Natalie Segev

Youth-onset type 2 diabetes (T2D) is increasing, prompting expanded use of pharmacotherapies previously approved only for adults. Sodium–glucose cotransporter-2 (SGLT2) inhibitors, approved for pediatric use in 2023, improve glycemic control by promoting glucosuria, but they carry a known risk of euglycemic diabetic ketoacidosis (DKA) in adults. We describe a unique pediatric case of SGLT2 inhibitor–associated euglycemic DKA in a 12-year-old female with T2D. The patient developed DKA with normal glucose shortly after initiating an SGLT2 inhibitor, leading to diagnostic uncertainty and recognition only after exclusion of more common etiologies. She was successfully treated with intravenous insulin and fluids with resolution of DKA and subsequently transitioned to subcutaneous insulin therapy. This case underscores that euglycemic DKA can occur in youth receiving SGLT2 inhibitors, particularly during puberty when physiologic insulin resistance may heighten risk, and that subtle presentations can complicate early recognition if clinicians rely on hyperglycemia alone. As SGLT2 inhibitors enter broader pediatric use, heightened diagnostic vigilance, guided assessment of ketones and acid–base status in symptomatic patients, and patient and family education are essential to ensure safe use in children and adolescents with T2D.

Aim: Youth‐onset type 2 diabetes and obesity are rising public health burdens. While newer type 2 diabetes medications lower HbA1c, their impact on paediatric weight loss is inconsistent. In contrast, bariatric surgery improves glycemia and weight in youth and adults, though glycemia post‐vertical sleeve gastrectomy (VSG), now the predominant bariatric surgery in youth, remains unstudied in youth‐onset type 2 diabetes. We aimed to assess immediate post‐VSG glycemic patterns using continuous glucose monitoring (CGM) in adolescents with type 2 diabetes. Materials and Methods: In the Surgical or Medical Treatment for Paediatric Type 2 Diabetes (ST ₂ OMP) study, 73 adolescents with type 2 diabetes underwent 14 days of CGM monitoring: 33 participants beginning in the 1–2 days post‐VSG (mean age 17.6 years, 67% female, HbA1c 7.2%, BMI 50.0 kg/m ² ) and 40 participants receiving advanced medical therapy (AMT) (mean age 16.9 years, 53% female, HbA1c 7.8%, BMI 42.2 kg/m ² ). CGM analyses included glucose management indicator (GMI), time in range, coefficient of variability, standard deviation, mean amplitude glycemic excursion, percent > 140, 180, and 200, percent < 70 and 60 mg/dL, 7 a.m., and midnight‐6 a.m. Results: Mean glucose was 84.3 ± 23.4 in the post‐VSG group versus 149.8 ± 78.8 mg/dL in the AMT group ( p < 0.001). Mean CGM GMI was normal (5.3%, 34 mmol/mol) post‐VSG versus in the diabetes range (6.9%, 52 nmol/mol) with AMT ( p < 0.001). VSG participants spent more time < 70 mg/dL, 55 mg/dL, and 45 mg/dL (all p < 0.01). After BMI adjustment, preoperative HbA1c predicted postoperative glucose metrics. Conclusion: Adolescents with type 2 diabetes experience early glycemic normalization post‐VSG, even before major weight loss.

Generalized glucocorticoid (GC) resistance (Chrousos syndrome) results from impaired GC receptor signaling due to variants in the NR3C1 gene. Severe neonatal presentations are extremely rare. We report an 8-week-old male infant born at 31-week gestation, with progressive respiratory failure, refractory hypotension, hypokalemic alkalosis, anasarca, jaundice, and multiorgan dysfunction. Laboratory evaluation demonstrated persistently elevated serum cortisol [>60 µg/dL (SI: >1655 nmol/L) (reference range 2.5-9.1 µg/dL, SI: 69.0-251.0 nmol/L)], adrenocorticotropic hormone [>2400 pg/mL (SI: >528 pmol/L) (reference range 7.2-63.3 pg/mL, SI: 1.6-13.9 pmol/L)], aldosterone [2036.0 ng/dL (SI: 56 nmol/L) (reference range 7.0-99.0 ng/dL, SI: 0.2-2.7 nmol/L)], and androgens despite treatment with escalating doses of dexamethasone (up to 12 mg, > 2000 mg/m2/day of hydrocortisone-equivalency). Whole-genome sequencing identified 2 NR3C1 variants: a maternally inherited variant of uncertain significance (c.2181+5 G>C) and a de novo likely pathogenic ∼7.9 kb deletion encompassing exon 8. In silico analyses suggested both variants could disrupt the GC receptor ligand-binding domain, potentially resulting in complete loss of GC receptor function. Autopsy demonstrated adrenomegaly with marked proliferation of zona fasciculata, cholestasis with bile duct paucity, and chronic neonatal lung disease. This case represents a rare and fatal manifestation of complete generalized GC resistance. It highlights the broad physiological role of GC in neonatal homeostasis.

