Type 1 diabetes onset in children and adolescents: Clinical and temporal analysis in a tertiary referral center.

We report five new cases of neonatal or early childhood-onset diabetes caused by biallelic pathogenic variants in IL2RA. Autoimmune diabetes was the presenting feature in most individuals and occurs in 64% of all reported cases of immunodeficiency 41. Patients typically presented in infancy with diabetic ketoacidosis, low C-peptide, and GAD antibody positivity, highlighting an autoimmune etiology. The diabetes phenotype was consistent across cases but not linked to variant type or location. IL2RA should be included in genetic testing for neonatal diabetes and considered in children with diabetes plus immune dysregulation.

The coexistence of overweight/obesity and type 1 diabetes (T1D) may increase disease burden and management complexity. We assessed the prevalence of overweight/obesity in children newly diagnosed with T1D in Kuwait and characterized their baseline clinical, metabolic, and immunological features. This retrospective review analyzed medical records of children aged 14 years or younger diagnosed with T1D from 2017 to 2022. Data were obtained from the Childhood-Onset Diabetes electronic Registry (CODeR). Overweight/obesity was defined using WHO growth standards, and T1D diagnosis was confirmed based on the 2018 ISPAD guidelines. From 2,066 children with T1D in CODeR, 1,265 had BMI data and were included in the present study. Of these, 29.9% (378 children) were overweight/obese at diagnosis. Males were more likely to be overweight/obese than females (55.3% vs. 44.9%, p=0.001). Overweight/obese children were older at diagnosis compared to non-obese children (median age 9.3 vs. 7.3 years, respectively, p=0.0001). These children had a milder clinical presentation, with fewer cases of DKA, lower HbA1c, and lower triglycerides at diagnosis. After adjusting for age and gender, higher BMI z-scores were associated with lower HbA1c levels, reduced odds of DKA, and lower odds of celiac autoimmunity. Overweight/obesity influence the presentation of type 1 diabetes in children, highlighting the need for early screening and targeted prevention. Longitudinal follow-up with genetic integration is warranted to better understand their relationship with disease progression and metabolic risk.

Clinical and Genetic Characteristics of Neonatal Diabetes in Kuwait: Results from the Childhood-Onset Diabetes e-Registry

Are children with familial type 1 diabetes from Kuwait different? Report on prevalence, clinical, biochemical, and immunological characteristics.

Objective: Identifying gene polymorphisms linked to childhood-onset diabetes mellitus (DM), a multifactorial disease, will illuminate its genetic underpinnings. This study aimed to explore the association between childhood DM and the polymorphisms Paraoxonase1 (PON1) 55 and PON1 192. Method: A total of 129 children who applied to our Child Health and Diseases Endocrinology outpatient clinic participated in this prospective research. The study included 75 children with diabetes, aged 3–15 years (Patient Group-PG), and 54 healthy children (Control Group-CG) as a control. Genotyping of PON1 55 and PON1 192 polymorphisms was performed in study patients using Polymerase Chain Reaction (PCR) and RFLP methods following DNA isolation. Results: Of 54 CG, 21 (38.9%) displayed the homozygous normal (LL) PON1 55 genotypes. The PG contained 25 (33.3%) homozygous normal patients out of 75. In the CG, 25 participants (46.3%) and 39 participants in the PG (52.0%) had the heterozygous (LM) genotype. The homozygous mutant (MM) genotype was observed in 8 (14.8%) of CG and 11 (14.7%) of PG. The CG showed 67 L alleles, representing 62.0% of the total alleles. On the other hand, the number was 89 (59.3%) in the PG. The two groups showed no statistically significant differences in gene polymorphisms, allele frequencies, and M and R allele distribution. Conclusion: No significant relationship was observed between PON1 55 and PON1 192 gene polymorphisms and DM in our study.

Abstract The uncommon genetic ailment known as Wolfram syndrome (WS) is regarded as the most representative example of endoplasmic reticulum disorders. Childhood-onset diabetes mellitus, ocular atrophy, deafness, diabetes insipidus, neurological symptoms and other anomalies are considered classic hallmarks of WS, which is rare. It has been determined that WFS1 and WFS2 are the two causal genes. While there are yet no effective therapies to stop or reverse the course of WS, patients can experience less suffering and a higher quality of life with the use of supportive care and close clinical monitoring. In this article, we discuss about nursing care of an adolescent with WS.

