Objective: To evaluate inhaled technosphere insulin (TI) in children with diabetes. Research Design and Methods: Youth 4 to 17 years old with type 1 (98%) or type 2 (2%) diabetes treated with multiple daily injections of insulin were randomly assigned 1:1 to TI or rapid-acting analogue (RAA) insulin plus continuation of long-acting basal insulin and continuous glucose monitoring (CGM) for 26 weeks. The primary outcome was change in HbA1c, tested for non-inferiority with margin of 0.4%. Results: In intent-to-treat analysis, mean HbA1c was 8.22±0.87% at baseline and 8.41±1.38% at 26 weeks with TI and 8.21±0.96% and 8.21±1.10%, respectively, with RAA (adjusted difference = 0.18%, 95% CI -0.07 to 0.43, non-inferiority p-value = 0.091). CGM-measured time-in-range 70-180 mg/dL was not significantly different between groups (adjusted difference -2.2%, 95% CI -7.0% to 2.7%, p=0.38). Two severe hypoglycemic events occurred in the TI group and one in the RAA group. Change in forced expiration volume in one second (FEV1) from baseline to 26 weeks did not differ comparing TI and RAA (p=0.53). The TI group reported greater treatment satisfaction (p=0.004) and had less gain in weight and body mass index percentile (p=0.009) than the RAA group. Conclusions and Relevance: The primary analysis did not meet the pre-specified criteria for HbA1c non-inferiority. However, TI use was safe over 26 weeks without impacting pulmonary function and was associated with greater treatment satisfaction and less weight gain compared with RAA, supporting TI as a treatment option for some pediatric patients with type 1 diabetes.

OBJECTIVE:The adoption of continuous glucose monitors (CGMs) in inpatient settings in the pediatric population has been slow because of a scarcity of data on their reliability in hospitalized children. RESEARCH DESIGN AND METHODS:We retrospectively reviewed the accuracy of the Dexcom G6 CGM system in pediatric patients with diabetes admitted to our academic children's hospital from March 2018 to September 2023. We cross-referenced the Dexcom Clarity database against an internal database of inpatient admissions to identify all children with CGM data admitted to the hospital. We recorded sensor glucose readings from Clarity and values for point-of-care (POC) glucose, blood urea nitrogen (BUN), and pH from the electronic medical record. CGM accuracy and clinical reliability were measured by mean absolute relative difference (MARD) and Clarke error grid (CEG) analyses. RESULTS:There were 3,200 admissions of children with diabetes in this period, of which 277 (from 202 patients age 2-18 years) had associated CGM data. Paired CGM and POC measurements (n = 2,904) were compared, resulting in an MARD of 15.9%, with 96.6% of the values in zones A and B of the CEG analysis. Approximately 62% of paired values fell within a 15% or 15 mg/dL difference, whichever was larger (15%/15 mg/dL range), 74% within 20%/20, and 88% within 30%/30. Serum pH, sodium, and BUN had no impact on CGM values or absolute relative difference in linear regression analysis. CONCLUSIONS:CGMs demonstrated acceptable accuracy in hospitalized children with diabetes. CGM data should be integrated into hospital electronic records to optimize management.

Context Adverse outcomes (death or intensive care unit [ICU] stays longer than 48 hours) in children with diabetic ketoacidosis (DKA) or hyperglycemic-hyperosmolar syndrome (HHS) can be predicted by a composite risk score based on severity of hyperglycemia and acidosis, and presence of type 2 diabetes.Objective Because most high-risk patients nevertheless do not experience an adverse outcome, we tried to identify differences in management or other clinical characteristics that influenced outcomes.Methods In a previously defined group of 4565 admissions for DKA-HHS in 2010-2023, 109 had adverse outcomes. We conducted a nested case-control study using the composite risk score to match 84 cases from the adverse outcome group with an equal number of controls without or with briefer ICU stays of 0 to 24 hours.Results The groups did not differ in risk score or initial pH, maximum blood glucose, or proportion with type 2 diabetes. However, the case group had more patients with new-onset diabetes and higher initial serum sodium and blood urea nitrogen. The case group had slower resolution of hyperglycemia, acidosis, and hypernatremia. The groups did not differ in total administered fluid bolus volumes, total fluid volumes, or urine output at 12 and 24 hours. Total insulin received did not differ between groups after 12 hours, but cases were more likely to still require intravenous insulin at 24 hours.Conclusion Hypernatremia is more likely to be present at admission and to persist over the first 24 hours of treatment in children with DKA-HHS who have adverse outcomes. This is not associated with differences in management.

