabetes Mellitus Tipo 1/genética , Humanos , Insulina , Resistencia a la Insulina/genética , Polimorfismo de Nucleótido Simple , Proteína 2 Similar al Factor de Transcripción 7/genéticaRESUMEN
Since the 1980s, there has been a dramatic rise in the prevalence of overweight and obesity in pediatric populations, in large part driven by sedentary lifestyles and changing dietary patterns with more processed foods. In parallel with the rise in pediatric obesity in the general population, the prevalence of overweight and obesity has increased among children and adolescents with type 1 diabetes. Adiposity has been implicated in a variety of mechanisms both potentiating the risk for type 1 diabetes as well as exacerbating long-term complications, particularly cardiovascular disease. Treatment options targeting the unique needs of obese pediatric patients, both before and after diagnosis of type 1 diabetes, are limited. In this review, we discuss the history of the epidemiology of the obesity epidemic in the context of pediatric type 1 diabetes, highlight the possible role of obesity in type 1 diabetes pathogenesis and review the concept of "double diabetes". The impact of obesity at and after diagnosis will be discussed, including noted differences in clinical and biochemical markers, lipid abnormalities, and long-term cardiovascular complications. Finally, we will review the existing literature on pharmacologic and nutritional interventions as potential treatment strategies for youth with coexisting type 1 diabetes and obesity.
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Diabetes Mellitus Tipo 1/complicaciones , Obesidad Infantil/complicaciones , Conducta Sedentaria , Adiposidad/fisiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Estado Nutricional , Factores de RiesgoRESUMEN
AIMS/HYPOTHESIS: We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes. METHODS: Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10-14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05. RESULTS: In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2-10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p < 0.001 in time-varying Cox regression), and similarly with joint modelling. CONCLUSIONS/INTERPRETATION: In children at genetic risk of type 1 diabetes, being overweight at 2-10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777.
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Desarrollo del Adolescente , Autoinmunidad/genética , Desarrollo Infantil , Diabetes Mellitus Tipo 1/epidemiología , Islotes Pancreáticos/inmunología , Obesidad Infantil/epidemiología , Adolescente , Factores de Edad , Australia/epidemiología , Alimentación con Biberón , Niño , Preescolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Europa (Continente)/epidemiología , Femenino , Predisposición Genética a la Enfermedad , Herencia , Humanos , Incidencia , Lactante , Fórmulas Infantiles , Recién Nacido , Masculino , América del Norte/epidemiología , Obesidad Infantil/inmunología , Obesidad Infantil/prevención & control , Linaje , Fenotipo , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de RiesgoAsunto(s)
Diabetes Mellitus Tipo 1 , Cetoacidosis Diabética/diagnóstico , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Factores de RiesgoRESUMEN
AIMS/HYPOTHESIS: The aim of this work was to examine the relationship between family history of type 1 diabetes, birthweight, growth during the first 2 years and development of multiple beta cell autoantibodies in children with a first-degree relative with type 1 diabetes and HLA-conferred disease susceptibility. METHODS: In a secondary analysis of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), clinical characteristics and development of beta cell autoantibodies were compared in relation to family history of type 1 diabetes (mother vs father vs sibling) in 2074 children from families with a single affected family member. RESULTS: Multiple autoantibodies (≥2 of 5 measured) developed in 277 (13%) children: 107 (10%), 114 (16%) and 56 (18%) born with a mother, father or sibling with type 1 diabetes, respectively (p < 0.001). The HR for time to multiple autoimmunity was 0.54 (95% CI 0.39, 0.75) in offspring of affected mothers (n = 107/1046, p < 0.001) and 0.81 (95% CI 0.59, 1.11) (n = 114/722, p = 0.19) in offspring of affected fathers, compared with participants with a sibling with type 1 diabetes (comparator group n = 56/306). The time to the first autoantibody present (to insulin, GAD, tyrosine phosphatase-related insulinoma-associated 2 molecules, islet cell or zinc transporter 8) was similar in the three groups. Height velocity (z score/year) in the first 24 months was independently associated with developing multiple antibodies in the total cohort (HR 1.31 [95% CI 1.01, 1.70], p = 0.04). A higher birthweight in children born to an affected mother vs affected father or an affected sibling was not related to the risk of multiple autoimmunity. CONCLUSIONS/INTERPRETATION: The risk of developing multiple autoantibodies was lower in children with maternal type 1 diabetes. For the whole group, this risk of developing multiple autoantibodies was independent of birthweight but was greater in those with increased height velocity during the first 2 years of life. However, the risk associated with paternal type 1 diabetes was not linked to differences in birthweight or early growth. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777 Graphical abstract.
