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Diabetes is one of the most common chronic diseases among persons aged <20 years (1). Onset of diabetes in childhood and adolescence is associated with numerous complications, including diabetic kidney disease, retinopathy, and peripheral neuropathy, and has a substantial impact on public health resources (2,3). From 2002 to 2012, type 1 and type 2 diabetes incidence increased 1.4% and 7.1%, respectively, among U.S. youths (4). To assess recent trends in incidence of diabetes in youths (defined for this report as persons aged <20 years), researchers analyzed 2002-2015 data from the SEARCH for Diabetes in Youth Study (SEARCH), a U.S. population-based registry study with clinical sites located in five states. The incidence of both type 1 and type 2 diabetes in U.S. youths continued to rise at constant rates throughout this period. Among all youths, the incidence of type 1 diabetes increased from 19.5 per 100,000 in 2002-2003 to 22.3 in 2014-2015 (annual percent change [APC] = 1.9%). Among persons aged 10-19 years, type 2 diabetes incidence increased from 9.0 per 100,000 in 2002-2003 to 13.8 in 2014-2015 (APC = 4.8%). For both type 1 and type 2 diabetes, the rates of increase were generally higher among racial/ethnic minority populations than those among whites. These findings highlight the need for continued surveillance for diabetes among youths to monitor overall and group-specific trends, identify factors driving these trends, and inform health care planning.

Defects in IL-2R Signaling Contribute to Diminished Maintenance of FOXP3 Expression in CD4 + CD25 + Regulatory T-Cells of Type 1 Diabetic Subjects S. Alice Long 1 , Karen Cerosaletti 1 , Paul L. Bollyky 1 , Megan Tatum 1 , Heather Shilling 1 , Sheng Zhang 2 , Zhong-Yin Zhang 2 , Catherine Pihoker 3 , Srinath Sanda 1 , Carla Greenbaum 1 and Jane H. Buckner 1 1 Benaroya Research Institute at Virginia Mason, Seattle, Washington; 2 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; 3 Seattle Children's Hospital, Seattle, Washington. Corresponding author: Jane H. Buckner, jbuckner{at}benaroyaresearch.org . Abstract OBJECTIVE In humans, multiple genes in the interleukin (IL)-2/IL-2 receptor (IL-2R) pathway are associated with type 1 diabetes. However, no link between IL-2 responsiveness and CD4 + CD25 + FOXP3 + regulatory T-cells (Tregs) has been demonstrated in type 1 diabetic subjects despite the role of these IL-2–dependent cells in controlling autoimmunity. Here, we address whether altered IL-2 responsiveness impacts persistence of FOXP3 expression in Tregs of type 1 diabetic subjects. RESEARCH DESIGN AND METHODS Persistence of Tregs was assessed by culturing sorted CD4 + CD25 hi natural Tregs with IL-2 and measuring FOXP3 expression over time by flow cytometry for control and type 1 diabetic populations. The effects of IL-2 on FOXP3 induction were assessed 48 h after activation of CD4 + CD25 − T-cells with anti-CD3 antibody. Cytokine receptor expression and signaling upon exposure to IL-2, IL-7, and IL-15 were determined by flow cytometry and Western blot analysis. RESULTS Maintenance of FOXP3 expression in CD4 + CD25 + Tregs of type 1 diabetic subjects was diminished in the presence of IL-2, but not IL-7. Impaired responsiveness was not linked to altered expression of the IL-2R complex. Instead, IL-2R signaling was reduced in Tregs and total CD4 + T-cells of type 1 diabetic subjects. In some individuals, decreased signal transducer and activator of transcription 5 phosphorylation correlated with significantly higher expression of protein tyrosine phosphatase N2, a negative regulator of IL-2R signaling. CONCLUSIONS Aberrant IL-2R signaling in CD4 + T-cells of type 1 diabetic subjects contributes to decreased persistence of FOXP3 expression that may impact establishment of tolerance. These findings suggest novel targets for treatment of type 1 diabetes within the IL-2R pathway and suggest that an altered IL-2R signaling signature may be a biomarker for type 1 diabetes. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received May 8, 2009. Accepted October 16, 2009. © 2010 by the American Diabetes Association.

