Maria J Redondo

Background. Elevated serum IgA levels have been observed in various autoimmune conditions, including type 1 diabetes (T1D). However, whether children with T1D and elevated serum IgA have unique features has not been studied. We aimed to evaluate the prevalence and characteristics associated with elevated serum IgA at the onset of pediatric T1D. Materials and Methods. We analyzed demographic, clinical, and laboratory data retrospectively collected from 631 racially diverse children (6 months–18 years of age) with T1D who had serum IgA levels measured within 90 days of T1D diagnosis. Univariable and multivariable logistic regression models were used to identify characteristics that were significantly associated with elevated versus normal IgA. Results. Elevated serum IgA was present in 20.3% (128/631) of the children with newly diagnosed T1D. After adjusting for other variables, A1c level (), positive insulin autoantibodies (IAA) (), negative glutamic acid decarboxylase autoantibodies (GADA) () and Hispanic ethnicity () were significantly associated with elevated serum IgA. After adjustment for confounders, the odds of elevated serum IgA were significantly increased with positive IAA (OR 1.653, 95% CI 1.019–2.679), higher HbA1c (OR 1.132, 95% CI 1.014–1.268) and Hispanic ethnicity (OR 3.279, 95% CI 2.003–5.359) but decreased with GADA positivity (OR 0.474, 95% CI 0.281–0.805). Conclusions. Elevated serum IgA is present in 20.3% of the children at T1D onset and is associated with specific demographic and clinical characteristics, suggesting a unique pathogenesis in a subset of individuals. Further studies are warranted …

Aims Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)‐supported multicenter, prospective, observational study that enrols children and adolescents with non‐secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. Materials and Methods The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non‐fasting serum C‐peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it …

Classifying diabetes at diagnosis is crucial for disease management but increasingly difficult due to overlaps in characteristics between the commonly encountered diabetes types. We evaluated the prevalence and characteristics of youth with diabetes type that was unknown at diagnosis or was revised over time. We studied 2073 youth with new-onset diabetes (median age [IQR] = 11.4 [6.2] years; 50% male; 75% White, 21% Black, 4% other race; overall, 37% Hispanic) and compared youth with unknown versus known diabetes type, per pediatric endocrinologist diagnosis. In a longitudinal subcohort of patients with data for ≥ 3 years post-diabetes diagnosis (n = 1019), we compared youth with steady versus reclassified diabetes type. In the entire cohort, after adjustment for confounders, diabetes type was unknown in 62 youth (3%), associated with older age, negative IA–2 autoantibody, lower C-peptide, and no …

Context Metabolic measures are frequently used to predict T1D and to understand effects of disease-modifying therapies. Objective Compare metabolic endpoints for their ability to detect preventive treatment effects and predict T1D. Design Six-month changes in metabolic endpoints were assessed for: 1) detecting treatment effects by comparing placebo and treatment arms from the randomized controlled teplizumab prevention trial and 2) predicting T1D in the TrialNet Pathway to Prevention natural history study. Setting Multicenter clinical trial network Intervention 14-day intravenous teplizumab infusion Main Outcome Measures T-values from t tests for detecting a treatment effect were compared to Chi-square values from proportional hazards regression for predicting T1D for each metabolic …

OBJECTIVE Mixed-meal tolerance test–stimulated area under the curve (AUC) C-peptide at 12–24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy. RESEARCH DESIGN AND METHODS We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial. RESULTS Among trials meeting their primary end point, we …

OBJECTIVE With high prevalence of obesity and overlapping features between diabetes subtypes, accurately classifying youth-onset diabetes can be challenging. We aimed to develop prediction models that, using characteristics available at diabetes diagnosis, can identify youth who will retain endogenous insulin secretion at levels consistent with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS We studied 2,966 youth with diabetes in the prospective SEARCH for Diabetes in Youth study (diagnosis age ≤19 years) to develop prediction models to identify participants with fasting C-peptide ≥250 pmol/L (≥0.75 ng/mL) after >3 years’ (median 74 months) diabetes duration. Models included clinical measures at the baseline visit, at a mean diabetes duration of 11 months (age, BMI, sex, waist circumference, HDL cholesterol), with and without islet autoantibodies (GADA …

