Maria Jose Redondo

Aims/Hypothesis: Atypical forms of diabetes often provide diagnostic challenges and are suboptimally treated. We sought to determine whether type 1 and 2 diabetes polygenic scores (PS) would help improve classification of islet autoantibody-negative (IAb-) atypical diabetes cases. Methods: We implemented type 1 diabetes PS (T1D PS) and type 2 diabetes PS (T2D PS) in 309 IAb-individuals’ genome sequencing from the Rare and Atypical Diabetes Network (RADIANT), the largest and most comprehensively phenotyped collection of unsolved and atypical diabetes cases. We performed regression analyses to assess associations between PS, clinical characteristics, and glycemic measures. Results: Both T1D and T2D PS were significantly higher in RADIANT than in ancestry-matched controls from UK Biobank. Both PS were associated with C-peptide measures throughout participant oral glucose tolerance tests (OGTT), although in opposite directions; T1D PS was associated with lower C-peptide measures, while T2D PS was associated with higher measures. Participants with T1D PS above a previously established optimal PS value for differentiating cases and controls (T1D PS GRS2>12.88) had 13-fold higher odds of both insulin deficiency on OGTT and use of both basal and bolus insulin therapy. Conclusions/Interpretation: Individuals in RADIANT with ambiguous diabetes subtypes displayed genetic enrichment for both type 1 and type 2 diabetes, despite ascertainment to remove standard type 1 and type 2 diabetes. T1D PS identified individuals with an unrecognized “type 1 diabetes- like ” phenotype with insulin deficiency and need for intensive insulin in the absence of islet autoantibodies. PS may help identify individuals with atypical diabetes who will ultimately benefit from insulin therapy.

OBJECTIVE: Insulin dose–adjusted hemoglobin A1c (IDAA1c = HbA1c [%] + [4 × total daily dose in units/kg/day]) ≤9 is widely used to define partial remission in pediatric type 1 diabetes and as an eligibility criterion or outcome in disease-modifying therapy trials. However, it has not been validated in U.S. youth. Because higher BMI increases insulin resistance and insulin requirements, we hypothesized that IDAA1c would perform suboptimally in participants with overweight or obesity. RESEARCH DESIGN AND METHODS: We analyzed data from 422 SEARCH for Diabetes in Youth study participants with mixed-meal tolerance test (MMTT)-stimulated C-peptide within 12 months of diagnosis. Partial remission was defined using MMTT-stimulated area under the curve (AUC) mean C-peptide. Participant characteristics were compared by BMI category (<85th percentile [normal or underweight] and ≥85th percentile [overweight or obese]) using Wilcoxon rank sum and Fisher exact tests. Sensitivity, specificity, and receiver operating characteristic (ROC) AUC of IDAA1c ≤9 for identifying partial remission were evaluated. RESULTS: Participants with normal or underweight versus participants with overweight or obesity had lower IDAA1c (8.95 vs. 9.28, P = 0.043) despite lower stimulated C-peptide (1.25 vs. 1.88 ng/mL, P < 0.001). Overall, IDAA1c ≤9 had 61% sensitivity and 79% specificity for predicting C-peptide ≥0.91 ng/mL with an ROC AUC of 0.77. Among participants with overweight or obesity, sensitivity was 45% and specificity 81%. A Youden index–derived cutoff of IDAA1c ≤11.6 improved sensitivity to 93%, with specificity of 54% in participants with overweight or obesity. CONCLUSIONS: IDAA1c ≤9 demonstrated suboptimal accuracy as a screening test for partial remission, especially underestimating β-cell function in youth with overweight or obesity. BMI-specific cutoffs improved sensitivity but reduced specificity.