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Cystic fibrosis (CF), a genetic disorder caused by pathogenic variants in the CFTR gene, is associated with various complications including cystic fibrosis-related diabetes (CFRD). CFRD is an entity distinct from type 1 or type 2 diabetes. We report a rare case of diabetic ketoacidosis (DKA) in a pediatric patient with CFRD, occurring during a significant pulmonary exacerbation. The patient's management involved addressing fluid and electrolyte imbalances, careful monitoring of nutritional status, and correction of hyperglycemia with insulin. This case serves as a reminder to consider DKA in the differential diagnosis of patients with CF presenting with respiratory distress, even in the absence of typical symptoms such as polyuria and polydipsia.

Abstract Disclosure: P.C. White: Consulting Fee; Self; Neurocrine Biosciences, Inc.. Research Investigator; Self; Neurocrine Biosciences, Inc. G.P. Sen: Employee; Self; Neurocrine Biosciences, Inc. F. Tang: Employee; Self; Cytel. J. Chen: Employee; Self; PicnicHealth. K. Lin-Su: Advisory Board Member; Self; CARES Foundation. D. Matos: Employee; Self; CARES Foundation. H. Cheng: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. G.S. Jeha: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Patients with congenital adrenal hyperplasia (CAH) are exposed to excess androgens and glucocorticoids (GC), which can affect growth and lead to obesity and other metabolic complications. CAHtalog is an active US-based CAH registry developed in partnership with CARES Foundation on the PicnicHealth platform to abstract retrospective and prospective medical record data. This study reports auxological and comorbidity data for pediatric and adult patients in the CAHtalog registry. Methods: All available medical records for consented adult and pediatric patients were collected. Data were abstracted and structured into a de-identified dataset. CAHtalog data available as of October 2023 were included for analysis. Auxological data were compared to the 2000 CDC growth data. Changes in body mass index (BMI) since the first documented measurements were evaluated. Comorbidities were defined based on diagnosis codes (ICD-9/10), laboratory measurements, vital signs, and/or clinical notes. Results: Data from 32 adult (mean age: 35.8±12.7 years; 72% female) and 35 pediatric patients (mean age: 12.7±5.5 years; 51% female) were available. From the first through last medical record with relevant ages (≥18 or <18 years), median follow-up durations were 13 years (adult) and 11 years (pediatric). Pediatric patients had early growth acceleration (that was more pronounced in females) with 95% confidence intervals for height-for-age of 66-99th percentile for females (2-10 years) and 42-87th percentile for males (2-13 years), followed by blunted pubertal growth. The mean peak bone age to chronological age ratio was 1.2±0.2 at age 7 years. The mean BMI-for-age consistently exceeded the 90th percentile in children aged ≥6 years, particularly for females. In adults, obesity (BMI ≥30) was highly prevalent in both females (74%) and males (33%) at all ages (61% overall), exceeding NHANES 2017-2018 general population prevalence (42%). Hypertension (53%), fatigue (47%), acne (36%), hyperlipidemia (33%), and insomnia/sleep disturbances (28%) were common comorbidities. Conclusion: Our CAH data reveal a persistent abnormal growth pattern, characterized by accelerated growth in early childhood and a deceleration in adolescents; early obesity was noted and sustained into adulthood. The anomalous growth trajectory and high rate of comorbidities reiterate the importance of early intervention and targeted disease management in this population. Presentation: 6/2/2024

