Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S.

Abstract

To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODSFor prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTSIn the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher-versus lower-risk genotypes was 40% (28-50) vs. 12% . The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in #2 years or >7.4 years, respectively. CONCLUSIONSThe number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

Evolución de la ginecología peruana al Bicentenario, y el futuro

“…En conclusión, el número de autoanticuerpos de los islotes en el momento de la seroconversión predice de manera fiable el riesgo de tener diabetes tipo 1 a los 15 años. En los niños que conservan un solo autoanticuerpo, los genotipos HLA-DR-DQ pueden afinar aún más el riesgo de progresión (73) .…”

Quantifying the utility of islet autoantibody levels in the prediction of type 1 diabetes in children

“…In our previous work [ 17 ], we harmonised IAb levels from our large, prospective Type 1 Diabetes Intelligence (T1DI) study cohort [ 18 ], identified the IAb type-specific titre thresholds (measured at the time of confirmed positivity) that maximised discrimination of 5-year type 1 diabetes risk, and used the thresholds to risk-stratify children in various age groups via survival analysis. This prior work demonstrated that IAb levels were useful in predicting type 1 diabetes onset, and motivated us to perform a more comprehensive assessment of the utility of measurement of IAb levels.…”

INnoVative trial design for testing the Efficacy, Safety and Tolerability of 6‐month treatment with incretin‐based therapy to prevent type 1 DIAbetes in autoantibody positive participants: A protocol for three parallel double‐blind, randomised controlled trials (INVESTDIA)

“…When multiple autoantibodies against islet-derived peptides are observed in childhood, at least 70% of children progress to clinical diabetes within 10 years through identifiable disease stages, including stage 1 (multiple islet autoantibodies and normoglycemia in an oral glucosetolerance test [OGTT]), stage 2 (multiple islet autoantibodies and dysglycemia in an OGTT) and stage 3 (clinical type 1 diabetes fulfilling WHO and ADA criteria). [2][3][4][5][6] However, stage 3 type 1 diabetes includes a very heterogenous group of people from an early-diagnosed asymptomatic hyperglycaemia observed in an OGTT to late-diagnosed severe ketoacidosis. Thus, careful definition of eligibility criteria according to the two presymptomatic stages of type 1 diabetes, and strict criteria within stage 3, can identify homogeneous study groups.…”

“…T A B L E 1 Primary and secondary end points of three type 1 diabetes prevention trials testing incretin-based therapy in islet autoantibody positive participants F I G U R E 1 Overview of the design and recruitment for three parallel type 1 diabetes prevention trials testing incretin-based therapy in islet autoantibody positive participants at various stages of type 1 diabetes. 1 See ref [5,6]; 2 See ref [4]; 3 Primary endpoint assessed before and at the end of intervention; 4 IAA (insulin autoantibody), GADA (glutamic acid decarboxylase antibody), IA-2A (insulinoma-associated protein 2 antibody), ZnT8A (zinc transporter 8 antibody). The majority of the islet autoantibody multipositive participants are recruited from The Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study, a populationrepresentative birth cohort study ongoing in three university hospitals in Finland.…”