Autoantibodies in Diabetes Catherine Pihoker , Lisa K. Gilliam , Christiane S. Hampe and Åke Lernmark From the Departments of Pediatrics and Medicine, University of Washington, Seattle, Washington Address correspondence and reprint requests to Dr. Catherine Pihoker, Department of Pediatrics, University of Washington, Seattle, WA 98195. E-mail: catherine.pihoker{at}seattlechildrens.org Abstract Islet cell autoantibodies are strongly associated with the development of type 1 diabetes. The appearance of autoantibodies to one or several of the autoantigens—GAD65, IA-2, or insulin—signals an autoimmune pathogenesis of β-cell killing. A β-cell attack may be best reflected by the emergence of autoantibodies dependent on the genotype risk factors, isotype, and subtype of the autoantibodies as well as their epitope specificity. It is speculated that progression to β-cell loss and clinical onset of type 1 diabetes is reflected in a developing pattern of epitope-specific autoantibodies. Although the appearance of autoantibodies does not follow a distinct pattern, the presence of multiple autoantibodies has the highest positive predictive value for type 1 diabetes. In the absence of reliable T-cell tests, dissection of autoantibody responses in subjects of genetic risk should prove useful in identifying triggers of islet autoimmunity by examining seroconversion and maturation of the autoantibody response that may mark time to onset of type 1 diabetes. The complexity of the disease process is exemplified by multiple clinical phenotypes, including autoimmune diabetes masquerading as type 2 diabetes in youth and adults. Autoantibodies may also provide prognostic information in clinically heterogeneous patient populations when examined longitudinally. DAA, diabetes autoantibody DAISY, Diabetes Autoimmunity Study in the Young DASP, Diabetes Autoantibody Standardization Program DPT-1, Diabetes Prevention Trial GAD65Ab, GAD65 autoantibody IA-2, insulinoma-antigen 2 IA-2Ab, IA-2 autoantibody IAA, insulin autoantibody ICA, islet cell antibody LADA, latent autoimmune diabetes in the adult Footnotes This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier. Accepted May 4, 2005. Received March 4, 2005. DIABETES

Background Incidence is one of the most important epidemiologic indices in surveillance. However, determining incidence is complex and requires time-consuming cohort studies or registries with date of diagnosis. Estimating incidence from prevalence using mathematical relationships may facilitate surveillance efforts. The aim of this study was to examine whether a partial differential equation (PDE) can be used to estimate diabetes incidence from prevalence in youth. Methods We used age-, sex-, and race/ethnicity-specific estimates of prevalence in 2001 and 2009 as reported in the SEARCH for Diabetes in Youth study. Using these data, a PDE was applied to estimate the average incidence rates of type 1 and type 2 diabetes for the period between 2001 and 2009. Estimates were compared to annual incidence rates observed in SEARCH. Precision of the estimates was evaluated using 95% bootstrap confidence intervals. Results Despite the long period between prevalence measures, the estimated average incidence rates mirror the average of the observed annual incidence rates. Absolute values of the age-standardized sex- and type-specific mean relative errors are below 8%. Conclusions Incidence of diabetes can be accurately estimated from prevalence. Since only cross-sectional prevalence data is required, employing this methodology in future studies may result in considerable cost savings.

Background Disease surveillance of diabetes among youth has relied mainly upon manual chart review. However, increasingly available structured electronic health record (EHR) data have been shown to yield accurate determinations of diabetes status and type. Validated algorithms to determine date of diabetes diagnosis are lacking. The objective of this work is to validate two EHR-based algorithms to determine date of diagnosis of diabetes. Methods A rule-based ICD-10 algorithm identified youth with diabetes from structured EHR data over the period of 2009 through 2017 within three children’s hospitals that participate in the SEARCH for Diabetes in Youth Study: Cincinnati Children’s Hospital, Cincinnati, OH, Seattle Children’s Hospital, Seattle, WA, and Children’s Hospital Colorado, Denver, CO. Previous research and a multidisciplinary team informed the creation of two algorithms based upon structured EHR data to determine date of diagnosis among diabetes cases. An ICD-code algorithm was defined by the year of occurrence of a second ICD-9 or ICD-10 diabetes code. A multiple-criteria algorithm consisted of the year of first occurrence of any of the following: diabetes-related ICD code, elevated glucose, elevated HbA1c, or diabetes medication. We assessed algorithm performance by percent agreement with a gold standard date of diagnosis determined by chart review. Results Among 3777 cases, both algorithms demonstrated high agreement with true diagnosis year and differed in classification ( p  = 0.006): 86.5% agreement for the ICD code algorithm and 85.9% agreement for the multiple-criteria algorithm. Agreement was high for both type 1 and type 2 cases for the ICD code algorithm. Performance improved over time. Conclusions Year of occurrence of the second ICD diabetes-related code in the EHR yields an accurate diagnosis date within these pediatric hospital systems. This may lead to increased efficiency and sustainability of surveillance methods for incidence of diabetes among youth.

