High Prevalence of A-ß+ Ketosis-Prone Diabetes in Children with Type 2 Diabetes and Diabetic Ketoacidosis at Diagnosis: Evidence from the Rare and Atypical Diabetes Network (RADIANT).

Background: A-ß+ ketosis-prone diabetes (KPD) in adults is characterized by presentation with diabetic ketoacidosis (DKA), negative islet autoantibodies, and preserved ß-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-ß+ 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-ß+ 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-ß+ 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-ß+ KPD. They manifest the key characteristics of obesity, preserved ß-cell function, male predominance, and potential to discontinue insulin therapy, similar to adults with A-ß+ KPD.

Variants of Unknown Significance (VUS) in Maturity-Onset Diabetes of the Young (MODY): High Rate of Conundrum Resolution via VUS Reanalysis.

INTRODUCTION: In the era of next-generation sequencing, clinicians frequently encounter variants of unknown significance (VUS) in genetic testing. VUS may be reclassified overtime as genetic knowledge grows. We know little about how best to approach VUS in maturity-onset diabetes of the young (MODY). Therefore, our study aimed to determine the utility of reanalysis of previous VUS results in genetic confirmation of MODY. METHODS: A single center retrospective chart review identified 85 subjects with a MODY clinical diagnosis. We reanalyzed genetic testing in 10 subjects with 14 unique VUS on MODY genes that was performed > 3 years before the study. Demographic, clinical, and biochemical data was collected for those individuals. Results After reanalysis, 43% (6/14) of the gene variants were reclassified to a different category: 7% (1/14) "likely pathogenic" and 36% (5/14) "benign" or "likely benign". The reclassified pathogenic variant was in HNF1A and all reclassified benign variants were in HNF1A, HNF1B and PDX1. The median time between MODY testing and reclassification was 8 years (range: 4-10 years). CONCLUSION: In sum, iterative reanalyzing the genetic data from VUS found during MODY testing may provide high-yield diagnostic information. Further studies are warranted to identify the optimal time and frequency for such analyses.

Genetic Associations with C-peptide Levels before Type 1 Diabetes Diagnosis in At-Risk Relatives.

OBJECTIVE: We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) are associated with C-peptide preservation before type 1 diabetes diagnosis. METHODS: We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known SNPs and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis. RESULTS: Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (ß=-0.06, P<0.0001) and multivariate (ß=-0.03, P=0.005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (ß=-0.11, P=0.002) and multivariate (ß=-0.06, P=0.018) analyses. CONCLUSIONS: The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC prior to diagnosis of type 1 diabetes, with implications for the design of prevention trials.

Inaccurate diagnosis of diabetes type in youth: prevalence, characteristics, and implications.

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 diabetic ketoacidosis (all, p < 0.05). In the longitudinal subcohort, diabetes type was reclassified in 35 youth (3.4%); this was not statistically associated with any single characteristic. In sum, among racially/ethnically diverse youth with diabetes, 6.4% had inaccurate diabetes classification at diagnosis. Further research is warranted to improve accurate diagnosis of pediatric diabetes type.

Diabetes Study of Children of Diverse Ethnicity and Race: Study design.

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 reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3-10 years) for a cross-sectional evaluation or with recent onset diabetes (duration 3 weeks-15 months) for the longitudinal observation with annual visits for 3 years. Cross-sectional data will be used to develop models. Longitudinal data will be used to externally validate the best-fitting model. RESULTS: The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. CONCLUSIONS: Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease.

Utility and precision evidence of technology in the treatment of type 1 diabetes: a systematic review.