Objective: Develop a multivariable model to identify children with diabetic ketoacidosis (DKA) and/or hyperglycemic hyperosmolar state (HHS) at increased risk of adverse outcomes and apply it to analyze adverse outcomes during and after the COVID-19 pandemic. Methods: Retrospective review of clinical data from 4565 admissions (4284 with DKA alone, 31 [0.7%] only HHS, 250 [5.4%] hyperosmolar DKA) to a large academic children's hospital from January 2010 to June 2023. Data from 2010-2019 (N = 3004) were used as a training dataset, and 2020-2021 (N = 903) and 2022-2023 (N = 658) data for validation. Death or intensive care unit stays > 48 hours comprised a composite "Adverse Outcome" group. Risks for this composite outcome were assessed using generalized estimating equations. Results: There were 47 admissions with Adverse Outcomes (1.5%) in 2010-2019, 46 (5.0%) in 2020-2021, and 16 (2.4%) in 2022-2023. Eight patients died (0.18%). Maximum serum glucose, initial pH, and diagnosis of type 2 diabetes most strongly predicted Adverse Outcomes. The proportion of patients with type 2 diabetes was highest in 2020-2021. A multivariable model incorporating these factors had excellent discrimination (area under receiver operator characteristic curve [AUC] of 0.948) for the composite outcome in the training dataset, and similar predictive power (AUC 0.960 and 0.873) in the 2020-2021 and 2022-2023 validation datasets, respectively. In the full dataset, AUC for death was 0.984. Conclusion: Type 2 diabetes and severity of initial hyperglycemia and acidosis are independent risk factors for Adverse Outcomes and explain the higher frequency of Adverse Outcomes during the COVID-19 pandemic. Risks decreased in January 2022 to June 2023.

Introduction & Objective: Adolescents with Type 1 diabetes (T1D) have higher hemoglobin A1c (A1c) than other age groups. Poorly controlled diabetes increases the risk for diabetic ketoacidosis (DKA) and other diabetic complications. We hypothesized that real-time, remote, continuous glucose monitoring with real-time coaching via two-way text messaging will improve the A1c of adolescents with poorly controlled T1D. Methods: We are conducting a prospective, single-arm, pilot study. Phase 1 is a run-in phase using a continuous glucose monitor (CGM). Phase 2 consists of 3 months of real-time, remote, glucose monitoring (RTM) with two-way text messaging with a pediatric endocrinologist to provide coaching, glucose trend review and insulin dose adjustments. During the 3-month final phase, we assess A1c changes after cessation of RTM. We also follow psychosocial measures. Inclusion criteria include patients with T1D ages 13 to 18 years, with 30% annual risk of developing DKA or A1c ≥ 12%. Primary exclusion criteria include other types of diabetes and chronic conditions or use of glucocorticoids that affect glycemic control. Results: Nine participants began the RTM phase. One participant had a malfunctioning phone, which adversely impacted CGM data sharing. Therefore, the corresponding data were not included in the results. Average baseline A1c was 11.4%. Following 3 months of RTM, A1c improved by 0.7% (p = 0.15). Alc increased after cessation of RTM. Time in range improved an average of 1.8% during RTM but decreased during Phase 3. Participants with greater correspondence frequency with the monitoring physician had greater improvement in A1c (decreased by 1.6-3%). During the study, no participants were admitted for DKA. Conclusion: RTM and coaching improved the overall glycemic control of our pilot study participants. However, the improvement was not sustained without RTM. The level of return engagement might be associated with some level of improvement in A1c. Disclosure P. Choudhari: None. A. Marwa: None. P.C. White: Consultant; Provention Bio, Inc. Research Support; MannKind Corporation, National Institute of Diabetes and Digestive and Kidney Diseases. A. Choudhary: None. Funding Children's Medical Center Foundation Dexcom, Inc provided CGMs (External study number IIS-2020-076)

Objective: Innate immune responses may be involved in the earliest phases of type 1 diabetes. Research Design and Methods: To test whether blocking innate immune cells modulated progression of the disease we randomized 273 individuals with stage 1 type 1 diabetes to treatment with hydroxychloroquine (n=183, 5 mg/kg/d to a maximum of 400 mg) or placebo (n=90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e. two or more islet autoantibodies with abnormal glucose tolerance). Results: After median follow up of 23.3 months, the trial was stopped prematurely by the Data Safety Monitoring Board because of futility. There were no safety concerns in the hydroxychloroquine arm, including in annual ophthalmologic exams. Preplanned secondary analyses showed a transient decrease in the glucose average area under the curve to oral glucose in the hydroxychloroquine-treated arm at month 6 and a reduced titer of anti-GAD and anti-insulin autoantibodies and acquisition of positive autoantibodies in the hydroxychloroquine arm (p=0.032). Conclusions: We conclude that hydroxychloroquine does not delay the progression to stage 2 type 1 diabetes in individuals with stage 1 disease. Drug treatment reduces the acquisition of additional autoantibodies and the titers of autoantibodies to GAD and insulin.

