Increased inflammation is associated with islet autoimmunity and type 1 diabetes in the Diabetes Autoimmunity Study in the Young (DAISY)

<div><p>Background</p><p>Type 1 diabetes (TID) is characterized by a loss of pancreatic islet beta cell function resulting in loss of insulin production. Genetic and environmental factors may trigger immune responses targeting beta cells thus generating islet antibodies (IA). Immune response pathways involve a cascade of events, initiated by cytokines and chemokines, producing inflammation which can result in tissue damage.</p><p>Methods</p><p>A nested case-control study was performed to identify temporal changes in cytokine levels in 75 DAISY subjects: 25 diagnosed T1D, 25 persistent IA, and 25 controls. Serum samples were selected at four time points: (T1) earliest, (T2) just prior to IA, (T3) just after IA, and (T4) prior to T1D diagnosis or most recent. Cytokines (IFN-α2a, IL-6, IL-17, IL-1β, IP-10, MCP-1, IFN-γ, IL-1α, and IL-1ra) were measured using the Meso Scale Discovery system Human Custom Cytokine 9-Plex assay.</p><p>Results</p><p>Multivariate mixed models adjusting for HLA risk, first-degree relative status, age, and gender, showed MCP-1 and IFN-үto be significantly higher at T3 in T1D compared to IA subjects. At T4, IP-10 was significantly higher in IA subjects than controls.</p><p>Conclusions</p><p>This repeated measures nested case-control study identified increased inflammatory markers in IA children who developed T1D compared to IA children who had not progressed to clinical disease. It also showed increased inflammation in both T1D and IA children when compared to controls. Results suggest inflammation may be related to both the development of IA and progression to T1D.</p></div

Characteristics of DAISY nested case-control study.

<p>Characteristics of DAISY nested case-control study.</p

The Mixed Model Estimate of Change from Time 1.

<p>Pattern of change in serum cytokine or chemokine concentrations over time for the T1D, IA, and control groups. The log mean concentration for each individual cytokine is depicted as the difference from T1, the baseline (T2-T1, T3-T1, T4-T1).</p

Difference in Log Means Concentration of Cytokines (Adjusted for gender, age, HLA and FDR status).

<p>Difference in Log Means Concentration of Cytokines (Adjusted for gender, age, HLA and FDR status).</p

CGM Metrics Identify Dysglycemic States in Subjects from the TrialNet Pathway to Prevention Study

   OBJECTIVE  Continuous glucose monitoring (CGM) parameters may identify subjects at risk of progressing to overt type 1 diabetes. We aimed to determine whether CGM metrics provides additional insights into progression to clinical Stage 3 type 1 diabetes.  RESEARCH DESIGN AND METHODS  One hundred and five relatives of 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 is reported here. Three groups were evaluated: individuals with 1) Stage 2 type 1 diabetes (n=42) with ≥2 diabetes-related autoantibodies and abnormal OGTT; 2) Stage 1 type 1 diabetes (n=53) with ≥2 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 ≥140 mg/dL (p=0.02), ≥5% time ≥160 mg/dL (p = 0.0001) and ≥8% of the time spent at 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 day-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 subjects, including those with a normal OGTT, who are likely to rapidly progress to Stage 3 type 1 diabetes. </p

Merged genetic score in TEDDY children according to their islet autoantibody outcome, geographic location, and sex.

<p>Islet autoantibody outcome (A); geographic location (B); sex (C). Red horizontal lines indicate the median genetic score value in each group.</p

Cumulative risks of 1 or more islet autoantibody, multiple islet autoantibody, and type 1 diabetes in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype.

<p>The cumulative risk for 1 or more islet autoantibodies (A), multiple islet autoantibodies (B), and type 1 diabetes (C) for TEDDY children (<i>y-</i>axis) is shown relative to the age of the children (<i>x-</i>axis) and was calculated using the Kaplan–Meier method. The shaded area represents the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.</p

Cumulative risks of 1 or more islet autoantibody, multiple islet autoantibody, and type 1 diabetes development in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype stratified by their merged score.

<p>The cumulative risk of developing 1 or more islet autoantibodies (A), multiple islet autoantibodies (B), and type 1 diabetes (C) (<i>y-</i>axis) is shown relative to age in years (<i>x-</i>axis) and was calculated using the Kaplan–Meier method. Curves are shown for children with genetic scores in the upper (orange line), lower (green line), and 2 middle (blue line) quartiles. The shaded areas represent the 95% confidence interval of the cumulative risk. The numbers at risk indicate the number of children included in the analysis at each age.</p

Cumulative risks and the proportion of cases identified for 1 or more islet autoantibodies, multiple islet autoantibodies, and type 1 diabetes in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype according to increasing thresholds of the merged genetic score.

<p>Cumulative risk for developing islet autoantibodies by age 6 years and diabetes by age 10 years (A) and the proportion of cases positive for islet autoantibodies by age 6 years and diabetes by age 10 years (sensitivity; B) in TEDDY children with the HLA DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype stratified by their merged genetic score. The risk and sensitivity are shown for each increment in the genetic score by the 5th percentile of scores in the TEDDY children, ranging from >12.1 (the 5th percentile of children) to >15.4 (the 95th percentile of children). The risk and sensitivity are shown for the development of 1 or more islet autoantibodies (left panels), multiple islet autoantibodies (middle panels), and type 1 diabetes (right panels). Error bars indicate 95% confidence intervals.</p