INTRODUCTION: The rising incidence of pediatric diabetes underscores the need for accurate glucose monitoring tools to facilitate early detection. Although both Blood Glucose Meters (BGM) and Continuous Glucose Monitoring (CGM) are widely used, their comparative effectiveness in predicting diabetes onset in children remains contested. This study evaluated and compared the predictive utility of BGM and CGM in high-risk pediatric populations. METHODS: A nine-month prospective observational study (January–September 2024) was conducted at the Health Polytechnic of the Ministry of Health, Sorong, involving 76 children aged 10–18 years diagnosed with Acanthosis Nigricans and positive FINDRISC scores. Participants were allocated to either BGM (every 3 days) or CGM (15-minute intervals). Key outcome measures included Time in Range (TIR), mean glucose levels, frequencies of hypo- and hyperglycaemic episodes, adherence rates, and Mean Absolute Relative Difference (MARD). RESULTS: CGM significantly outperformed BGM across all parameters: higher TIR (78.9% vs. 63.4%, p<0.001), lower average glucose levels (145.3 vs. 162.7 mg/dL, p=0.003), fewer hypoglycaemic (1.1 vs. 2.8, p=0.015) and hyperglycaemic events (2.6 vs. 4.5, p=0.002), and superior adherence (88.7% vs. 71.3%, p<0.001). CGM also showed a lower MARD (7.2% vs. 10.8%, p=0.004), indicating greater accuracy. CONCLUSIONS: CGM offers more reliable and comprehensive glucose monitoring than BGM for predicting diabetes onset in children at risk, supported by better glycaemic control, higher adherence, and improved accuracy. These findings endorse CGM as the preferred approach for early diabetes detection in pediatric populations.

Background. The hypothesis on correlation between SARS-CoV-2 infection and diabetic ketoacidosis (DKA) development in patients with newly diagnosed type 1 diabetes (T1D) was proposed during the COVID-19 pandemic. The results of testing this hypothesis remain contradictory. Objective. Aim of the study — to analyse the correlation between COVID-19 and clinical characteristics of T1D onset in children. Methods. The study included data from the medical records of patients with newly diagnosed T1D and hospitalized from March 2020 to March 2021. The study group included patients with IgG to SARS-CoV-2 10 U/ml at hospital admission, control group — patients with no laboratory signs of COVID-19. Clinical forms of disease manifestation (hyperglycemia, ketosis, DKA) were recorded among T1D features, as well as DKA severity according to blood pH levels (mild — pH 7.3; moderate — pH = 7.1–7.2; severe — pH < 7.1). Results. The study group included data from 119 children, the control group — 320 with newly established T1D. Both groups were comparable in gender and age. T1D manifested with hyperglycemia in 35 (29.4%) patients, with ketosis — in 41 (34.5%), with DKA — in 43 (36.1%) in the study group; and in 81 (25.3%), 89 (27.8%) and 150 (46.9%) patients in the control group, respectively (p = 0.127). DKA was mild in 9 (20.9%), moderate in 24 (55.8%), and severe in 10 (23.3%) patients of study group; and in 36 (24%), 73 (48.7%) and 41 (27.3%) patients in the control group, respectively (p = 0.747). Conclusion: COVID-19 is not associated with the clinical form and severity of DKA at T1D onset.

Proinsulin has three distinct regions: the well-folded A- and B-chains and the dynamic disordered C-peptide. The highly conserved B-chain is a hotspot for diabetes-associated mutations, including the severe loss-of-function R(B22)Q mutation linked to childhood-onset diabetes. Here, we explore R(B22)'s role in proinsulin stability using AlphaFold-predicted structures and metadynamics simulations to achieve enhanced sampling of the free energy landscape. Our results show that R(B22) stabilizes proinsulin by interacting with N86. Substituting R(B22) with E or Q disrupts this interaction, increasing conformational flexibility. The R(B22)Q variant exhibits a flattened free energy landscape, favoring unfolded states. Additional substitutions, including Gly, Ala, Lys, Tyr, Asp, and Phe, destabilize proinsulin to varying extents by weakening hydrogen bonding. Disrupting the R(B22)-N86 interaction broadly reduces inter-chain contacts, raising the risk of aggregation-prone states. Given the link between R(B22) mutations and diabetes, our study provides crucial molecular insights into proinsulin instability. These findings highlight the role of key inter-domain (A-Chain-B-chain, B-Chain-C-peptide, and A-Chain-C-peptide) interactions in maintaining protein structures and the implications this has for understanding disease-associated proinsulin variants.