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Autoinmunidad/genética , Estatura/fisiología , Diabetes Mellitus Tipo 1/inmunología , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Células Secretoras de Insulina/inmunología , Autoanticuerpos/análisis , Peso al Nacer , Preescolar , Estudios de Cohortes , Método Doble Ciego , Padre , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Anamnesis , Madres , Factores de RiesgoRESUMEN
OBJECTIVE: Glucose response curves (GRCs) during oral glucose tolerance tests (OGTTs) are predictive of type 1 diabetes. We performed a longitudinal analysis in pancreatic autoantibody-positive individuals to assess 1) characteristic GRC changes during progression to type 1 diabetes and 2) GRC changes in relation to ß-cell function changes and to combined glucose and C-peptide response curve (GCRC) changes. RESEARCH DESIGN AND METHODS: Among antibody-positive individuals with serial OGTTs in the TrialNet Pathway to Prevention study, GRC changes from first to last OGTTs were compared between progressors (n = 298) to type 1 diabetes and nonprogressors (n = 2,216). GRC changes from last OGTT before diagnosis to diagnostic OGTTs were studied in progressors. RESULTS: GRCs changed more frequently from biphasic (two peaks) to monophasic (one peak) GRCs between first and last OGTTs in progressors than in nonprogressors (75.4% vs. 51.0%, respectively; P < 0.001). In contrast, GRCs of progressors changed less frequently from monophasic to biphasic than those of nonprogressors (12.6% vs. 30.6%; P < 0.001). Monotonic (continuous increase) GRCs were present in 47.7% of progressors at diagnosis. The early (30-0 min) C-peptide response decreased in progressors with GRCs changing from biphasic to monophasic between first and last OGTTs (P < 0.001) and from monophasic to monotonic between last and diagnostic OGTTs (P < 0.001). Conversely, the early C-peptide response increased among nonprogressors with GRCs changing from monophasic to biphasic (P < 0.001). Changes in GRCs were related to changes in GCRCs. CONCLUSIONS: Characteristic GRC changes, biphasic to monophasic to monotonic, occur during the progression to type 1 diabetes. These GRC changes correspond to decreasing ß-cell function.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/patología , Progresión de la Enfermedad , Adolescente , Autoanticuerpos/sangre , Péptido C/sangre , Niño , Preescolar , Diabetes Mellitus Tipo 1/diagnóstico , Familia , Femenino , Estudios de Seguimiento , Prueba de Tolerancia a la Glucosa , Humanos , Células Secretoras de Insulina/metabolismo , Estudios Longitudinales , Masculino , Páncreas/inmunología , Páncreas/metabolismo , Adulto JovenRESUMEN
We examined whether the timing of the C-peptide response during an oral glucose tolerance test (OGTT) in relatives of patients with type 1 diabetes (T1D) is predictive of disease onset. We examined baseline 2-h OGTTs from 670 relatives participating in the Diabetes Prevention Trial-Type 1 (age: 13.8 ± 9.6 years; body mass index z-score: 0.3 ± 1.1; 56% male) using univariate regression models. T1D risk increased with lower early C-peptide responses (30-0 min) (χ2 = 28.8, P < 0.001), and higher late C-peptide responses (120-60 min) (χ2 = 23.3, P < 0.001). When both responses were included in a proportional hazards model, they remained independently and oppositely associated with T1D, with a stronger overall association for the combined model than either response alone (χ2 = 41.1; P < 0.001). Using receiver operating characteristic curve analysis, the combined early and late C-peptide response was more accurately predictive of T1D than area under the curve C-peptide (P = 0.005). Our findings demonstrate that lower early and higher late C-peptide responses serve as indicators of increased T1D risk.