Background: Management of diabetic ketoacidosis (DKA) in pediatric patients is well established, but optimal management for hyperglycemic hyperosmolar state (HHS) and mixed DKA/HHS is uncertain. Aims: Develop a model to identify patients at increased risk of adverse events and identify management differences associated with adverse outcomes. Methods: Retrospective chart review of 5,346 admissions from 3,104 unique patients with type 1 diabetes (T1D) or T2D at a large children’s hospital from 1/1/2010-7/1/2022 requiring IV insulin to manage DKA (pH <7.3, glucose > 200 mg/dl) and/or HHS (glucose >600 mg/dl). An ICU stay >48 hours (h) was a surrogate for severe adverse events. Risk of death or ICU stay >48 h (high risk [HR] group) was modeled using generalized estimating equations on a training dataset of 3,979 admissions from 2010-2019. Admissions 2020-2022 were the test dataset. Discrimination was assessed with receiver-operator-characteristic (ROC) curves. Using this predictive model, we selected a control (C) group at similar risk of adverse events to identify outcome-related management differences. Results: There were 810 ICU admissions; 90 were >48 h. There were 8 diabetes-related deaths, 5 in 2020-2022. In the multivariate model, risk factors for severe adverse events included initial pH, glucose, absolute value of the deviation of glucose-corrected serum Na from 140, and a diagnosis of T2D. Discrimination was excellent; area under the ROC curve was 0.938 and 0.964 in the training and test datasets respectively. HR and C groups were similar for pH, glucose and sodium on admission, but altered mental status was more frequent in the HR group. Glucose and sodium corrected more slowly in the HR patients. Conclusions: The prediction model accurately identified patients at increased risk of prolonged ICU stay or death. Rates of death and prolonged ICU stay increased during the Covid pandemic, correlated with more severe clinical presentation. Slower correction of metabolic abnormalities was associated with prolonged ICU stay. Disclosure M.Yousif: None. S.Adhikari: None. P.C.White: Consultant; Provention Bio, Inc.

Three disorders result from mutations involving two closely linked 11 beta-hydroxylase genes. Steroid 11 beta-hydroxylase deficiency results from mutations in CYP11B1. This is a form of congenital adrenal hyperplasia (CAH) characterized by hypertension and signs of androgen excess. Mutations in CYP11B2 cause aldosterone synthase deficiency, an isolated defect of aldosterone biosynthesis. Recombinations between these two genes cause glucocorticoid suppressible hyperaldosteronism, an autosomal dominant form of hypertension.

Background: Diabetes technology can improve glycemic control and diabetes outcomes, but there are disparities in patient use. Aims: Identify racial, ethnic, and socioeconomic disparities in technology utilization and determine provider, patient, and parent identified barriers to this. Methods: Technology (continuous glucose monitors [CGM] and pump) usage and demographic data on patients at a large urban pediatric hospital were obtained from a clinical database. Providers (physicians, nurse practitioners, diabetes educators [CDEs]) completed a survey on diabetes technology prescribing habits. English and Spanish speaking patients ages 8 to 17 years with type 1 or type 2 diabetes on insulin and their guardians completed patient and parent specific surveys that assessed attitudes and perceived benefits and burdens of diabetes technology. Responses (16 physicians, 11 CDEs, 109 patients, 117 parents) were analyzed with Kruskal-Wallis tests. Results: From August 2020-2021, independent of socioeconomic status, non-Hispanic Black (NHB) and Hispanic children were less likely to be prescribed pump (odds ratio 0.40 and 0.35 respectively) or CGM (0.50 and 0.49) compared to non-Hispanic White (NHW) children. For pump eligibility, CDEs placed higher importance on subjective factors such as parental education, health literacy, and psycho-social stability (p value < 0.05) compared to physicians. Hispanic and NHB patients and parents learned about diabetes technology later after diagnosis compared to NHW group. Physicians and CDEs identified patient perceived barriers to CGM use (i.e., embarrassment and/or discomfort in wearing devices) as reasons for not discussing technology, though patients did not identify such factors as barriers. Conclusions: There are marked disparities in diabetes technology use among youth with diabetes. Families and providers perceive different barriers to utilization. This study adds perspective of patients with T2D as well as targeted recruitment of underrepresented minorities. Disclosure P.Singh: None. E.Grishman: None. D.Naranjo: None. L.S.Hynan: None. P.C.White: Consultant; Provention Bio, Inc. O.Gupta: None.