BackgroundIslet autoantibodies form the foundation for type 1 diabetes (T1D) diagnosis and staging, but heterogeneity exists in T1D development and presentation. We hypothesized that autoantibodies can identify heterogeneity before, at, and after T1D diagnosis, and in response to disease-modifying therapies.MethodsWe systematically reviewed PubMed and EMBASE databases (6/14/2022) assessing 10 years of original research examining relationships between autoantibodies and heterogeneity before, at, after diagnosis, and in response to disease-modifying therapies in individuals at-risk or within 1 year of T1D diagnosis. A critical appraisal checklist tool for cohort studies was modified and used for risk of bias assessment.ResultsHere we show that 152 studies that met extraction criteria most commonly characterized heterogeneity before diagnosis (91/152). Autoantibody type/target was most frequently …

3. BackgroundType 1 diabetes (T1D) is a multifactorial disease, representing the end result of a combination of genetic susceptibility and environmental exposures. The risk of T1D is significantly greater amongst first-degree relatives of individuals with T1D (8-15 times higher than in the background population) 1, 2 3, 4. However, studies have consistently shown the risk to be higher (around twice as high) if the affected relative is the father rather than the mother5-13. Comparison with data from siblings has demonstrated this to be due to a relatively lower than expected risk of T1D amongst the offspring of affected mothers. Though maternal protection is only relative, as the risk remains higher than in the background population, it remains clinically significant.Published studies describing the risk of T1D in the offspring of mothers compared with fathers, have focused specifically on the risk of T1D developing during the childhood and early adult life of offspring (maximum follow up to age 30 years6-13.) It is therefore not known whether maternal T1D offers short-term relative protection against T1D in offspring, effectively delaying disease development as compared with paternal T1D. Alternatively, maternal protection could result in long-term or even lifelong relative protection against T1D as compared with paternal disease.

We are grateful to Tetsuro Kob-ayashi and Takashi Kadowaki for their correspondence on our Review (Redondo, MJ, Morgan, NG Heterogeneity and endotype of type 1 diabetes mellitus. Nat. Rev. Endocrinol. 19, 542–554 (2023)) 1, their insights into the immunopathology of slowly progressive type 1 diabetes mellitus (SPIDDM)(Kobayashi, T. & Kadowaki, T. Slowly progressive insulindependent diabetes mellitus in type 1 diabetes endotype 2. Nat. Rev. Endocrinol. https://doi. org/10.1038/s41574-024-00975-z (2024) 2) and their suggestion that the features of this disease might assist in defining more fully an endotype we refer to as T1DE2 (ref. 1), in accord with our 2020 study 3.We agree with Kobayashi and Kadowaki that obesity and other diabetogenic mechanisms characteristic of type 2 diabetes mellitus (T2DM) are not necessarily present in slowly progressive forms of diabetes mellitus, in which development of …

Background. A−β+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved β-cell function in persons with a phenotype of obesity-associated type 2 diabetes (T2D). The prevalence of KPD has not been evaluated in children. We investigated children with DKA at “T2D” onset and determined the prevalence and characteristics of pediatric A−β+ KPD within this cohort. Methods. We reviewed the records of 716 children with T2D at a large academic hospital and compared clinical characteristics of those with and without DKA at onset. In the latter group, we identified patients with A−β+ KPD using criteria of the Rare and Atypical Diabetes Network (RADIANT) and defined its prevalence and characteristics. Results. Mean age at diagnosis was 13.7 ± 2.4 years: 63% female; 59% Hispanic, 29% African American, 9% non-Hispanic White, and 3% other. Fifty-six (7.8%) presented with DKA at diagnosis and lacked islet autoantibodies. Children presenting with DKA were older and had lower C-peptide and higher glucose concentrations than those without DKA. Twenty-five children with DKA (45%) met RADIANT A−β+ KPD criteria. They were predominantly male (64%), African American or Hispanic (96%), with substantial C-peptide (1.3 ± 0.7 ng/mL) at presentation with DKA and excellent long-term glycemic control (HbA1c 6.6% ± 1.9% at follow-up (median 1.3 years postdiagnosis)). Conclusions. In children with a clinical phenotype of T2D and DKA at diagnosis, approximately half meet criteria for A−β+ KPD. They manifest the key characteristics of obesity …

