Pediatric Diabetes最新文献

Objective: This study aimed to present a quantitative modeling and simulation approach for oral henagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. Methods: A physiologically-based pharmacokinetic (PBPK) model for henagliflozin was developed using in vitro metabolism and clinical pharmacokinetic (PK) data, with validation across multiple contexts, including healthy adults, and hepatic impairment populations. Additionally, empirical pharmacodynamic (PD) modeling was employed to optimize pediatric dosing based on exposure-response relationships for urinary glucose excretion (UGE). Predicting henagliflozin exposure in pediatric patients poses challenges due to UGT enzyme ontogeny and the scarcity of clinical PK data in younger age groups. Using twofold acceptance criteria, model-predicted and observed drug exposures and PK parameters (area under the curve and peak concentration) were compared in diverse scenarios, including monotherapy in healthy adults (single/multiple doses), hepatic impairment, and extrapolation to pediatric age groups. Results: The PBPK model accurately captured observed exposures within a twofold range in both adults and adolescents, supporting the model's predictive utility. The verified PBPK and empirical PD models informed dosing recommendations in pediatric populations aged 1 month to 18 years, achieving henagliflozin exposures comparable to those in adult patients receiving a 5-10 mg dose. Conclusion: This study shows that PBPK and PD modeling effectively guide pediatric dosing of henagliflozin, reducing trial reliance and supporting real-world validation.

Objective: Children with type 1 diabetes (T1D) have an increased risk of developing additional autoimmune diseases. The risk of developing celiac disease (CD) is 3-4 times higher in children with T1D. Guidelines recommend regular screening for transglutaminase antibodies (TgAbs) in T1D children. CD could be an additional burden for T1D children as both diseases affect food intake. We describe the screening practice for CD during the last 25 years in our outpatient clinic in children with T1D. Methods: We retrospectively analyzed the development of CD-specific antibodies in our children with T1D (diabetes onset since 1998). We did not routinely recommend endoscopy when CD-specific antibodies (TgAb, endomysium [EAb], and gliadin) were positive and patients had no CD-specific symptoms. Results: We analyzed 304 patients. In total 122 had CD-specific antibodies. In 98 of them, they disappeared after a short time or had been only slightly elevated. The diagnosis of CD was confirmed in 12. All 12 showed CD-specific symptoms, such as failure to thrive, anemia, hypoglycemia, or gastrointestinal problems. In six patients, even severely elevated EAb and/or TgAb disappeared on average after 7.1 years (range 4.9-13.5 years) on gluten-containing diet. The remaining six had antibodies without CD-specific symptoms by the end of the observation period. In this group the duration of antibody-positivity was 4 years (range 1.8-11.6 years). Conclusion: We conclude that even highly elevated CD-specific antibodies can disappear in children with T1D and that screening for CD-specific antibodies is therefore only useful in symptomatic children with T1D.

Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane (TM) structural protein (wolframin), is essential for several biological processes. Mutations of WFS1, autosomal dominant or recessive inherited, are related to a broad clinical spectrum. Molecular genetic tests were performed, and clinical phenotypes of three WFS1-associated cases were evaluated. The expression of WFS1, viability, and endoplasmic reticulum (ER) stress of the MIN6 cell and structural analysis of the variant WFS1 protein were revealed. Furthermore, a total of 75 pathogenic WFS1 variants from ClinVar were included to analyze variant-phenotype association. Genetic testing revealed 3 mutations with unclear pathogenicity in WFS1 of the 3 patients with early-onset diabetes, including c.613G >A (p.G205S), c.2053C >T (p.R685C), and c.169G >A (p.A57T). Decreased expression, reduced β-cell viability and enhanced ER stress were found in all variants. Protein stability and structural analysis showed increased protein stability and molecule flexibility of variants p.R685C in the ER-lumenal domain and p.A57T in the ATP6VIA-interaction region, while destabilized protein and rigidificated structure by p.G205S variant in the EF-hand domain at the cytoplasm region. Remarkably, topology was found an independent risk factor with urological symptoms (USs) (p=0.007, odds ratio [OR] 4.768 [95% confidence interval (CI): 1.531-14.854]). Surprisingly, variants in the cytoplasm had the highest risk with US than ones in the ER-lumenal domain (p=0.008, OR 22.013 [95% CI: 2.270-213.428]). The functional analysis of the three variants of uncertain significance in WFS1 indicated a quantitative and qualitative damage to wolframin with proven pathogenicity. The topology of the WFS1 protein may play an important role in the pathogenesis of β-cell and urological defects in WFS1-associated disease.