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Autoanticuerpos , Péptido C , Diabetes Mellitus Tipo 1 , Prueba de Tolerancia a la Glucosa , Adolescente , Adulto , Glucemia , Péptido C/metabolismo , Niño , Preescolar , Diabetes Mellitus Tipo 1/diagnóstico , Femenino , Humanos , Masculino , Curva ROC , Adulto JovenRESUMEN
OBJECTIVE: Sustained excess BMI increases the risk of type 1 diabetes (T1D) in autoantibody-positive relatives without diabetes of patients. We tested whether elevated BMI also accelerates the progression of islet autoimmunity before T1D diagnosis. RESEARCH DESIGN AND METHODS: We studied 706 single autoantibody-positive pediatric TrialNet participants (ages 1.6-18.6 years at baseline). Cumulative excess BMI (ceBMI) was calculated for each participant based on longitudinally accumulated BMI ≥85th age- and sex-adjusted percentile. Recursive partitioning analysis and multivariable modeling defined the age cut point differentiating the risk for progression to multiple positive autoantibodies. RESULTS: At baseline, 175 children (25%) had a BMI ≥85th percentile. ceBMI range was -9.2 to 15.6 kg/m2 (median -1.91), with ceBMI ≥0 kg/m2 corresponding to persistently elevated BMI ≥85th percentile. Younger age increased the progression to multiple autoantibodies, with age cutoff of 9 years defined by recursive partitioning analysis. Although ceBMI was not significantly associated with progression from single to multiple autoantibodies overall, there was an interaction with ceBMI ≥0 kg/m2, age, and HLA (P = 0.009). Among children ≥9 years old without HLA DR3-DQ2 and DR4-DQ8, ceBMI ≥0 kg/m2 increased the rate of progression from single to multiple positive autoantibodies (hazard ratio 7.32, P = 0.004) and conferred a risk similar to that in those with T1D-associated HLA haplotypes. In participants <9 years old, the effect of ceBMI on progression to multiple autoantibodies was not significant regardless of HLA type. CONCLUSIONS: These data support that elevated BMI may exacerbate islet autoimmunity prior to clinical T1D, particularly in children with lower risk based on age and HLA. Interventions to maintain normal BMI may prevent or delay the progression of islet autoimmunity.
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Autoinmunidad , Índice de Masa Corporal , Diabetes Mellitus Tipo 1/etiología , Islotes Pancreáticos/inmunología , Obesidad Infantil/complicaciones , Obesidad Infantil/inmunología , Adolescente , Adulto , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Niño , Preescolar , Estudios de Cohortes , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/patología , Progresión de la Enfermedad , Femenino , Haplotipos , Humanos , Lactante , Islotes Pancreáticos/patología , Masculino , Persona de Mediana Edad , Obesidad Infantil/epidemiología , Factores de Riesgo , Adulto JovenRESUMEN
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
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Variación Biológica Poblacional/fisiología , Diabetes Mellitus Tipo 1/clasificación , Diabetes Mellitus Tipo 1/patología , Fenotipo , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/terapia , Progresión de la Enfermedad , Humanos , Insulina/metabolismo , Medicina de Precisión/métodos , Medicina de Precisión/tendenciasRESUMEN
CONTEXT: Multiple islet autoantibody positivity usually precedes clinical (stage 3) type 1 diabetes (T1D). OBJECTIVE: To test the hypothesis that individuals who develop stage 3 T1D with only a single autoantibody have unique metabolic differences. DESIGN: Cross-sectional analysis of participants in the T1D TrialNet study. SETTING: Autoantibody-positive relatives of individuals with stage 3 T1D. PARTICIPANTS: Autoantibody-positive relatives who developed stage 3 T1D (at median age 12.4 years, rangeâ =â 1.4-58.6) and had autoantibody data close to clinical diagnosis (nâ =â 786, 47.4% male, 79.9% non-Hispanic white). MAIN OUTCOME MEASURES: Logistic regression modeling was used to assess relationships between autoantibody status and demographic, clinical, and metabolic characteristics, adjusting for potential confounders and correcting for multiple comparisons. RESULTS: At diagnosis of stage 3 T1D, single autoantibody positivity, observed in 119 (15.1%) participants (72% GAD65, 13% microinsulin antibody assay, 11% insulinoma-associated antigen 2, 1% islet cell antibody, 3% autoantibodies to zinc transporter 8 [ZnT8]), was significantly associated with older age, higher C-peptide measures (fasting, area under the curve, 2-hour, and early response in oral glucose tolerance test), higher homeostatic model assessment of insulin resistance, and lower T1D Index60 (all Pâ <â 0.03). While with adjustment for age, 2-hour C-peptide remained statistically different, controlling for body mass index (BMI) attenuated the differences. Sex, race, ethnicity, human leukocyte antigen DR3-DQ2, and/or DR4-DQ8, BMI category, and glucose measures were not significantly associated with single autoantibody positivity. CONCLUSIONS: Compared with multiple autoantibody positivity, single autoantibody at diagnosis of stage 3 T1D was associated with older age and insulin resistance possibly mediated by elevated BMI, suggesting heterogeneous disease pathogenesis. These differences are potentially relevant for T1D prevention and treatment.