OBJECTIVE: Elevated BMI is associated with increased risk of progression to stage 3 type 1 diabetes (T1D). We tested whether normalization of BMI is associated with lower stage 3 risk among autoantibody-positive individuals with overweight or obesity. RESEARCH DESIGN AND METHODS: We studied 833 autoantibody-positive participants in the TrialNet Pathway to Prevention study with overweight or obesity at baseline. Cumulative incidence of stage 3 T1D was evaluated using Cox proportional hazards models. Reported P values were adjusted for baseline age, BMI z score, and T1D stage, unless otherwise noted. RESULTS: During follow-up, BMI normalized in 26.8% of participants and was associated with a lower risk of progression to stage 3 T1D (hazard ratio 0.516, P < 0.001) over a median follow-up time of 4.1 years. This association was primarily observed in youth (n = 421, hazard ratio 0.497, P = 0.001), including boys <12 years old (n = 140, P < 0.001) and girls ≥12 years old (n = 73, P = 0.043), but not in adults (n = 412, P = 0.130). BMI normalization was also associated with a lower risk of transition from stage 1 to stage 2 and from stage 2 to stage 3, but not clearly from stage 0 to stage 1 (P = 0.010, P = 0.003, and P = 0.051, respectively, adjusted for baseline age and BMI z score). In exploratory models, adjustment for insulin sensitivity/resistance indices or oral disposition index weakened the association between BMI normalization and lower progression risk, whereas adjustment for insulin secretion, glycemia-adjusted C-peptide, or progression-risk indices generally strengthened it. CONCLUSIONS: Among autoantibody-positive individuals with overweight or obesity, BMI normalization was associated with a 48.4% lower risk of clinical T1D, primarily in youth.

Objectives: Overweight and obesity are highly prevalent in the general population but remain understudied in pediatric type 1 diabetes (T1D). We aimed to estimate the incidence and identify associated factors for developing elevated BMI in a contemporary, real-world cohort of racially diverse lean youth with new-onset T1D. Methods: We reviewed medical records from 1,394 youth who were lean (BMI 1c , p<0.001) and obesity (female, p=0.003). There were no statistically significant associations with age at T1D diagnosis, health insurance type, or positivity for thyroid or celiac antibodies. Conclusions: In sum, over 33 % of lean youth developed elevated BMI within a median of 2.4 years after T1D onset. Early identification of characteristics associated with incident overweight and obesity in youth with T1D may inform targeted weight-management interventions following diagnosis.

The regulatory approval and growing pipeline of disease-modifying therapies for presymptomatic type 1 diabetes have sparked an increase in screening for the presence of islet autoantibodies in individuals who may not have yet developed clinical symptoms of disease. The staging system that is currently employed to define type 1 diabetes diagnosis in presymptomatic and symptomatic phases is based on the presence of islet autoantibodies and glycemic status. Here, we make the case to consider using C-peptide values to provide context for glycemia. Inclusion of C-peptide could result in better prediction of progression to clinical disease and more specificity for features typically associated with type 1 diabetes (and, thus, be less susceptible to confounding influences on glycemia like age and insulin resistance). It also could more rapidly identify responses to disease-modifying therapies. The implementation and translation of these findings will be key to long-term success in type 1 diabetes prediction and disease modification strategies.

We report a 9-year-old female who presented with mild, persistent hyperglycemia, with hemoglobin A1c and oral glucose tolerance test results in the prediabetes range, relatively preserved C-peptide, and mildly positive glutamate decarboxylase 65 autoantibody levels. A strong family history of lean, noninsulin-dependent diabetes suggested a possible monogenic cause. Genetic testing with a 28-gene maturity-onset diabetes of the young (MODY) panel identified a heterozygous variant of uncertain significance in GCK (NM_000162.5:c.179C>T [p.Thr60Ile]). Following review by the ClinGen Monogenic Diabetes Variant Curation Expert Panel, the GCK variant was reclassified as pathogenic, confirming a diagnosis of glucokinase (GCK)-MODY/GCK-hyperglycemia, a stable form of mild hyperglycemia that does not require pharmacologic treatment. Subsequent genetic testing of the father confirmed paternal inheritance. Due to the presence of a positive islet autoantibody, she was counseled on the potential for autoimmune diabetes and advised to continue periodic monitoring. This case illustrates the diagnostic complexity of differentiating monogenic hyperglycemia from autoimmune diabetes in children.