Background. After-hours triage of pediatric patients by trained nurses improves consistency of triage decisions, access, and quality of care, and decreases burden on physicians on-call. There is a lack of published experience with this approach in the pediatric diabetes population. Methods. An after-hours call service was established in September 2019 in our large urban pediatric teaching hospital. Barton Schmitt guidelines, which are widely accepted as the standard for telephone triage care, were modified to include institution specific diabetes management protocols. We analyzed demographics, reasons for call, clinical presentation to the emergency room, and clinical disposition of the callers. Results. The after-hours call service handled 70% of calls without physician involvement. There were no patients triaged to home care who subsequently required an emergency room visit or hospitalization. Patients who called the after-hours nurse line prior to coming to the emergency room were less sick and were discharged more often from the emergency room. Spanish-speaking parents utilized the service less than English speakers. There were no disparities in utilization based on the insurance status or race. Conclusions. The after-hours service accurately triaged calls and reduced physician burden. Patients of all races and insurance statuses utilized the after-hours service equally well. Language was a barrier in the utilization.

The adrenal has played a major role in the history of pediatric endocrinology. Cases of congenital adrenal hyperplasia (CAH) were reported in the 19th century, leading to the understanding that the adrenal influenced sexual phenotypes as well as being mysteriously required for survival. Numerous adrenal steroids were isolated in the early 20th century, and bioassays eventually distinguished glucocorticoids, mineralocorticoids, and androgens. Treatment of CAH with cortisone in 1950 by Wilkins and by Bartter and Albright revolutionized clinical endocrinology and launched a productive era of pediatric adrenal research. Through careful clinical studies, Wilkins established the contemporary approach to treating CAH. Alfred Bongiovanni identified defective 21-hydroxylation in CAH in 1957, followed by deficiencies of 3β-hydroxysteroid dehydrogenase and 11β-hydroxylase. P450 enzymes were described in 1962–1964, and 21-hydroxylation was the first activity ascribed to a P450. Accurate assays for 17OH-progesterone in newborns and in response to ACTH permitted the diagnosis of CAH in children and families. Application of the techniques of molecular genetics elucidated genetic and biochemical bases of these disorders from 1984 to 2004. Pediatric endocrinologists played central roles in identifying the genes responsible for both common and rare forms of congenital adrenal hyperplasia and determining their most appropriate treatments.

PURPOSE OF REVIEW:Although the basic treatment of congenital adrenal hyperplasia (CAH) is well established, there are active clinical research projects to more closely mimic the normal diurnal rhythm of cortisol secretion and to reduce total glucocorticoid doses to minimize adverse metabolic effects.RECENT FINDINGS:We review clinical studies on CAH treatment published in the last 18 months or currently underway according to ClinicalTrials.gov listings. These can be grouped into several broad themes: alternative dosing forms of hydrocortisone with altered pharmacokinetics or easier dose titration; corticotropin-releasing hormone receptor antagonists that reduce corticotropin (ACTH) secretion and thereby reduce adrenal androgen secretion; androgen biosynthesis inhibitors; a first clinical trial of a gene therapy vector.SUMMARY:Alternative dosing forms of hydrocortisone are, or will shortly be, marketed, but cost may be a barrier to utilization, at least in the US market. Trials of corticotropin releasing hormone receptor antagonists and androgen biosynthesis inhibitors are currently underway. The author believes that trials of gene therapy for CAH are premature.