Type 1 diabetes (T1D) can develop at different stages in life, from infancy (1) to older adulthood (2). Younger children are more prone to diabetic ketoacidosis (DKA)(3) and a shorter partial remission period (“honeymoon”)(4) compared with older individuals presenting with T1D. These clinical indicators of poor b-cell function correlate with lower serum C-peptide levels in young children with new-onset T1D (5) and are consistent with the histopathological observation of more profound loss of b-cells in the pancreas in children with T1D under 7 years of age (6). In addition, there is an inverse correlation between age of onset and the burden of T1D-associated genes (7). Longitudinal studies with autoantibodypositive pediatric and adult participants initially without diabetes have demonstrated that the risk of progression from single to multiple islet autoantibody positivity and then to clinical T1D is higher in younger …

TAYLOR M. TRIOLO, HEMANG M. PARIKH, MUSTAFA TOSUR, LAURIC A. FERRAT, LU YOU, PETER GOTTLIEB, RICHARD A. ORAM, SUNA ONENGUT-GUMUSCU, JEFFREY KRISCHER, STEPHEN S. RICH, ANDREA STECK, MARIA J. REDONDO; 216-LB: Genetic Influences on Beta-Cell Function before Type 1 Diabetes Diagnosis. Diabetes 20 June 2023; 72 (Supplement_1): 216–LB. https://doi. org/10.2337/db23-216-LB

ObjectivesDiabetes can lead to loss of protective sensation (LOPS) in the feet. Identifying LOPS requires use of screening tests, such as the standard monofilament test (SMT) and the Ipswich Touch Test (IpTT). The aim of this validation study was to compare the SMT (criterion) with the IpTT (new test).MethodsEach participant was randomly tested using the SMT, IpTT and Neuropathy Disability Score to identify LOPS. Sixteen health-care providers assessed 8 participants in randomized order using a specific protocol.ResultsThe IpTT, compared with the SMT, demonstrated a specificity of 100% for all raters and a mean sensitivity of 93.8% for LOPS. Kappa coefficient was 0.97 for SMT and 0.83 for IpTT.ConclusionsThe IpTT can be used by health-care providers as an effective tool for screening for LOPS in people with diabetes. This study validated the IpTT to the SMT in identifying LOPS.

BackgroundType 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Efforts to prevent T1D have focused on modulating immune responses and supporting beta cell health; however, heterogeneity in disease progression and responses to therapies have made these efforts difficult to translate to clinical practice, highlighting the need for precision medicine approaches to T1D prevention.MethodsTo understand the current state of knowledge regarding precision approaches to T1D prevention, we performed a systematic review of randomized-controlled trials from the past 25 years testing disease-modifying therapies in T1D and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.ResultsWe identified 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 describing treatments aimed at preventing beta cell loss in individuals at disease onset. Seventeen agents tested, mostly immunotherapies, showed benefit compared to placebo (only two prior to T1D onset). Fifty-seven studies employed precision analyses to assess features linked to treatment response. Age, measures of beta cell function and immune phenotypes were most frequently tested. However, analyses were typically not prespecified, with inconsistent methods reporting, and tended to report positive findings.ConclusionsWhile the quality of prevention and intervention trials was overall high, low quality of precision analyses made it difficult to draw meaningful conclusions that inform clinical practice. Thus, prespecified precision analyses should be …

The current staging system for T1D development is used for participant selection in prevention trials. This system is based on multiple Ab+ and the presence or absence of dysglycemia, but does not address C-peptide measures or single Ab+ individuals. Since a limited number of Ab+ individuals are available for trials, we used TrialNet Pathway to Prevention (TNPTP) study data to assess whether a composite glucose and C-peptide measure, Index60, could identify single Ab+ individuals (designated as Stage 0) with comparable risk to those in Stages 1 or 2 for progression to Stage 3. Table 1A compares normoglycemic Stage 0 individuals with Index60 values above the median (>-0.045) of the full TNPTP cohort (n= 6107) vs. those at Stage 1 with Index60 below the median (<-0.045). Table 1B compares those at Stage 0 with dysglycemia and higher Index60 vs. those at Stage 2 with lower Index60. In both …

