BACKGROUND:Pediatric hypoglycemia has heterogeneous, age-dependent causes. Both growth hormone (GH) deficiency and adrenal insufficiency (AI) may present with hypoglycemia; AI can lead to fatal adrenal crisis. OBJECTIVES:To assess cortisol and GH responses to spontaneous hypoglycemia and determine the prevalence of AI (cortisol <500 nmol/L). METHODS:Retrospective cohort of 133 children (1992-2022) with laboratory glucose ≤50 mg% during hypoglycemia. RESULTS:In critical samples (CS), cortisol <500 nmol/L was observed in 51.1% (n=68) and <276 nmol/L in 23.3% (n=31). AI was ultimately diagnosed in 5 patients (3.7%): four with multiple pituitary hormone deficiency and one with primary AI. Children with CS cortisol <500 nmol/L had higher median CS GH than the rest of the cohort (7.6 vs. 3.7 ng/mL, p<0.001) and more frequent detectable insulin (53.3% vs. 35.6%, p=0.052), with no other clinical or biochemical differences. CS cortisol correlated with fasting-test nadir cortisol (r=0.574, p<0.001) and Synacthen-stimulated cortisol (r=0.448, p=0.004), but not with age (r=0.026, p=0.765) or CS glucose (r=0.025, p=0.802). CS cortisol was inversely associated with CS insulin (r=-0.242, p=0.009). A CS GH <7.5 ng/mL was present in 56.9% of patients. CS GH showed inverse associations with age (r=-0.489, p<0.001) and glucose (r=-0.332, p<0.001), but not with height-SDS or weight-SDS (r=-0.046, p=0.694; r=-0.021, p=0.819). CONCLUSIONS:Blunted cortisol responses to spontaneous hypoglycemia in children are frequent, whereas AI is rare. In the absence of a reliable clinical discriminator, Synacthen testing is indicated. Suboptimal growth hormone responses are also common, and further assessment should be guided by clinical judgment.

Introduction:We investigated the role of SIRT1 in linear growth and bone structure, focusing on the response of the epiphyseal growth plate (EGP) to nutritional manipulation. Methods:A ColX-Cre driver was used to target hypertrophic chondrocytes (HZ), and generate hypertrophic specific Sirt1 knockout (CKO) mice. Results:We found that Sirt1 deletion in hypertrophic chondrocytes markedly impaired growth in males, with a 33% reduction in body weight and 10-11% shorter long bones and EGP height (P<0.05). In females, effects were milder (12% reduction in weight, 5-7% shorter long bones; P<0.05 in both) but EGP height was reduced similarly to the males. These mice were next tested in a catch-up (CU) growth model involving food restriction followed by refeeding. Under CU conditions, male CKO mice showed an unexpected exaggerated response, surpassing the weight and bone length of normally fed CKO. Discussion:We therefore conclude that targeted Sirt1 deletion in the hypertrophic zone revealed a strong sex-dependent effect on skeletal growth and bone quality. Both male and female CKO mice exhibited growth impairment under normal conditions compared to littermate control (CTL), however while male showed hyper-responsiveness to refeeding, females CKO showed only moderate alterations. This targeted approach uncovers sex-dependent role for SIRT1 in regulating growth and bone quality, moving beyond its generally understood functions in cartilage and bone development. The distinct responses to both basal conditions and nutritional stress between sexes represent a significant new finding, extending its known role beyond general cartilage and bone development.

The ability to reduce the risk of developing diabetic ketoacidosis (DKA) remains a major care gap for people with diabetes, particularly those on intensive insulin therapy. The anticipated availability of continuous ketone monitoring (CKM) has the potential to reduce the risk of developing DKA, one of the most life-threatening acute complications of type 1 and type 2 diabetes. International clinical guidelines have established ketone thresholds for suspected and confirmed diagnoses of DKA, based on use of point-of-care testing, as part of a triad of markers with allied thresholds for hyperglycaemia and acidosis. The increasing occurrence of euglycemic DKA, with glucose concentrations below established diagnostic thresholds, makes the availability and use of CKM technology an important addition to the diabetes management toolkit. CKM data could alert the user when the risk of acute DKA is high on sick days in addition to signalling that individuals might be predicted to be at greater overall risk of future DKA on the basis of the distribution and degree of ketone measures in daily life. If widespread use of CKM devices is to be safe and effective in reducing the occurrence of DKA, it is important to establish clear ketone thresholds which notify CKM users when action on their part is required. In defining these thresholds and actions, it was important to ensure that the CKM user is not exposed to avoidable anxiety or suffers alarm fatigue, thus adding to the burden of living with diabetes. In the absence of substantial evidence that can identify appropriate ketone thresholds for CKM use, a panel of international experts in the management of DKA was convened with the aim of developing a number of objective, practical recommendations on how this novel diabetes technology could improve outcomes for individuals at risk of DKA, the results of which we report in this Personal View. These recommendations have been endorsed by the International Society for Pediatric and Adolescent Diabetes (ISPAD).