BACKGROUND: The greatest change in the treatment of people living with type 1 diabetes in the last decade has been the explosion of technology assisting in all aspects of diabetes therapy, from glucose monitoring to insulin delivery and decision making. As such, the aim of our systematic review was to assess the utility of these technologies as well as identify any precision medicine-directed findings to personalize care. METHODS: Screening of 835 peer-reviewed articles was followed by systematic review of 70 of them (focusing on randomized trials and extension studies with ≥50 participants from the past 10 years). RESULTS: We find that novel technologies, ranging from continuous glucose monitoring systems, insulin pumps and decision support tools to the most advanced hybrid closed loop systems, improve important measures like HbA1c, time in range, and glycemic variability, while reducing hypoglycemia risk. Several studies included person-reported outcomes, allowing assessment of the burden or benefit of the technology in the lives of those with type 1 diabetes, demonstrating positive results or, at a minimum, no increase in self-care burden compared with standard care. Important limitations of the trials to date are their small size, the scarcity of pre-planned or powered analyses in sub-populations such as children, racial/ethnic minorities, people with advanced complications, and variations in baseline glycemic levels. In addition, confounders including education with device initiation, concomitant behavioral modifications, and frequent contact with the healthcare team are rarely described in enough detail to assess their impact. CONCLUSIONS: Our review highlights the potential of technology in the treatment of people living with type 1 diabetes and provides suggestions for optimization of outcomes and areas of further study for precision medicine-directed technology use in type 1 diabetes.

In the last decade, there have been significant advances in how technology is used in the treatment of people living with type 1 diabetes. These technologies primarily aim to help manage blood sugar levels. Here, we reviewed research published over the last decade to evaluate the impact of such technologies on type 1 diabetes treatment. We find that various types of novel technologies, such as devices to monitor blood sugar levels continuously or deliver insulin, improve important diabetes-related measures and can reduce the risk of having low blood sugar levels. Importantly, several studies showed a positive impact of technologies on quality of life in people living with diabetes. Our findings highlight the benefits of novel technologies in the treatment of type 1 diabetes and identify areas for further research to optimize and personalize diabetes care.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Plasma amino acid signatures define types of pediatric diabetes.

BACKGROUND & AIMS: Metabolic biomarkers with pathophysiological relevance is lacking in pediatric diabetes. We aimed to identify novel metabolic biomarkers in pediatric type 1 (T1D) and type 2 diabetes (T2D). We hypothesized that (1) targeted plasma metabolomics, focused on plasma amino acid concentrations, could identify distinctively altered patterns in children with T1D or T2D, and (2) there are specific changes in concentrations of metabolites related to branch chain amino acids (BCAA) and arginine metabolism in children with T2D. METHODS: In a pilot study, we enrolled children with T1D (n = 15) and T2D (n = 13), and healthy controls (n = 15). Fasting plasma amino acid concentrations were measured by ultra-performance liquid chromatography, and compared between the groups after adjustment for confounding factors. RESULTS: The mean age (SD) of participants was 16.4 (0.9) years. There were no group differences in age, gender, race/ethnicity, or 24-h protein intake. Mean BMI percentile was higher in the T2D than the T1D group or controls (p < 0.001). The T2D group had lower arginine, citrulline, glutamine, glycine, phenylalanine, methionine, threonine, asparagine and symmetric dimethylarginine (SDMA) but higher aspartate than controls, after adjusting for BMI percentiles (all p < 0.05). Children with T2D also had lower glycine but higher ornithine, proline, leucine, isoleucine, valine, total BCAA, lysine and tyrosine than those with T1D after adjusting for confounding factors (all p < 0.05). Children with T1D had lower phenylalanine, methionine, threonine, glutamine, tyrosine, asymmetric dimethylarginine (ADMA) and SDMA than controls (all p < 0.05). CONCLUSIONS: Children with T2D and T1D have distinct fasting plasma amino acid signatures that suggest varying pathogenic mechanisms and could serve as biomarkers for these conditions.

Imprecise Diagnosis of Diabetes Type in Youth: Prevalence, Characteristics, and Implications.

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, and no diabetic ketoacidosis (all, p<0.05). In the longitudinal subcohort, diabetes classification changed in 35 youth (3.4%); this was not statistically associated with any single characteristic. Having unknown or revised diabetes type was associated with less continuous glucose monitor use on follow-up (both, p<0.004). In sum, among racially/ethnically diverse youth with diabetes, 6.5% had imprecise diabetes classification at diagnosis. Further research is warranted to improve accurate diagnosis of pediatric diabetes type.

Characteristics of Type 2 Diabetes in Female and Male Youth.

The incidence of type 2 diabetes in children is rising and carries a worse prognosis than in adults. The influence of sex on pediatric type 2 diabetes outcomes has not been well investigated. We studied 715 youth with type 2 diabetes diagnosed at a median age of 13.7 years and compared sex differences in demographic, clinical, and laboratory characteristics within the first year of diagnosis. Females diagnosed with type 2 diabetes were younger and at a higher stage of pubertal development than males, yet presented with lower A1Cs, a lower prevalence of diabetic ketoacidosis, and higher HDL cholesterol levels.