Paediatric metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease in children and adolescents worldwide and is increasing alongside rising rates of paediatric obesity and type 2 diabetes. Paediatric MASLD most often arises in the setting of obesity and metabolic dysfunction but can occur without obesity and is influenced by early life exposures, genetics and environmental factors. Paediatric MASLD and youth-onset type 2 diabetes are tightly linked given the shared and bidirectional pathophysiological mechanisms. Hepatic steatosis often develops early in the course of insulin resistance, even in preschool-age children. Epidemiology in children varies by sex and ancestry and carries major prognostic implications, with a higher MASLD prevalence in male and Hispanic youth, more severe liver disease when MASLD coexists with impaired glucose tolerance or type 2 diabetes, and an alarming increased risk of mortality in late childhood and young adulthood. Paediatric MASLD is distinct from adult disease, with 20-25% of affected youth demonstrating clinically significant fibrosis on histology, distinct periportal (zone 1) patterns unique to childhood disease, and more severe liver histology in those with impaired glucose tolerance or diabetes. Early life determinants, such as maternal obesity and diabetes, are associated with childhood steatosis beginning early in life. Further, puberty represents a critical window of vulnerability, as physiological insulin resistance, sex-specific effects of androgens, and obesity-related metabolic stress drive sharp increases in both MASLD and youth-onset type 2 diabetes, with distinct sex differences in prevalence and severity. Current management for MASLD in paediatrics is evolving, relying primarily on lifestyle modification and targeted screening but with emerging evidence supporting the benefits of glucagon-like peptide-1 receptor agonists and bariatric surgery in selected youth with obesity, type 2 diabetes and related comorbidities, underscoring the urgent need for paediatric-specific therapeutic trials.

Objective: Pediatric prediabetes is common among youth with obesity, yet most do not progress to type 2 diabetes, and many regress to normoglycemia. Youth-onset type 2 diabetes has a severe course not well predicted by degree of adiposity or hemoglobin A1c (HbA1c) alone. This study used continuous glucose monitoring (CGM) to characterize glycemic patterns in youth with prediabetes and to determine whether baseline CGM metrics identify those at highest risk for HbA1c progression over 6 months. Research Design and Methods: Youth aged 10–18 years with obesity and HbA1c 5.7%–6.4% were enrolled in a prospective 6-month observational cohort study, with baseline and follow-up assessments including HbA1c and 14 days of CGM wear. CGM metrics were derived using the R iglu package. Changes over time and associations with follow-up HbA1c and HbA1c change were analyzed using paired t -tests and PRESS-based forward-selected linear regression models, adjusting for clinical covariates. Results: Among 29 youth with prediabetes, HbA1c and most CGM metrics remained stable over 6 months, with 32% regressing to normoglycemia. One participant progressed to HbA1c 6.5% who demonstrated markedly elevated baseline CGM glycemic variability and hyperglycemia. While multiple baseline CGM metrics were associated with follow-up HbA1c and HbA1c change in univariable analyses, PRESS-based multivariable models identified time spent above 140 mg/dL as the strongest and only consistent independent predictor of both higher follow-up HbA1c and worsening glycemic trajectory. Conclusions: CGM metrics outperformed HbA1c in predicting short-term glycemic progression in youth with prediabetes, supporting CGM as a promising adjunctive tool for early risk stratification.

Tyrosine kinase inhibitors that target vascular endothelial growth factor receptor [VEGFR-TKI] are a class of targeted therapies approved for treatment of several malignancies and are increasingly used in the pediatric population. Development of hypothyroidism during VEGFR-TKI therapy is well described in adults; however, there are no available data in children. Importantly, hypothyroidism during childhood can negatively impact growth and neurodevelopment. This retrospective study is the first to document frequency and severity of VEGFR-TKI induced hypothyroidism in pediatric and young adult patients. Patients included were ≤25 years of age and treated with at least one VEGFR-TKI between 2010 and 2018 at Cincinnati Children’s Hospital Medical Center. After review of clinical and demographic data, 69 patients were identified. Of these, 19 (27.5%) developed thyroid dysfunction defined as Thyroid-stimulating hormone≥5 mIU/mL during therapy. Twelve of those patients had overt hypothyroidism with documentation of low free thyroxine and/or levothyroxine initiation. Mean exposure time to VEGFR-TKI before thyroid dysfunction was 2.8 (0.5-10.4) months. These results suggest moderate risk of developing thyroid dysfunction during VEGFR-TKI therapy in pediatric and young adult patients. Baseline thyroid hormone screening should be performed and repeated frequently during the first year of therapy in the pediatric population.

Hyperglycemia is detrimental to postoperative islet cell survival in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT). This makes continuous glucose monitoring (CGM) a useful management tool. We evaluated the accuracy of the Dexcom G6 CGM in pediatric intensive care unit patients following TPIAT. Twenty-five patients who underwent TPIAT had Dexcom G6 glucose values compared to paired serum glucose values. All paired glucose samples were obtained within 5 minutes of each other during the first seven days post TPIAT. Data were evaluated using mean absolute difference (MAD), mean absolute relative difference (MARD), %20/20, %15/15 accuracy, and Clarke Error Grid analysis. Exclusions included analysis during the CGM “warm-up” period and hydroxyurea administration (known drug interference). A total of 183 time-matched samples were reviewed during postoperative days 2–7. MAD was 14.7 mg/dL and MARD was 13.4%, with values of 15.2%, 14.0%, 12.1%, 11.4%, 13.2% and 14.1% at days 2, 3, 4, 5, 6 and 7, respectively. Dexcom G6 had a %20/20 accuracy of 78%, and a %15/15 accuracy of 64%. Clarke Error Grid analysis showed that 77% of time-matched values were clinically accurate, and 100% were clinically acceptable. The Dexcom G6 CGM may be an accurate tool producing clinically acceptable values to make reliable clinical decisions in the immediate post-TPIAT period.