Among the most impactful therapeutic advances in the management of diabetes over the past two decades has been the development of incretin-based therapies, specifically glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and in combination with glucose-dependent insulinotropic polypeptide (GIP) RAs. Since the introduction of exenatide in 2005, a growing number of these drugs has transformed the management of type 2 diabetes (T2D). Their pleiotropic effects include weight loss, reduced insulin resistance, improved glucose regulation, and reductions in known risk markers for diabetic kidney disease and cardiovascular disease. To date, these important noninsulin glucose-lowering therapies have only received regulatory approval for use in T2D, obesity, sleep apnea, and metabolic dysfunction-associated steatohepatitis with moderate-advanced fibrosis, supported by randomized controlled trials (RCTs) and real-world data that demonstrate efficacy and safety. Regulatory approval for use of weekly GLP-1 and GLP-1/GIP RAs in type 1 diabetes (T1D) has not yet been achieved, in part because of the limited number of inconsistent, small-scale, RCTs and real-world studies for glycemic impacts of these agents in T1D. Larger RCTs are ongoing or planned in participants with T1D. Potential safety risks include hypoglycemia and hyperglycemia-related ketosis in T1D after initiation of GLP-1/GIP RA drugs. While RCTs are ongoing to further investigate GLP-1 and GLP-1/GIP RA agents as adjunct therapy for people with T1D, access to these drugs is already possible, based on their use to treat overweight and obesity. However, without regulatory approval for the T1D indication, access and opportunities for people with T1D to engage with important education regarding the safety of GLP-1 and GLP-1/GIP RA therapy may be limited. This precludes support from diabetes health care professionals to optimize diabetes management of these agents alongside expected insulin dose changes. The purpose of this consensus report is to review the current literature and provide guidelines for diabetes clinicians and people with T1D to facilitate the safe use of GLP-1/GIP RAs in the management of T1D. This consensus statement has been endorsed by the following professional associations: Advanced Technologies & Treatments for Diabetes (ATTD), International Diabetes Federation-Europe, American Association of Clinical Endocrinologists (AACE), Breakthrough T1D, International Society for Pediatric and Adolescent Diabetes (ISPAD), Association of Diabetes Care and Education Specialists (ADCES).

OBJECTIVE:Daily growth hormone (GH) injections restore normal growth and improve psychological outcomes in children with idiopathic short stature (ISS) but treatment burden is significant. The objective of this study is to demonstrate efficacy and safety of once-weekly somapacitan, a long-acting GH, in children with ISS. DESIGN:REAL8 (ClinicalTrials.gov: NCT05330325) is a global, randomized, open-labelled, active-comparator, phase 3 basket study including 4 non-GH deficiency indications comprising a 52-week main phase and 104-week extension. Here, we present 52-week results from the REAL8 ISS study. METHODS:Eighty-eight pre-pubertal, treatment-naive children with ISS at clinics in 20 countries were randomized 2:1 to somapacitan .24 mg/kg/week or daily GH 0.050 mg/kg/day, both administered subcutaneously. Eighty-five children completed the main 52-week treatment period. RESULTS:Observed mean height velocity, HV, (SD) at week 52 was 10.2 (1.7) and 10.6 (1.6) cm/year for somapacitan and daily GH groups, respectively (estimated treatment difference [ETD]: -0.3 cm/year [-1.00;0.42]95%CI, non-inferiority confirmed). Safety profiles were similar (somapacitan: 191 events in 47 (79.7%) participants, daily GH: 87 events in 22 (78.6%) participants) with most adverse events (AEs) mild and unlikely related to study product. Disease and treatment burden questionnaires presented favourable results. CONCLUSIONS:Similar efficacy and safety were confirmed for once-weekly somapacitan versus daily GH in treatment-naïve children with ISS, with favourable patient-reported outcome measures, setting the ground for future treatment for ISS with a once-weekly option. CLINICAL STUDY REGISTRATION:NCT05330325.