Background: Hispanic youth are disproportionately impacted by obesity and subsequent type 2 diabetes (T2D) yet remain underrepresented in diabetes prevention research. Digital health interventions hold promise for increasing the accessibility to and engagement in disease prevention programming, particularly among high-risk populations. However, there is a significant gap in the literature regarding digital T2D prevention programs for adolescents or Hispanic youth. Objective: The objective of this article is to describe the protocol for examining the feasibility of a 12-week digital diabetes prevention program among Hispanic adolescents with obesity. Methods: Participants (N=40; aged 12-16 years) will be randomized (1:1) to a 12-week intervention group or a control group. Youth in the intervention group will receive access to an e-learning platform with 12 nutrition and wellness video content sessions, a Fitbit Charge 5, and daily SMS text messages grounded in the self-determination theory to promote physical activity. Youth in the standard control group will receive information on diet and physical activity guidelines and guidance on setting behavior change goals. The study findings will focus on the evaluation of feasibility criteria: (1) recruitment of 40 Hispanic adolescents aged 12 to 16 years; (2) retention of 80% of the participants for postassessments; (3) integrity of the study protocol, defined as 70% or higher completion of content sessions and Fitbit wear on 5 days per week or more with response to 80% of SMS text messages when prompted; (4) 10% or lower incidence of technical issues; and (5) 80% or higher satisfaction among participants. Results: This study was funded in August 2022 and intervention implementation is ongoing. To date, 35 participants have been enrolled. Study findings will be available before December 2026 and will focus on an evaluation of the a priori feasibility criteria on participant recruitment, data collection, integrity of the study protocol, technical issues, and satisfaction. Study findings will also focus on secondary outcomes. Conclusions: The feasibility and process evaluation data obtained from this study will provide novel insights on the use of digital T2D prevention strategies among Hispanic youth and families and will inform the development of future digital health interventions among high-risk pediatric populations.

Type 1 diabetes arises from the interplay of genetic susceptibility and environmental exposures, leading to autoimmune β-cell destruction. Although disease-modifying therapies (DMTs) can delay progression to clinical (stage 3) type 1 diabetes, treatment responses remain inconsistent and transient. The marked heterogeneity of type 1 diabetes, shaped by age, sex, race/ethnicity, and genetic background, underscores the need to elucidate distinct mechanistic pathways. Among environmental contributors, obesity stands out as a compelling modifiable target. Data from The Environmental Determinants of Diabetes in the Young (TEDDY), Type 1 Diabetes TrialNet, and other longitudinal cohorts link BMI and adiposity to the onset of islet autoimmunity, progression through preclinical stages, and development of stage 3 type 1 diabetes. These associations are not uniform; heightened susceptibility to adiposity-related risk is seen among younger children, Hispanic populations, and individuals with specific HLA genotypes. Despite robust epidemiologic evidence, the biological pathways connecting elevated BMI to autoimmune β-cell destruction remain incompletely defined. Emerging data implicate a network of immunologic and metabolic disturbances, including insulin resistance, β-cell stress, chronic adipose tissue inflammation, altered adipokine signaling, and gut microbiome changes, that collectively heighten β-cell vulnerability, amplify autoreactive immune responses, and drive metabolic decompensation toward clinical disease. Elucidating these mechanisms and identifying related biomarkers are critical to advancing precision prevention. In future studies, investigators should evaluate whether modifying elevated BMI or targeting obesity-associated immunologic and metabolic pathways can alter the preclinical trajectory of type 1 diabetes. Such mechanistic understanding may help curb type 1 diabetes incidence and improve outcomes for populations most vulnerable to obesity-related risk.

Context: Maternal (vs paternal) type 1 diabetes is associated with a relative reduction in type 1 diabetes risk in offspring during early life. Objective: To determine whether this effect extends into later life. To clarify the importance of intrauterine exposure to maternal type 1 diabetes, and baseline genetic susceptibility in this context. Methods: We compared the proportion of individuals with type 1 diabetes diagnosed aged 0 to 88 years of age with affected mothers and fathers across 5 observational studies (n = 11 475), and used random-effects meta-analyses to generate overall effect estimates. We examined this by age at diagnosis, and timing of parental diagnosis relative to offspring birth. We compared the type 1 diabetes genetic risk score (T1D-GRS2) of individuals with affected mothers and fathers. Results: Almost half as many individuals with type 1 diabetes had an affected mother vs father (odds ratio [OR], 0.55; 95% CI, 0.48-0.64; P < .0001). A lower proportion of individuals with affected mothers than fathers was apparent even among individuals diagnosed as adults (>18 years) (OR, 0.63; 95% CI, 0.43-0.91; P = .01). The lower proportion of individuals with maternal vs paternal type 1 diabetes was only observed if maternal diagnosis preceded offspring birth (OR, 0.51; 95% CI, 0.37-0.70; P < .001 vs OR 0.97; 95% CI, 0.69-1.38; P = .87 after birth). T1D-GRS2 was similar between individuals with affected mothers and fathers (P = .25). Conclusion: Our analyses suggest intrauterine exposure to maternal type 1 diabetes is associated with long-lasting relative protection against offspring type 1 diabetes, which is independent of genetic susceptibility as measured by T1D-GRS2.