BackgroundFood insecurity (FI) is linked to mental health outcomes cross-sectionally, but little is known about temporal patterns of FI and changes in mental health. FI can exacerbate the mental health challenges of managing diabetes, creating a vicious cycle that worsens youth and young adults’ (YYAs) mental well-being.PurposeWe investigated the association of temporal patterns of FI with symptoms of depression, anxiety, and stress, and changes therein in YYAs with youth-onset type 1 (T1D) and type 2 diabetes (T2D).MethodsLongitudinal data (2016–2022) including three time points (t1, t2, and t3) from 747 YYAs with T1D and 97 YYAs with T2D were analyzed using multivariable linear regression. Ascertained with the Household Food Security Survey Module, food security was classified as persistently food secure, persistently food insecure (PFI), and intermittently food insecure (IFI). Mental health at t3 and changes from t2 to t3 were characterized with the Center for Epidemiologic Studies Depression Scale, the Generalized Anxiety Disorder Scale, and Cohen’s Perceived Stress Scale.FindingsAmong YYAs with T1D and T2D, 6.6% and 16.5% were PFI, 20.3% and 42.3% were IFI, respectively. In YYA with T1D, PFI and IFI were associated with greater depressive, anxiety, and stress symptoms at t3, and with increased symptoms over time. In YYA with T2D, PFI was associated with greater depressive symptoms at t3 but not with changes over time.InterpretationThe study identified a previously unrecognized link between prolonged exposure to FI and increased incidence of mental health issues. Both persistent and intermittent FI were associated with adverse mental health symptoms in YYA with diabetes, more so for those with PFI. Subsequent research should prioritize interventions that address FI in this population to evaluate their effectiveness in enhancing both physical and psychological well-being. It should be designed to not only address FI, but also comprehensive support, including mental health services and education.

OBJECTIVE: To determine the extent of β-cell function in youth with diabetes and GAD65 and/or IA2 autoantibodies. RESEARCH DESIGN AND METHODS: Fasting C-peptide levels from 2,789 GAD65- and/or IA2 autoantibody-positive youth aged 1-23 years from the SEARCH for Diabetes in Youth study were used. Preserved β-cell function was defined on the basis of cut points derived from the Diabetes Control and Complications Trial (DCCT) (fasting C-peptide greater-than-or-equal0.23 ng/ml) and from the U.S. adolescent population of the National Health and Nutrition Examination Survey (NHANES) 5th percentile for fasting C-peptide (greater-than-or-equal1.0 ng/ml). We compared the clinical characteristics between those with and without preserved β-cell function. RESULTS: Within the first year of diagnosis, 82.9% of youth had a fasting C-peptide greater-than-or-equal0.23 ng/ml and 31.2% had values greater-than-or-equal1.0 ng/ml. Among those with greater-than-or-equal5 years of diabetes duration, 10.7% had preserved β-cell function based on the DCCT cutoff and 1.0% were above the 5th percentile of the NHANES population. CONCLUSIONS: Within the 1st year of diagnosis, four of five youth with autoantibody-positive diabetes have clinically significant amounts of residual β-cell function and about one-third have fasting C-peptide levels above the 5th percentile of a healthy adolescent population. Even 5 years after diagnosis, 1 of 10 has fasting C-peptide above a clinically significant threshold. These findings have implications for clinical classification of youth with diabetes as well as clinical trials aimed to preserve β-cell function after diabetes onset.

Objective. Hyperglycemia early in the course of type 1 diabetes (T1D) may increase the risk of cardiometabolic complications later in life. We tested the hypothesis that there were temporal trends in population-level glycemia and insulin pump use near T1D diagnosis among incident youth cohorts diagnosed between 2002 and 2016. Methods. Weighted and adjusted regression models were applied to data from the SEARCH for Diabetes in Youth study to analyze trends in hemoglobin A1c (HbA1c), suboptimal glycemia (HbA1c>9% or not), and insulin pump use among youth with T1D within 30 months of diagnosis. We tested the interaction of year with race and ethnicity, sex, and insulin regimen to assess potential disparities. Results. Among the 3,956 youth with T1D, there was a small, clinically insignificant reduction in HbA1c between 2002 (7.9%±1.5) and 2016 (7.8%±2.4) (fully adjusted change by year (-0.013% [95% CI -0.026, -0.0008], p=0.04). The proportion of youth with suboptimal glycemia increased with each year, but the adjusted odds did not change. Insulin pump use increased more than fivefold. Although interaction effects of time with race and ethnicity, sex, and insulin regimen were not detected, in 2016, suboptimal glycemia was 4.3 and 1.8 times more prevalent among Black and Hispanic than among non-Hispanic White youth, respectively. Conclusions. There was not a clinically significant population-level improvement in glycemia across incident youth cohorts early in the course of T1D, despite severalfold increases in insulin pump use. Comprehensive clinical interventions to improve glycemia early in the T1D course and address disparities are urgently needed.