INTRODUCTION AND OBJECTIVE:Understanding the relationship between hemoglobin A1c (HbA1c) and continuous glucose monitoring (CGM)-derived Glucose Management Indicator (GMI) is essential for accurate glycemic assessment. This study evaluates the correlation between paired capillary HbA1c and GMI across different assessment periods and identifies factors associated with significant discrepancies. METHODS:This retrospective observational study included 270 youth with type 1 diabetes (mean age 15.85 ± 5.99 years, 56% male, median HbA1c 7.4% (interquartile range: 6.7-8.1). Capillary HbA1c and CGM data obtained during the same clinical visit were analyzed to assess discrepancies between measured HbA1c and GMI values, calculated using 14, 30, and 90 days of CGM data. For each individual, two paired measurements were collected over time. RESULTS:Across paired measurements, 37.3% of individuals demonstrated a HbA1c-GMI discrepancy greater than 0.5%, while 11.8% exceeding a discrepancy of 1%. Discrepancies showed no significant correlation with age, sex, body mass index, and disease duration. Glucose-6-phosphate dehydrogenase deficiency, present in 1.9% of the cohort, was consistently correlated with discrepancies >1% in all measurements. A significant proportional bias was identified (β = 0.260, P < 0.001), with HbA1c underestimating GMI at lower values and overestimating at higher values. Among CGM metrics, mean glucose, GMI, and time in normal glucose (TING) (70-140 mg/dL) showed similar associations with HbA1c, whereas TIR showed a slightly lower magnitude of association. CONCLUSION:A significant number of participants exhibited discrepancies between HbA1c and GMI. This discrepancy was unrelated to CGM sampling duration and stable within individuals, suggesting intrinsic factors may contribute. HbA1c and GMI each reflect different aspects of glycemic control, and neither is sufficient alone. Combining HbA1c with CGM-derived metrics, such as TING, may provide a more accurate and comprehensive assessment of glycemic exposure.

BACKGROUND:Novel advances in food technology enable the production of foods with significantly reduced sucrose without the use of additives. We tested the glycemic response of subjects with Type 1 Diabetes (T1D) to a novel sucrose-reduced chocolate spread, as well as its acceptance and palatability. METHODS:A randomized, double-blind, crossover, active-controlled trial comparing the glycemic response to two test-meals: 20 grams of the sugar-reduced spread (1.6 grams sucrose), and 20 grams of control chocolate spread, (11 grams sucrose) in people with T1D. RESULTS:Thirty adults (50% males), aged 18-28 years (mean 23.0 ± 3.0), mean HbA1C of 55 ± 9 mmol/mol (7.2 ± 0.9%) were recruited. Postprandial glucose (PPG) excursions were significantly lower following consumption of the study spread compared to the control spread: pre-meal to peak glucose difference (mean 25.8 ± 34.9 mg/dL lower, P < 0.001), postprandial CGM iAUC (mean 2271 ± 3789 min×mg/dL, P = 0.003). Median time in range was higher for the study versus control spread (100% and 64.6%, respectively, P = 0.030). In the sweetness scale questionnaire, the study spread rated higher than the control ("right degree of sweetness" 53.3% and 26.7% respectively, P < 0.001). CONCLUSIONS:This new technology for producing sugar-reduced food is able to reduce PPG with a limited effect on palatability.

INTRODUCTION:Somatrogon is a once-weekly, long-acting growth hormone approved to treat children with growth hormone deficiency (GHD). This study evaluated the long-term efficacy and safety of once-weekly somatrogon in children with GHD following up to 3 years of treatment. METHODS:During the 12-month main study, patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week). Patients could then enter an open-label extension (OLE), wherein somatrogon-treated patients continued receiving somatrogon and somatropin-treated patients switched to somatrogon (0.66 mg/kg/week). Data to the end of the second year of the OLE (OLE year [Y] 2) are reported. Of the 222 patients who completed the main study, 212 entered OLE Y1 and 177 entered OLE Y2. RESULTS:Mean (SD) height velocity (HV) was 8.11 (1.84) and 7.91 (1.84) cm/year at OLE Y1 and Y2, respectively. Mean (SD) height SD score (SDS) was -1.42 (0.90) and -0.95 (0.84) in OLE Y1 and Y2, respectively. In OLE Y1 and Y2, mean change in height SDS (ΔHSDS) was 1.36 and 1.61, respectively, and mean insulin-like growth factor I (IGF-I) SDS remained >1, confirming the efficacy of the treatment. Patients who switched from somatropin to somatrogon had similar HV, height SDS, and ΔHSDS to those who received somatrogon continuously. The incidence of adverse events (all causality) was 71.7% and 72.3% in OLE Y1 and Y2, respectively; most were mild or moderate in severity. Injection site pain and injection site erythema were the most commonly reported treatment-related adverse events in the OLE period. In OLE Y1 and Y2, up to one quarter of patients had IGF-I SDS >2 at two consecutive assessments, meeting protocol criteria for dose reduction. CONCLUSION:Following up to 3 years of somatrogon treatment, children with GHD showed a persistent increase in linear growth velocity compared to baseline. Somatrogon was well tolerated, with no new safety signals identified.