Objective: Having been facing a progressive increase in the prevalence of type 1 diabetes (T1D), there might be a growing risk of the development of diabetic ketoacidosis (DKA) at disease onset. The prevalence of DKA varies widely by geographic region, ranging from approximately 13% in Sweden to 80% in the United Arab Emirates. This study aimed to compare the prevalence of DKA in childhood-onset T1D from Greater Poland (Poland) in two 9-year periods. Methods: We assessed the prevalence of DKA in children aged <18 years with newly diagnosed T1D in Greater Poland (Poland) in two 9-year periods, 2006-2014 and 2015-2023, in a retrospective review of a complete regional cohort. DKA and its severity were classified according to International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines. Results: Over the 18 years, 2432 children below 18 years of age with newly diagnosed T1D were recorded. The overall prevalence of DKA was 51.3% (n = 1248), and it rose significantly in two nine-year periods, from 47.7% in 2006-2014 to 53.4% in 2015-2023 (p=0.007). There was a significant shift toward more severe presentations of DKA. While the prevalence of mild DKA decreased slightly from 51.3% to 47.0% (p=0.145), and moderate DKA had a notable decline from 33.1% to 25.2% (p=0.003), the proportion of severe DKA cases rose sharply from 15.5% to 27.7% (p < 0.001). Conclusions: Despite the increasing incidence of T1D in Poland, healthcare, and parental awareness of T1D symptoms remain low, which results in delayed T1D recognition. The escalating prevalence of DKA at T1D onset in children is a concerning public health issue that necessitates a multifaceted approach to education, prevention, and early intervention. Addressing these challenges might help reduce the prevalence of DKA and improve clinical outcomes for children with T1D.

Aim: Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1D). We determined the incidence, trends, cost and characteristics of children with and without DKA at T1D diagnosis and association with DKA readmissions. Methods: Children aged <16 years with T1D and residing in New South Wales, Australia, were identified from population-based hospital records (Admitted Patient Data Collection; APDC) for 2002-2019. Diagnoses of T1D and DKA were identified using ICD10 codes. Costs were determined using the 'Australian Refined-Diagnosis Related Group' (AR-DRG) code multiplied by the cost weight and National Efficient Price for the admission year. Associations were assessed using Chi-squared analyses and multivariate regression. Results: A total of 5832 children with T1D were identified, and 36% had DKA at diagnosis. The proportion with DKA at diagnosis was 34.4% in 2002-2003 and 41.0% in 2018-2019, with limited evidence to support a meaningful change over time (Cochrane-Armitage test-for-trend, p=0.062). DKA at diagnosis was associated with age <2 years, lower socio-economic status (SES) and rural/regional areas. DKA at diagnosis was also associated with an increased risk of readmission(s) for DKA (odds ratio [OR]: 1.35 [95% confidence interval [CI] 1.23, 1.49]). DKA doubled the costs/person, considering all available follow-up ($20,571 [interquartile range: $10,825, $37,845] vs. $9743 [$4980, $18,287]). Conclusion: DKA at diagnosis of T1D is a common and expensive health issue in Australia, with the rate of DKA at diagnosis not improving over the last two decades. Effective strategies are needed to improve health outcomes and reduce the economic burden.

Aims: Assessment of celiac disease and gluten-free diet (GFD) associations with metabolic control and growth parameters in children and adolescents with type 1 diabetes mellitus (T1DM) during the first year after diagnosis of celiac disease. Methods: This was a retrospective case-control study that included 47 children and adolescents with T1DM aged <18 years who attended the pediatric diabetes clinic at Sohag University Hospital, Egypt, and had a biopsy-proven diagnosis of celiac disease between January 2017 and December 2021. Each case had two age-, sex-, and duration of diabetes-matched control participants with T1DM who had persistently negative celiac screening tests. Clinical characteristics, growth parameters, insulin doses, celiac autoantibody titers, and HbA1c levels throughout the first year after diagnosis of celiac disease were obtained from the medical records. Results: Children and adolescents with celiac disease had significantly lower insulin doses at diagnosis (p=0.002) compared to their matched controls. There were no significant differences between both groups regarding the HbA1c levels at diagnosis of celiac disease or after 1 year (p=0.27 and 0.81, respectively). Patients with celiac disease had significantly lower weight, height, and body mass index (BMI) standard deviation scores (SDSs) at diagnosis and after 1 year. There were no significant differences between both groups regarding the fasting lipid profiles at diagnosis or after 1 year. Patients with villous atrophy at diagnosis had significantly higher HbA1c levels after 1 year (p=0.04). There were no significant improvements in weight, height, and BMI SDS after 1 year even in patients with normalized celiac autoantibodies. Conclusions: Children and adolescents with T1DM had lower insulin requirements and growth parameters at diagnosis of celiac disease. Villous atrophy at diagnostic small bowel biopsies was associated with worsening glycemic control after 1 year. Longer follow-up periods are required to detect significant improvements in growth parameters.

Hypertriglyceridemia (HTG) in the setting of newly diagnosed diabetes is common in both adult and pediatric populations, as insulin deficiency promotes lipolysis and impairs triglyceride (TG) clearance. Severe HTG (defined as TG levels above 1000 mg/dL) in pediatric patients with new-onset type 1 diabetes mellitus (T1D) is rare; the true incidence and sequela of this phenomenon have not been well characterized. We present a single-center experience on severe HTG in pediatric patients with new-onset T1D between 2013 and 2022 and summarize the cases previously reported in the literature. Our cases display variability in their presentation and in their association with high-risk complications, such as acute pancreatitis. We discuss suggestions of early screening for HTG and pancreatitis in patients with protracted abdominal pain, and close monitoring of those identified to have significant HTG.