Aims. To explore how changes in insulin regimen are associated with estimated adiposity over time among youths and young adults with type 1 diabetes and whether any associations differ according to sex. Materials and Methods. Longitudinal data were analyzed from youths and young adults with type 1 diabetes in the SEARCH for Diabetes in Youth study. Participants were classified according to insulin regimen categorized as exclusive pump (“pump only”), exclusive injections (“injections only”), injection-pump transition (“injections-pump”), or pump-injection transition (“pump-injections”) for each follow-up visit completed. Estimated body fat percentage (eBFP) was calculated using validated equations. Sex-specific, linear mixed effects models examined the relationship between the insulin regimen group and change in eBFP during follow-up, adjusted for baseline eBFP, baseline insulin regimen, time-varying insulin dose, sociodemographic factors, and baseline HbA1c (≥9.0% vs. <9.0%). Results. The final sample included 284 females and 304 males, of whom 80% were non-Hispanic white with mean diagnosis age of 12.7±2.4 years. In fully adjusted models for females, exclusive pump use over the study duration was associated with significantly greater increases in eBFP compared to exclusive use of injections (difference in rate of change=0.023% increase per month, 95%CI=0.01, 0.04). Injection-to-pump transitions and pump-to-injection transitions were also associated with greater increases in eBFP compared to exclusive use of injections (difference in rate of change=0.02%, 95%CI=0.004, 0.03, and 0.02%; 95%CI=0.0001, 0.04, respectively). There was no relationship between the insulin regimen and eBFP among males. Conclusions. Among females with type 1 diabetes, exclusive and partial pump use may have the unintended consequence of increasing adiposity over time compared to exclusive use of injections, independent of insulin dose.

Identification of Novel HLA-A*0201–Restricted Epitopes in Recent-Onset Type 1 Diabetic Subjects and Antibody-Positive Relatives Nathan E. Standifer 1 , Qin Ouyang 2 , Constadina Panagiotopoulos 3 , C. Bruce Verchere 2 , Rusung Tan 2 , Carla J. Greenbaum 1 , Catherine Pihoker 4 and Gerald T. Nepom 1 1 Benaroya Research Institute at Virginia Mason, Seattle, Washington 2 Department of Pathology and Laboratory Medicine, British Columbia Children’s Hospital, Child and Family Research Institute, and University of British Columbia, Vancouver, British Columbia, Canada 3 Department of Pediatrics, British Columbia Children’s Hospital, Child and Family Research Institute, and University of British Columbia, Vancouver, British Columbia, Canada 4 Department of Pediatrics, University of Washington, Seattle, Washington Address correspondence and reprint requests to Nathan E. Standifer, Benaroya Research Institute at Virginia Mason, 1201 Ninth Ave., Room 260, Seattle WA, 98101. E-mail: nstand{at}benaroyaresearch.org Abstract Cytotoxic T-lymphocytes (CTLs) are considered to be essential for β-cell destruction in type 1 diabetes. However, few islet-associated peptides have been demonstrated to activate autoreactive CTLs from type 1 diabetic subjects. In an effort to identify novel epitopes, we used matrix-assisted algorithms to predict peptides of glial fibrillary acidic protein (GFAP), prepro-islet amyloid polypeptide (ppIAPP), and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) that likely bind to HLA-A*0201 with a strong affinity and contain a COOH-terminal proteasomal cleavage site. Seven peptides stabilized HLA-A*0201 expression in binding assays and were used to stimulate peripheral blood mononuclear cells and were evaluated for granzyme B secretion. We found that 5 of 13 type 1 diabetic subjects and 4 of 6 antibody-positive relatives exhibited greater numbers of granzyme B–secreting cells in response to at least one putative epitope compared with healthy control subjects. The most prevalent responses in antibody-positive and type 1 diabetic subjects were to ppIAPP(9-17). Other peptides recognized by type 1 diabetic or antibody-positive subjects included GFAP(143-151), IGRP(152-160), and GFAP(214-222). These data implicate peptides of ppIAPP, GFAP, and IGRP as CTL epitopes for a heterogenous CD8 + T-cell response in type 1 subjects and antibody-positive relatives. Ab, antibody BIMAS, BioInformatics and Molecular Analysis Section CTL, cytotoxic T-lymphocyte ELISpot, enzyme-linked immunospot GFAP, glial fibrillary acidic protein IA-2, insulinoma-associated antigen 2 IGRP, islet-specific glucose-6-phosphatase catalytic subunit–related protein ppIAPP, prepro-islet amyloid polypeptide PBMC, peripheral blood mononuclear cell Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted July 25, 2006. Received January 13, 2006. DIABETES