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Autoanticuerpos/sangre , Diabetes Mellitus Tipo 1 , Resistencia a la Insulina , Islotes Pancreáticos/inmunología , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Niño , Preescolar , Estudios Transversales , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIMS: The aim was to determine if persistent c-peptide in long duration childhood onset (<17â¯years) type 1 diabetes (T1D) related to microvascular complications. METHODS: Pittsburgh Epidemiology of Diabetes Complications (EDC) participants (nâ¯=â¯185) had serum c-peptide levels measured by Mercodia ultra-sensitive ELISA at the 25-year follow-up exam. Microvascular complications between those with and without detectable c-peptide were compared. RESULTS: Eighteen (9.7%) participants had detectable median c-peptide levels of 3.8 (2.6, 12.2) pmol/L and did not differ from those without detectable levels. No differences in microalbuminuria, confirmed distal symmetric polyneuropathy, renal failure, or between those with one or more complications were found between the two groups. Proliferative retinopathy (PR) was marginally lower in those with detectable c-peptide (33.3% vs 55.1%, pâ¯=â¯0.08). However, those with c-peptide were somewhat less likely to have fasted for a full 8-h (66.7% vs. 84.9%, pâ¯=â¯0.09). Excluding those not fully fasted, PR no longer approached significance but macroalbuminuria became marginally lower in those with detectable levels (23.4% vs 0%, pâ¯=â¯0.07). CONCLUSIONS: Low levels of c-peptide in T1D patients of long duration were detected but were not strongly related to microvascular complications.
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Péptido C/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Angiopatías Diabéticas/epidemiología , Adolescente , Adulto , Albuminuria/sangre , Albuminuria/epidemiología , Glucemia/análisis , Angiopatías Diabéticas/sangre , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/epidemiología , Retinopatía Diabética/sangre , Retinopatía Diabética/epidemiología , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
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.
Asunto(s)
Autoanticuerpos , Diabetes Mellitus Tipo 1/diagnóstico , Cadenas HLA-DRB1/genética , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/inmunología , Adolescente , Adulto , Niño , Preescolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Femenino , Haplotipos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVE: The goal of this study was to use the risk and resistance framework to examine whether a set of psychosocial variables measured at age 12 in youth with Type 1 diabetes would predict the emergence of diabetes risk and complication variables 11 years and 13 years later. METHOD: We interviewed youth with Type 1 diabetes when they were average age 12 and followed them for 11 years until they were average age 23 and then average age 25. At age 12, we measured personality traits (unmitigated communion, unmitigated agency), relationship variables (parent relationship quality, friend support, friend conflict), indicators of psychological well-being (depressive symptoms, bulimic symptoms, self-worth), and self-care behavior. We used these psychosocial variables assessed at age 12 to predict diabetes risk factors, glycemic control, and the emergence of diabetes complications at follow-up. RESULTS: Higher unmitigated agency, poor quality parent relationships, higher friend conflict, bulimic symptoms, and lower self-worth predicted one or more diabetes outcomes. When statistical controls for age 12 glycemic control were employed, unmitigated agency emerged as the most robust predictor of diabetes outcomes. CONCLUSION: Unmitigated agency, which involves an overly inflated view of the self and a cynical view of others, predicted poor diabetes outcomes over an 11-year and 13-year period. The processes by which unmitigated agency could influence health are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).