Aims/hypothesisWolfram syndrome 1 (WS1) is an inherited condition mainly manifesting in childhood-onset diabetes mellitus and progressive optic nerve atrophy. The causative gene, WFS1, encodes wolframin, a master regulator of several cellular responses, and the gene’s mutations associate with clinical variability. Indeed, nonsense/frameshift variants correlate with more severe symptoms than missense/in-frame variants. As achieving a genotype–phenotype correlation is crucial for dealing with disease outcome, works investigating the impact of transcriptional and translational landscapes stemming from such mutations are needed. Therefore, we sought to elucidate the molecular determinants behind the pathophysiological alterations in a WS1 patient carrying compound heterozygous mutations in WFS1: c.316-1G>A, affecting the acceptor splice site (ASS) upstream of exon 4; and c.757A>T, introducing a premature termination codon (PTC) in exon 7.MethodsBioinformatic analysis was carried out to infer the alternative splicing events occurring after disruption of ASS, followed by RNA-seq and PCR to validate the transcriptional landscape. Patient-derived induced pluripotent stem cells (iPSCs) were used as an in vitro model of WS1 and to investigate the WFS1 alternative splicing isoforms in pancreatic beta cells. CRISPR/Cas9 technology was employed to correct ASS mutation and generate a syngeneic control for the endoplasmic reticulum stress induction and immunotoxicity assays.ResultsWe showed that patient-derived iPSCs retained the ability to differentiate into pancreatic beta cells. We demonstrated that the allele carrying the ASS mutation c.316-1G>A originates two PTC-containing alternative splicing transcripts (c.316del and c.316–460del), and two open reading frame-conserving mRNAs (c.271–513del and c.316–456del) leading to N-terminally truncated polypeptides. By retaining the C-terminal domain, these isoforms sustained the endoplasmic reticulum stress response in beta cells. Otherwise, PTC-carrying transcripts were regulated by the nonsense-mediated decay (NMD) in basal conditions. Exposure to cell stress inducers and proinflammatory cytokines affected expression levels of the NMD-related gene SMG7 (>twofold decrease; p<0.001) without eliciting a robust unfolded protein response in WFS1 beta cells. This resulted in a dramatic accumulation of the PTC-containing isoforms c.316del (>100-fold increase over basal; p<0.001) and c.316–460del (>20-fold increase over basal; p<0.001), predisposing affected beta cells to undergo apoptosis. Cas9-mediated recovery of ASS retrieved the canonical transcriptional landscape, rescuing the normal phenotype in patient-derived beta cells.Conclusions/interpretationThis study represents a new model to study wolframin, highlighting how each single mutation of the WFS1 gene can determine dramatically different functional outcomes. Our data point to increased vulnerability of WFS1 beta cells to stress and inflammation and we postulate that this is triggered by escaping NMD and accumulation of mutated transcripts and truncated proteins. These findings pave the way for further studies on the molecular basis of genotype–phenotype relationship in WS1, to uncover the key determinants that might be targeted to ameliorate the clinical outcome of patients affected by this rare disease.Data availabilityThe in silico predicted N-terminal domain structure file of WT wolframin was deposited in the ModelArchive, together with procedures, ramachandran plots, inter-residue distance deviation and IDDT scores, and Gromacs configuration files (doi/10.5452/ma-cg3qd). The deep-sequencing data as fastq files used to generate consensus sequences of AS isoforms of WFS1 are available in the SRA database (BioProject PRJNA1109747).Graphical

Objective: Exploring early-onset diabetes in terms of describing characteristics at time of diagnosis might aid in a better understanding of etiology and may have implications on management and prevention. The aim of this study was to investigate the prevalence of early-onset type 1 diabetes (T1D) in Kuwait as well as describe their baseline clinical, biochemical, and immunological characteristics. Methods: Medical records of children newly diagnosed with T1D and registered in the Childhood-Onset Diabetes electronic Registry (CODeR) in Kuwait between 2017 and 2022 were reviewed. Early-onset T1D was defined as diagnosis at age younger than 6 years. Results: 2,051 children were registered with new-onset T1D between 2017 and 2022, of which 657 (32.0%) were diagnosed at early onset. There has been a trend of slight increase in the percentage of early-onset T1D after 2020 (15.2%) with a prevalence of 18.4% and 20.2% in 2021 and 2022, respectively (p = 0.056). Age at onset was inversely related to admission to the pediatric intensive care unit (OR = 0.90, 95% CI: 0.85, 0.95, p < 0.0001) and was directly related to positive celiac autoimmunity (p = 0.022), higher hemoglobin A1C (p < 0.0001), and C-peptide levels (p < 0.0001). However, age at onset of T1D was inversely related to the higher vitamin D levels (p < 0.0001). Conclusion: These findings reinforce the need for increased attention to be given to study the development of T1D in children of younger age. This in turn will support special management and prevention measures targeted toward this vulnerable age group.

