Relative Frequency of Islet Autoimmunity in Children and Adolescents with Autoimmune Thyroid Disease

The present study aims to investigate islet autoimmunity and susceptibility to type 1 diabetes (T1D) in children/adolescents with autoimmune thyroid disease (AITD), and family members of AITD patients with islet autoimmunity. Islet-cell cytoplasmic, glutamic-acid decarboxylase and tyrosine-phosphatase autoantibodies were measured in 161 AITD patients [(127 with autoimmune thyroiditis (AT); 34 with Graves’ disease (GD)], 20 family members of AITD patients with islet autoimmunity, and 155 age-matched controls. Islet autoimmunity was found in 10.6% of AITD patients, significantly more frequent than in controls (1.9%; p=0.002). Higher prevalence of islet autoantibodies was found in females with AITD (p=0.011) but not in males (p=0.16) as well as in AT (p=0.013) but not GD patients (p=0.19), compared to corresponding controls. Two or three islet autoantibodies were found concurrently in six AITD patients with islet autoimmunity. They all developed T1D and had significantly higher islet autoantibodies titers (p=0.01) compared to AITD patients with single islet autoantibodies but normal glucose metabolism. T1D was found in 3.7% of AITD patients compared to 0.2% in age-matched, general Croatian population. Islet autoantibodies were found in 5/20 family members of AITD patients with islet autoimmunity, among which two developed T1D. None of the controls was positive to more than one islet autoantibodies or developed T1D. Conclusion: Children/adolescents with AITD (particularly females and patients with AT) represent a risk group for islet autoimmunity and T1D, as well as family members of AITD patients with positive islet autoantibodies, but last observation must be examined in a larger number of patients.

Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA

Background Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone. Methods Subjects (n = 57) at 2–50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24). Results Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2–4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was − 1.88 (− 2.71, − 1.05) p = 3.49 × 10–5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (− 0.80 (− 1.58, − 0.02), p = 0.046). Conclusions The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account. Trial registration ClinicalTrials.gov identifier: NCT02605148, November 16, 2015

General population screening for childhood type 1 diabetes: is it time for a UK strategy?

Type 1 diabetes (T1D) is a chronic autoimmune disease of childhood affecting 1:500 children aged under 15 years, with around 25% presenting with life-threatening diabetic ketoacidosis (DKA). While first-degree relatives have the highest risk of T1D, more than 85% of children who develop T1D do not have a family history. Despite public health awareness campaigns, DKA rates have not fallen over the last decade. T1D has a long prodrome, and it is now possible to identify children who go on to develop T1D with a high degree of certainty. The reasons for identifying children presymptomatically include prevention of DKA and related morbidities and mortality, reducing the need for hospitalisation, time to provide emotional support and education to ensure a smooth transition to insulin treatment, and opportunities for new treatments to prevent or delay progression. Research studies of population-based screening strategies include using islet autoantibodies alone or in combination with genetic risk factors, both of which can be measured from a capillary sample. If found during screening, the presence of two or more islet autoantibodies has a high positive predictive value for future T1D in childhood (under 18 years), offering an opportunity for DKA prevention. However, a single time-point test will not identify all children who go on to develop T1D, and so combining with genetic risk factors for T1D may be an alternative approach. Here we discuss the pros and cons of T1D screening in the UK, the different strategies available, the knowledge gaps and why a T1D screening strategy is needed.

Heterogeneity of Beta-cell Function in Subjects With Multiple Islet Autoantibodies in the TEDDY Family Prevention Study - TEFA

BackgroundIndividuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial one month apart for beta-cell function, glucose metabolism and continuous glucose monitoring. We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and continuous glucose monitoring (CGM) allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.MethodsSubjects (n=57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed one month later by OGTT, and one week of CGM (n=24).ResultsAutoantibodies against GAD65 (GADA; n=52), ZnT8 (ZnT8A; n=40), IA-2 (IA-2A; n=38) and insulin (IAA; n=28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2(FPIR) as the outcome and log2(OGTT glucose AUC) as the predictor, adjusting for age and sex was -1.88 (-2.71, -1.05) p = 3.49x10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W)A was associated with a lower log2-transformed FPIR (-0.80 (-1.58, -0.02), p = 0.046). Conclusions The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account. Trial registrationClinicalTrials.gov identifier: NCT02605148, November 16, 2015, https://clinicaltrials.gov/ct2/show/nct02605148