OBJECTIVE To characterize the distribution of time in tight and broader glycemic ranges in adults without diabetes, and to examine cross-sectional and longitudinal associations with metabolic health. RESEARCH DESIGN AND METHODS We analyzed continuous glucose monitoring data from 8,687 adults (40–70 years, 54% women) in the Human Phenotype Project, each contributing 1,149 ± 279 glucose readings from FreeStyle Libre Pro sensors. Age- and sex-adjusted correlations linked time-in-range metrics with 45 clinical phenotypes encompassing adiposity, vascular and liver markers, sleep indices, and nutrition. Cox models tested associations of time above glycemic thresholds with incident metabolic disease over 2.6 ± 1.3 years. RESULTS Participants spent a median 93.0% (IQR 91.8–98.2%) of CGM time within 70–140 mg/dL and 95.2% (IQR 95.1–99.8%) within 70–180 mg/dL. Time below 140 mg/dL and 180 mg/dL were 97.7% (IQR 97.6-97.8%) and 99.9% (IQR 99.9-99.9%) respectively. Lower time <140 mg/dL correlated with higher waist circumference, visceral fat, triglycerides, blood pressure, serum ALT, and liver attenuation, and with lower HDL cholesterol and mean nocturnal SpO₂. Associations weakened using the <180 mg/dL threshold. Lower time <180 mg/dL and <140 mg/dL were associated with higher risk of incident metabolic disease (HR 1.21 [1.15–1.26] and 1.34 [1.26–1.42], respectively). CONCLUSIONS We provide population references for time spent in different glycemic ranges by adults without diabetes. Although our study is observational and not designed to establish causality, our findings suggest that even within normoglycemic ranges, less time < 140 mg/dL is associated with unfavorable health parameters and higher incident metabolic disease risk.

A panel of experts in the use of continuous glucose monitoring (CGM) data in the treatment of diabetes met in Burlingame, California on October 27, 2025 to discuss the utility of the glycemia risk index (GRI) for clinical care research and population health management. The GRI composite metric is a single number (on a 0-100 percentile scale-lower is better) based on an expert-determined weighting of the seven individual components in the existing ambulatory glucose profile (AGP). The GRI describes the quality of glycemia based on glucose values collected in a 14-day CGM tracing, thus providing additional insights into CGM profiles beyond the AGP. During the meeting, the mathematical derivation of the GRI metric was presented along with its use for adult and pediatric individuals with diabetes and cancer who require medications that can adversely affect the glucose concentration. Examples where the GRI provided useful insights into the quality of CGM tracings were also discussed by the expert panel. In addition, a new smartphone application, the GRI Calculator, was presented. This app calculates the GRI of a CGM tracing and provides visualization of sequential CGM tracings for a specific individual. The GRI provides a reference measurement for the accuracy of artificial intelligence (AI) models assigning levels of glycemic quality to CGM tracings intended to match the assessments of clinicians. The GRI is now part of the data visualization panel for the Integration of Connected Diabetes Device Data into the Electronic Health Record (iCoDE-2) project, which standardizes both CGM and insulin dosing data. Further exploration of the potential value of the GRI for non-insulin users needs to be undertaken. The panel unanimously recommended that CGM manufacturers and developers of data visualization software for CGMs add the GRI to their data platforms for insulin users.

Introduction: Despite improvement in diabetes management, many adolescents with type 1 diabetes (T1D), especially those with disordered eating behaviors (DEB), struggle to reach glycemic targets and have higher HbA1c levels. We aimed to evaluate HbA1c and DEB trends in adolescents with T1D following insulin pump implementation. Methods: This prospective longitudinal study, with 12 months follow-up, included adolescents (n = 38) with T1D aged 10-20 years, who were assessed at baseline (prior to insulin pump implementation), and at 2-, 6-, and 12-months post-implementation. Data were collected from medical charts and self-reported questionnaires. Results: HbA1c and DEB levels showed no significant changes over time. However, adolescents with DEB consistently had higher HbA1c levels than those without (p = 0.003). Both HbA1c and DEB were elevated in adolescents with body dissatisfaction, particularly those desiring thinner bodies (p = 0.012 and p < 0.001, respectively). HbA1c trends varied by insulin delivery method (p = 0.005), with the greatest reduction observed in users of hybrid closed-loop (HCL) systems (p = 0.04). Conclusions: Despite insulin pump implementation, no significant overall changes were observed in HbA1c or DEB levels across the study period. However, adolescents using HCL systems showed reduced HbA1c, while levels remained elevated among those with DEB. Both HbA1c and DEB were higher in adolescents with body dissatisfaction, particularly those desiring thinner bodies. These findings highlight the need for targeted support during the adoption of diabetes technologies. Larger studies are warranted to guide effective interventions for this high-risk population.