Enrollment of underrepresented racial and ethnic groups in the Rare and Atypical Diabetes Network (RADIANT).

Introduction: Diabetes mellitus in underrepresented racial and ethnic groups (URG) is rapidly increasing in incidence and has worse outcomes than diabetes in non-Hispanic White individuals. Rare and Atypical Diabetes Network (RADIANT) established recruitment targets based on the racial and ethnic distribution of the USA to enroll a diverse study population. We examined participation of URG across RADIANT study stages and described strategies to enhance recruitment and retention of URG. Materials and Methods: RADIANT is a multicenter NIH-funded study of people with uncharacterized forms of atypical diabetes. RADIANT participants consent online and progress through three sequential study stages, as eligible. Results: We enrolled 601 participants with mean age 44 ± 16.8 years, 64.4% female. At Stage 1, 80.6% were White, 7.2% African American (AA), 12.2% other/more than one race, and 8.4% Hispanic. Enrollment of URG was significantly below preset targets across most stages. Referral sources differed by race (p < 0.001) but not ethnicity (p = 0.15). Most AA participants were referred by RADIANT investigators (58.5% vs. 24.5% in Whites), whereas flyers, news, social media, and family or friends were more frequent referral sources for White individuals (26.4% vs. 12.2% in AA). Ongoing initiatives to increase enrollment of URG in RADIANT include engaging with clinics/hospitals serving URG, screening electronic medical records, and providing culturally competent study coordination and targeted advertisement. Conclusions: There is low participation of URG in RADIANT, potentially limiting the generalizability of its discoveries. Investigations into barriers and facilitators for recruitment and retention of URG in RADIANT, with implications for other studies, are ongoing.

Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients.

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

Clinical Characterization of Data-Driven Diabetes Clusters of Pediatric Type 2 Diabetes.

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) (p = 0.0001) and were most prescribed metformin (p = 0.06). Those in Cluster 2 were most prone to polycystic ovarian syndrome (p = 0.001). Younger individuals with lowest family history of diabetes were least frequently diagnosed with diabetic ketoacidosis (p = 0.001) and microalbuminuria (p = 0.06). Low-BMI individuals with higher A1c had the lowest prevalence of acanthosis nigricans (p = 0.0003) and hypertension (p = 0.03). Conclusions: Utilizing clinical measures gathered at the time of diabetes diagnosis can be used to identify subgroups of pediatric T2D with prognostic value. Consequently, this advancement contributes to the progression and wider implementation of precision medicine in diabetes management.

Precision diabetes: Lessons learned from maturity-onset diabetes of the young (MODY).

Maturity-onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1-6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK-MODY, HNF1A-MODY, and HNF4A-MODY account for >90% of MODY cases. While some MODY forms do not require treatment (i.e., GCK-MODY), some others are highly responsive to oral agents (i.e., HNF1A-MODY). The risk of micro- and macro-vascular complications of diabetes also differ significantly between MODY forms. Despite its high clinical impact, 50-90% of MODY cases are estimated to be misdiagnosed as type 1 or type 2 diabetes. Although there are many clinical features suggestive of MODY diagnosis, there is no single clinical criterion. An online MODY Risk Calculator can be a useful tool for clinicians in the decision-making process for MODY genetic testing in some situations. Molecular genetic tests with a commercial gene panel should be performed in cases with a suspicion of MODY. Unresolved atypical cases can be further studied by exome or genome sequencing in a clinical or research setting, as available.

Cardiac crises: Cardiac arrhythmias and cardiomyopathy during TANGO2 deficiency related metabolic crises.

BACKGROUND: TANGO2 deficiency disorder (TDD) is an autosomal recessive disease associated with metabolic crisis, lethal cardiac arrhythmias, and cardiomyopathy. Data regarding treatment, management, and outcomes of cardiac manifestations of TDD are lacking. OBJECTIVE: The purpose of this study was to describe TDD-related cardiac crises. METHODS: Retrospective multicenter chart review was made of TDD patients admitted with cardiac crises, defined as development of ventricular tachycardia (VT), cardiomyopathy, or cardiac arrest during metabolic crises. RESULTS: Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4-9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504-600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events. CONCLUSION: TDD-related cardiac crises are associated with a high risk of arrhythmias, cardiomyopathy, cardiac arrest, and death. Although further studies are needed, early recognition and appropriate treatment are critical. Acutely, intravenous magnesium, isoproterenol, atrial pacing, and ECMO as a last resort seem to be the best current treatment options, and early initiation of feeds may prevent VT events.