Background: Developmental challenges of adolescence, such as puberty and social pressures, exacerbate the complexity of managing type 1 diabetes (T1D) as they transition from pediatric to adult care. However, there is a paucity of codesigned, evidence-based diabetes education and support programs and services to guide adolescents through this transition. Objective: This study aimed to explore the experiences, perspectives, facilitators, and barriers faced by adolescents with T1D in diabetes education and program services and to identify feasible approaches to support them as they transition from pediatric to adult care. Methods: Semistructured interviews were conducted with 13 adolescents aged 13-19 years with T1D. Thematic analysis was used to understand participants' past experiences, facilitators, barriers, and preferences regarding diabetes education programs and services. Results: Participants highly valued the opportunity to meet with peers living with T1D and the emotional support from those interactions. Participants also highlighted the need for age-appropriate content and interactive learning experiences. Suggested gamification features were well-received, with participants emphasizing the importance of interactivity. While there was not a strong preference between virtual or in-person game formats, it was suggested that online options offered flexibility and inclusiveness regardless of physical abilities. Participants were not as enthusiastic for a one-on-one live chat compared to an online community chat, again, for the opportunity for peer support. Conclusion: The study highlights the value that adolescents with T1D place on peer support that arises from opportunities to meet others through in-person events. It was evident that codesigning diabetes education programs and services with adolescents with T1D is key to develop tailored offerings for this population.

Introduction: Disorders of the lower limb are common in people with diabetes and may result in significant long-term complications. Currently, most evidence for lower limb complications in children with diabetes relies on infrequent clinical observations and occasionally invasive assessments that can cause discomfort. Clinical guidelines do not provide explicit guidance on frequency of neurovascular assessments for children with diabetes. Aim: To systematically review the prevalence and presentation of clinical neuropathy and vasculopathy in children with diabetes. Methods: A systematic search of the literature was conducted in March 2024 using the EMBASE, Cochrane, PubMed (including MEDLINE) and CINAHL databases. At least two authors independently screened studies for inclusion and assessed methodological quality for each paper using the downs and black quality appraisal checklist. Extracted data was summarised and tabulated. Meta-analysis was also performed. Results: Eighteen studies with 3533 participants were included. Participants were aged 3.5-18 years, and 95% had type 1 diabetes, while 5% had type 2 diabetes. These studies used a range of assessments, including monofilament, vibrioception, sharp-blunt discrimination, temperature perception, reflexes, muscle strength and tone, joint perception, pedal pulses, and ankle brachial index (ABI). Prevalence of clinical neuropathy ranged from 0% to 57.1% with a prospective cohort study reporting a 2.6-fold increase in 5 years, while prevalence of vascular complications ranged from 0% to 37.8%. The meta-analysis reported 0%-7% of children could report abnormality on assessments for neuropathy. Conclusion: The broad range may be due to heterogeneous methodological designs and diagnostic assessments, and potentially inadequate reporting. There is emerging evidence that children with diabetes may develop complications before age 18, which provides impetus for clinical caution. Higher quality evidence, particularly from longitudinal studies, is required to guide clinical screening for lower limb vascular and neurological complications in this vulnerable and growing paediatric population.

Background: Distress is one of the most common negative emotions in parents of children and adolescents diagnosed with type 1 diabetes (T1D). Because of the differences in the developmental stages between children and adolescents with T1D and their subsequent diabetes management needs, their parents may experience different levels of distress. This study aimed to compare diabetes-specific distress between parents of children with T1D and parents of adolescents with T1D in China and explore the associated factors. Methods: A cross-sectional design was used. Parents of children (aged 8-12 years) and adolescents (aged 13-18 years) diagnosed with T1D for >6 months were recruited online via social media. Using established online questionnaires, data were collected on sociodemographic and T1D-related characteristics, diabetes-specific distress, anxiety symptoms, perceived stress, depressive symptoms, and parent-child conflict. Hierarchical linear regression was conducted to explore the potential factors associated with parental diabetes-specific distress. Results: The final sample included 365 parents of children with T1D and 268 parents of adolescents with T1D. Notably, the parents of children with T1D exhibited a higher level of diabetes-specific distress compared to the parents of adolescents with T1D (p  < 0.001). Among the parents of children with T1D, higher parental diabetes-specific distress was associated with fathers with 9 years or less of education, higher annual family income (≥US$2857), higher levels of parental anxiety symptoms and perceived stress, and children's episodes of frequent hypoglycemia in the past 6 months (F = 8.497, p  < 0.001, R ² = 0.433, adjusted R ² = 0.382). Among the parents of adolescents with T1D, higher parental diabetes-specific distress was associated with fathers with 9 years or less of education and higher levels of parental anxiety symptoms and perceived stress (F = 4.955, p  < 0.001, R ² = 0.385, adjusted R ² = 0.308). Conclusions: The parents of children with T1D experienced higher levels of diabetes-specific distress than the parents of adolescents with T1D in China. Fathers with 9 years or less of education and parents with more anxiety and perceived stress were particularly affected in both groups; thus, interventions are warranted.