AIMS:Type 1 diabetes (T1D) exhibits age-dependent autoimmune heterogeneity. We examined islet autoantibody (IA) profiles at the time of childhood diagnosis and their clinical significance. METHODS:We analyzed IA status at diagnosis in a large population-based cohort of children with newly diagnosed T1D. The participants were stratified by age at diagnosis (1-6, 6-12, and > 12 years), and the number and combinations of IA were examined in relation to age and clinical presentation. Group comparisons were performed using appropriate statistical tests. RESULTS:Pronounced age-dependent heterogeneity in IA profiles was observed. Younger children were significantly more likely to present with multiple autoantibodies, frequently including insulin autoantibody (IAA), whereas older children were more commonly single-autoantibody positive, predominantly glutamic acid decarboxylase (GADA). Age-related patterns were observed in specific autoantibody combinations. Single-autoantibody positivity was not associated with milder clinical presentation, and metabolic severity at diagnosis was largely independent of the number or combination of autoantibodies. CONCLUSIONS:IA profiles at diagnosis demonstrate marked age-dependent heterogeneity with significant clinical meaning. Single-autoantibody positivity and antibody negativity were common, particularly among older children. Age-informed interpretation of autoantibody status is essential and has implications for clinical assessment and population-based screening strategies.

We describe continuous glucose monitoring (CGM) trajectories in five children with stage 2 type 1 diabetes treated with teplizumab in a real-world setting. Participants were followed longitudinally using CGM metrics, including glycemic variability (GV) and time above 140 mg/dL. Over 8-19 months of follow-up, four participants remained in stage 2, while one progressed to stage 3 diabetes within 4 months of treatment. CGM-derived metrics demonstrated heterogeneous trajectories. Most participants showed stabilization or improvement in GV and time above 140 mg/dL within 3-6 months, whereas the progressor exhibited increasing variability and worsening glycemic excursions over time. These changes were detectable early and were not paralleled by substantial changes in glycated hemoglobin. These observations suggest that CGM may capture early directional changes in glycemic dynamics following immunomodulatory therapy and may provide a practical approach for longitudinal monitoring. Findings should be interpreted as hypothesis-generating and require validation in larger cohorts.

CONTEXT:Over the past two decades, management of pediatric Graves' disease (GD) has shifted toward prolonged antithyroid drug therapy. Yet, longitudinal data describing how these changes have influenced long-term outcomes remain limited. OBJECTIVE:To examine secular trends in presentation, treatment strategies, and long-term outcomes of pediatric GD over a 25-year period at a tertiary center. DESIGN AND SETTING:A retrospective cohort study of children diagnosed with GD between 1999 and 2024. PARTICIPANTS:128 children (79.7% female), median age 13.8 years (IQR 10.0-15.6), median follow-up 6.0 years (IQR 3.3-10.4). MAIN OUTCOME MEASURES:Temporal changes in initial therapy, methimazole (MMI) dosing, definitive therapy radioactive iodine (RAI) ablation or thyroidectomy, remission and relapse rates, and treatment-related adverse events. RESULTS:Initial management shifted exclusively to MMI, with discontinuation of propylthiouracil (PTU) after 2009 (P < 0.001). Median initial MMI dose declined progressively over the study period from 30 mg/day in 1999-2004 to 10 mg/day in 2015-2020 (P < 0.001 for the trend), with a parallel reduction in weight-adjusted dosing from 0.59 to 0.32 mg/kg/day (P < 0.001 for trend). Similarly, the use of RAI decreased steadily across calendar periods, from 55.6% in 1999-2004 to 9.8% in 2020-2024 (P < 0.001 for trend). Remission and remission with relapse rates did not differ significantly across calendar periods. Lower FT4 levels at diagnosis were marginally associated with remission (B=0.41, SE=0.22, P=0.06). MMI-related AEs occurred in 20.3% of patients, with severe events in 1.6%. CONCLUSIONS:Over 25 years, pediatric GD management evolved toward lower-dose, prolonged MMI therapy with a marked decline in definitive treatment. These secular changes were not associated with worsening remission or relapse rates, supporting the feasibility of a sustained conservative approach without evidence of inferior long-term outcomes.