Background. Pediatric Type 2 diabetes (T2D) is highly heterogeneous. Previous reports on adult-onset diabetes demonstrated the existence of diabetes clusters. Therefore, we set out to identify unique diabetes subgroups with distinct characteristics among youth with T2D using commonly available demographic, clinical, and biochemical data. Methods. We performed data-driven cluster analysis (K-prototypes clustering) to characterize diabetes subtypes in pediatrics using a dataset with 722 children and adolescents with autoantibody-negative T2D. The six variables included in our analysis were sex, race/ethnicity, age, BMI Z-score and hemoglobin A1c at the time of diagnosis, and non-HDL cholesterol within first year of diagnosis. Results. We identified five distinct clusters of pediatric T2D, with different features, treatment regimens and risk of diabetes complications: Cluster 1 was characterized by higher A1c; Cluster 2, by higher non-HDL; Cluster 3, by lower age at diagnosis and lower A1c; Cluster 4, by lower BMI and higher A1c; and Cluster 5, by lower A1c and higher age. Youth in Cluster 1 had the highest rate of diabetic ketoacidosis (DKA) () and were most prescribed metformin (). Those in Cluster 2 were most prone to polycystic ovarian syndrome (). Younger individuals with lowest family history of diabetes were least frequently diagnosed with diabetic ketoacidosis () and microalbuminuria (). Low-BMI individuals with higher A1c had the lowest prevalence of acanthosis nigricans () and hypertension (). Conclusions. Utilizing clinical measures gathered at the time of diabetes diagnosis can be used to identify subgroups of pediatric T2D with …

BackgroundType 1 diabetes (T1D) results from immune-mediated destruction of insulin-producing beta cells. Prevention efforts have focused on immune modulation and supporting beta cell health before or around diagnosis; however, heterogeneity in disease progression and therapy response has limited translation to clinical practice, highlighting the need for precision medicine approaches to T1D disease modification.MethodsTo understand the state of knowledge in this area, we performed a systematic review of randomized-controlled trials with 50 participants cataloged in PubMed or Embase from the past 25 years testing T1D disease-modifying therapies and/or identifying features linked to treatment response, analyzing bias using a Cochrane-risk-of-bias instrument.ResultsWe identify and summarize 75 manuscripts, 15 describing 11 prevention trials for individuals with increased risk for T1D, and 60 …

Type 1 diabetes is a complex disease that has both genetic and environmental determinants. Based on twin and family studies from largely European-ancestry populations, the estimated contribution of genetic factors to type 1 diabetes risk is~ 50%. Genes and their variants within the human major histocompatibility complex (MHC), the human leukocyte antigen (HLA) loci, including class I (HLA-A,-B, and-C) and class II (HLA-DR,-DQ, and-DP), account for~ 50% of the genetic risk of type 1 diabetes. In addition to the MHC region, type 1 diabetes risk loci were initially identified through candidate gene and linkage studies, including variants in or near the INS, CTLA4, IL2RA, and PTPN22 genes. Genome-wide association approaches have revealed additional loci containing common variants with relatively small individual effects on type 1 diabetes risk. International efforts led by the Type 1 Diabetes Genetics …

We asked if assessment of islet autoimmunity and β cell function in children at diabetes diagnosis is useful for prognosis, using the “Aβ” system,[“A” representing autoimmunity (A+=≥ 1 autoantibody; A-= no antibodies),“β” representing β cell function (β+= random serum C-peptide≥ 0.6 ng/mL; β-= C-peptide< 0.6 ng/mL)]. We followed β cell function longitudinally with 2h post-prandial urinary C-peptide-creatinine ratio (UCPCR) at 3-12 wk (V1) and 6-12 m (V2). We compared clinical characteristics, glycemia and β cell function at baseline and clinical outcomes at V2 between the groups. The cohort (n= 74) was 50% female, 76% White, 22% non-Hispanic Black, 2% Other, 47% Hispanic. Median age (25p-75p) was 12.6 (8.5-14.6) years, median BMI 70.7 (16.7-96.1)% ile. Phenotypic frequencies were A+ β-(36.5%), A-β+(29.7%), A+ β+(31.1%) and A-β-(2.7%). Baseline serum C-peptide correlated with UCPCR at V1 (r …

Classifying diabetes at diagnosis is crucial for disease management but increasingly difficult due to overlaps in characteristics between the commonly encountered diabetes types. We evaluated the prevalence and characteristics of youth with diabetes type that was unknown at diagnosis or was revised over time. We studied 2073 youth with new-onset diabetes (median age [IQR]= 11.4 [6.2] years; 50% male; 75% White, 21% Black, 4% other race; overall, 37% Hispanic) and compared youth with unknown versus known diabetes type, per pediatric endocrinologist diagnosis. In a longitudinal subcohort of patients with data for≥ 3 years post-diabetes diagnosis (n= 1019), we compared youth with unchanged versus changed diabetes classification. In the entire cohort, after adjustment for confounders, diabetes type was unknown in 62 youth (3%), associated with older age, negative IA-2 autoantibody, lower C-peptide …