The germline p53 activation syndrome: A new patient further refines the clinical phenotype.

The tumor suppressor p53 has well known roles in cancer development and germline cancer predisposition disorders, but increasing evidence supports the role of activation of this transcription factor in the pathogenesis of inherited bone marrow failure and chromosomal instability disorders. Here we report a patient with red cell aplasia, which was steroid responsive, as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths, who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor. This is the third reported individual with a germline p53 activation syndrome, with several unique features that refine the clinical disease associated with these variants.

Optimizing maturity-onset diabetes of the young detection in a pediatric diabetes population.

INTRODUCTION: Maturity-onset diabetes of the young (MODY) is often misdiagnosed as type 1/type 2 diabetes. We aimed to define patient characteristics to guide the decision to test for MODY in youth with diabetes. RESEARCH DESIGN AND METHODS: Of 4750 patients enrolled in the Diabetes Registry at Texas Children's Hospital between July 2016 and July 2019, we selected ("Study Cohort", n = 350) those with: (1) diabetes diagnosis <25 years, (2) family history of diabetes in three consecutive generations, and (3) absent islet autoantibodies except for GAD65. We retrospectively studied their clinical and biochemical characteristics and available MODY testing results. Cluster analysis was then performed to identify the cluster with highest rate of MODY diagnosis. RESULTS: Patients in the Study Cohort were 3.5 times more likely to have been diagnosed with MODY than in the overall Diabetes Registry (4.6% vs. 1.3%, p < 0.001). The cluster (n = 16) with the highest rate of clinician-diagnosed MODY (25%, n = 4/16) had the lowest age (10.9 ± 2.5 year), BMI-z score (0.5 ± 0.9), C-peptide level (1.5 ± 1.2 ng/ml) and acanthosis nigricans frequency (12.5%) at diabetes diagnosis (all p < 0.05). In this cluster, three out of five patients who underwent MODY genetic testing had a pathogenic variant. CONCLUSIONS: Using a stepwise approach, we identified that younger age, lower BMI, lower C-peptide, and absence of acanthosis nigricans increase likelihood of MODY in racially/ethnically diverse children with diabetes who have a multigenerational family history of diabetes and negative islet autoantibodies, and can be used by clinicians to select patients for MODY testing.

Type 2 diabetes in prepubertal children.

OBJECTIVE: Puberty-induced insulin resistance is considered critical in the pathogenesis of type 2 diabetes (T2D) in youth. The development of T2D before puberty suggests distinct risk factors and pathophysiology but, because of its rarity, this has not been well studied. We aimed to describe the clinical characteristics of children with T2D diagnosed before the onset of puberty. RESEARCH DESIGN AND METHODS: We retrospectively studied all children with autoantibody-negative T2D and available pubertal development assessment seen at our center between July 2016 and July 2019, and compared characteristics of those at Tanner stage I (prepubertal, n = 35) versus those at Tanner II-V of pubertal development (n = 341). RESULTS: At T2D diagnosis, prepubertal children compared with those at Tanner II-V had higher body mass index z-score (p = 0.003) and higher C-peptide (p = 0.003) (while glucose levels were not significantly different), with differences retaining significance after adjustment for glucose, race/ethnicity and sex. Dyslipidemia occurred in 100% of prepubertal children versus 89.7% of those diagnosed later (p = 0.036). Of the prepubertal children diagnosed under age 10 (n = 13), 69.2% were female, 100% racial/ethnic minority, 100% had obesity with history of dyslipidemia and none with diabetic ketoacidosis. CONCLUSIONS: T2D, although rarely, can develop before puberty. Children with T2D diagnosed in the prepubertal period have more severe obesity, greater insulin resistance, and more frequent dyslipidemia than older youth. These findings suggest that children with prepubertal T2D are at increased risk for associated morbidity compared with older youth and underscore the significance of interventions to prevent and treat obesity in early childhood.