Wolfram syndrome (WS), also called diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, diabetes insipidus, optic atrophy, and deafness as well as several other disorders including neurodegeneration. It is well documented that genetic mutations in the genes WFS 1, that codes for the protein Wolframin and WFS 2, also known as CISD2, which encodes for a transmembrane protein located in the endoplasmic reticulum, are responsible for wolfram syndrome. It is usually observed in children born of consanguineous marriages, and there are currently no effective therapies to prevent or slow the progression of the condition. Current research focuses on evaluating several possible repurposed drugs and small molecules to reduce endoplasmic reticulum stress in WS and slow progression of the disease. This report describes the case of a 13-year-old female with uncontrolled glycemia and WS.

IntroductionTo study the HbA1c trajectory from the time of diagnosis to examine if patients at the greatest risk for severe microangiopathy can be identified early allowing clinicians to intervene as...

The increasing prevalence of childhood-onset type-1 diabetes (T1D) has brought to light its multifaceted implications on growth and development. This necessitates a holistic understanding of its long-term effects on physical, neurological, metabolic, and psychosocial aspects. Thus, this study systematically reviewed the long-term effects of childhood-onset T1D on growth and development in children and adolescents. Using the PRISMA guidelines, a comprehensive search was conducted mainly on PubMed for studies in English, resulting in the inclusion of nine studies with a collective participant count of 24,880. These studies spanned across various geographical locations, with a predominant focus on the younger demographic, averaging around 11 years of age. The findings indicated significant associations of T1D with altered physical growth patterns, neurological and cognitive implications, metabolic outcomes, and psychosocial challenges. Notably, growth complications and cognitive patterns seemed to intertwine with T1D onset and management. Studies showed that poor glycemic control and early T1D onset, negatively impact the projected adult height of the child. Additionally, poor glycemic control implications such as diabetic ketoacidosis have a negative impact on cognitive functions. Finally, psychosocial complications of T1D and obesity, particularly in adolescent girls, highlighted the importance of parental education and perceived stress on these vulnerable children. Childhood-onset T1D has profound implications on growth and development. While effective glycemic control is beneficial to reduce these complications, a multidisciplinary approach, encompassing endocrinology, neurology, and psychology, is essential for comprehensive care and improved life quality in these children.

INTRODUCTIONThe burden of Type 1 diabetes (T1D) care in adulthood is often overshadowed by the increasing Type 2 diabetes prevalence. In addition to the complexity of transitional care from adolescence to adulthood, there are multiple barriers to the care of these patients. Identifying these barriers is crucial to facilitate creating personalized and focused care for T1D patients. METHODOLOGYThis was a cross-sectional study recruiting all T1D patients who consulted in endocrinologist-led diabetes clinics in secondary and tertiary hospitals in Central Pahang, Malaysia. This included coverage areas of Bentong, Temerloh, Bera, Jengka, and Jerantut in Pahang. The study aimed to determine the demographic data, glycemic control, diabetes complications, and treatment patterns in T1D patients. Patient’s electronic medical records were retrieved for data collection. RESULTSFifty-eight patients were recruited into the study, with female predominance (63.8%), and the majority were of Malay ethnicity (67.2%). The mean age of the patients was 25.26, (SD = 7.5) with a mean age at diagnosis of 16.98 (SD = 6.9). The majority had a duration of illness of 7 years. Almost 66% of patients had prior testing for autoantibodies and c-peptide as diagnostic confirmation. Fifty percent of patients had childhood-onset diabetes, presenting early with diabetic ketoacidosis. For diabetes complications, 24.1% of patients had nephropathy, while 12.1% had diabetic retinopathy. Up to 10.3% had documented hypoglycemia, and 8.6% had DKA in the past six months. Despite poor glycemic control, there was still a statistically significant reduction of HbA1c from baseline compared to the latest follow up (10.93% vs 9.92%, p &lt;0.01). Only 32.1% of patients at the latest follow-up had HbA1c less than 8.5%. The mean total daily insulin usage was 0.84 SD 0.3 u/ kg/day. Only 17.2% of T1D patients had prior exposure to continuous glucose monitoring utilization. CONCLUSIONEnrolment in a specialized T1D clinic is important to deliver an appropriate and targeted approach to T1D patients. The poor control of T1D patients in this cohort reflects the barriers to care including treatment access, adequacy of glucose monitoring, disease understanding and peer and family support. Technology-based intervention in T1D patients is still underutilized and concerted effort to incorporate technology into treatment needs to be intensified.

Abstract Disclosure: D.H. Sacoto: None. C.A. Villavicencio: None. R. Belokovskaya: None. A.A. Franco-Akel, MD: None. Wolfram syndrome (WS) is a rare and fatal condition with a median age of death of about 39 years and affecting around 1 of 100,000 people in North America. Insulin is the mainstay of treatment in WS though, access to it may affect adherence and glycemic control which is correlated with neurodegenerative progression. We present a patient with WS whose complications exacerbated due to insulin access. A 19-year-old African American male with a history of type 1 diabetes mellitus (T1DM), presented to the ED with a 2 day-history of general malaise and emesis. Diabetic ketoacidosis (DKA) (blood glucose 802 mg/dL, pH 7.2, positive serum ketones) was diagnosed upon arrival. Right optic nerve atrophy was diagnosed at age of seven. At age of eight, patient was diagnosed with bilateral sensory-neuronal hearing loss (SNHL) which led to school withdrawal. It was then when suspicion of WS arose. Single nucleotide polymorphism microarray confirmed homozygosity from the region of linkage on chromosome 4p16.1, where the WFS1 gene lies. At the age of eighteen, patient was diagnosed with neurogenic bladder for which he requires frequent self-catheterization. Since his T1DM diagnosis, patient has faced multiple barriers accessing insulin secondary to insurance issues and lack of social support resulting in multiple hospital admissions for DKA and urinary retention episodes. WS is an autosomal recessive disorder resulting from WFS1 or WFS2 gene mutation on chromosome 4p. WS commonly presents as childhood-onset diabetes mellitus, optic atrophy, SNHL, and neurogenic bladder. Insulin is the first line treatment for optimal glycemic control in WS. Despite optimal glycemic control, WS symptoms and neurodegenerative progression may be influenced by other factors. First, treatment access for rare diseases has shown to be impacted by medical unconscious bias, in addition to systemic, linguistic, and socioeconomic challenges patients may face. Furthermore, Medicaid insurance covering rare diseases still varies widely between 15-67%, and in those insured, there is still a 61% chance of delay or denial due to pre-approval requirements. In addition, poor glycemic control has been correlated with lower socioeconomic status, lack of access to devices such as insulin pumps, migratory status, social support and environment, food security, and ethnic background. Since diabetes control in WS patients is paramount to a better quality of life, additional studies are needed to understand the full scope of barriers that can contribute to policies that facilitate better treatment access for patient and families living with WS. Presentation: Saturday, June 17, 2023

The Wolfram syndrome 1 gene (WFS1) is the main causative locus for Wolfram syndrome, an inherited condition characterized by childhood-onset diabetes mellitus, optic atrophy, and deafness. Global genome-wide association studies have listed at least 19 WFS1 variants that are associated with type 2 diabetes (T2D) and metabolic traits. It has been suggested that miRNA binding sites on WFS1 play a critical role in the regulation of the wolframin protein, and loss of WFS1 function may lead to the pathogenesis of diabetes. In the Hungarian population, it was observed that a 3' UTR variant from WFS1, namely rs1046322, influenced the affinity of miR-668 to WFS1 mRNA, and showed a strong association with T2D. In this study, we genotyped a large cohort of 2067 individuals of different ethnicities residing in Kuwait for the WFS1 rs1046322 polymorphism. The cohort included 362 Southeast Asians (SEA), 1045 Arabs, and 660 South Asians (SA). Upon performing genetic association tests, we observed significant associations between the rs1046322 SNP and obesity traits in the SEA population, but not in the Arab or SA populations. The associated traits in SEA cohort were body mass index, BMI (β=1.562, P-value=0.0035, Pemp=0.0072), waist circumference, WC (β=3.163, P-value=0.0197, Pemp=0.0388) and triglyceride, TGL (β=0.224, P-value=0.0340). The association with BMI remained statistically significant even after multiple testing correction. Among the SEA individuals, carriers of the effect allele at the SNP had significantly higher BMI [mean of 27.63 (3.6) Kg/m2], WC [mean of 89.9 (8.1) cm], and TGL levels [mean of 1.672 (0.8) mmol/l] than non-carriers of the effect allele. Our findings suggest a role for WFS1 in obesity, which is a risk factor for diabetes. The study also emphasizes the significant role the ethnic background may play in determining the effect of genetic variants on susceptibility to metabolic diseases.

Pathogenic GATA6 variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenic GATA6 variation in humans remains to be fully understood. Exome sequencing was performed in a family where four members had CHD. In vitro functional analysis of the GATA6 variant was performed using immunofluorescence, western blot, and dual-luciferase reporter assay. A novel, heterozygous missense variant in GATA6 (c.1403 G > A; p.Cys468Tyr) segregated with affected members in a family with CHD, including three with persistent truncus arteriosus. In addition, one member had childhood onset diabetes mellitus (DM), and another had necrotizing enterocolitis (NEC) with intestinal perforation. The p.Cys468Tyr variant was located in the c-terminal zinc finger domain encoded by exon 4. The mutant protein demonstrated an abnormal nuclear localization pattern with protein aggregation and decreased transcriptional activity. We report a novel, familial GATA6 likely pathogenic variant associated with CHD, DM, and NEC with intestinal perforation. These findings expand the phenotypic spectrum of pathologic GATA6 variation to include intestinal abnormalities. Exome sequencing identified a novel heterozygous GATA6 variant (p.Cys468Tyr) that segregated in a family with CHD including persistent truncus arteriosus, atrial septal defects and bicuspid aortic valve. Additionally, affected members displayed extracardiac findings including childhood-onset diabetes mellitus, and uniquely, necrotizing enterocolitis with intestinal perforation in the first four days of life. In vitro functional assays demonstrated that GATA6 p.Cys468Tyr variant leads to cellular localization defects and decreased transactivation activity. This work supports the importance of GATA6 as a causative gene for CHD and expands the phenotypic spectrum of pathogenic GATA6 variation, highlighting neonatal intestinal perforation as a novel extracardiac phenotype.

There are reports of increasing incidence of pediatric diabetes since the onset of the COVID-19 pandemic. Given the limitations of individual studies that examine this association, it is important to synthesize estimates of changes in incidence rates. To compare the incidence rates of pediatric diabetes during and before the COVID-19 pandemic. In this systematic review and meta-analysis, electronic databases, including Medline, Embase, the Cochrane database, Scopus, and Web of Science, and the gray literature were searched between January 1, 2020, and March 28, 2023, using subject headings and text word terms related to COVID-19, diabetes, and diabetic ketoacidosis (DKA). Studies were independently assessed by 2 reviewers and included if they reported differences in incident diabetes cases during vs before the pandemic in youths younger than 19 years, had a minimum observation period of 12 months during and 12 months before the pandemic, and were published in English. From records that underwent full-text review, 2 reviewers independently abstracted data and assessed the risk of bias. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline was followed. Eligible studies were included in the meta-analysis and analyzed with a common and random-effects analysis. Studies not included in the meta-analysis were summarized descriptively. The primary outcome was change in the incidence rate of pediatric diabetes during vs before the COVID-19 pandemic. The secondary outcome was change in the incidence rate of DKA among youths with new-onset diabetes during the pandemic. Forty-two studies including 102 984 incident diabetes cases were included in the systematic review. The meta-analysis of type 1 diabetes incidence rates included 17 studies of 38 149 youths and showed a higher incidence rate during the first year of the pandemic compared with the prepandemic period (incidence rate ratio [IRR], 1.14; 95% CI, 1.08-1.21). There was an increased incidence of diabetes during months 13 to 24 of the pandemic compared with the prepandemic period (IRR, 1.27; 95% CI, 1.18-1.37). Ten studies (23.8%) reported incident type 2 diabetes cases in both periods. These studies did not report incidence rates, so results were not pooled. Fifteen studies (35.7%) reported DKA incidence and found a higher rate during the pandemic compared with before the pandemic (IRR, 1.26; 95% CI, 1.17-1.36). This study found that incidence rates of type 1 diabetes and DKA at diabetes onset in children and adolescents were higher after the start of the COVID-19 pandemic than before the pandemic. Increased resources and support may be needed for the growing number of children and adolescents with diabetes. Future studies are needed to assess whether this trend persists and may help elucidate possible underlying mechanisms to explain temporal changes.