Ped endo journal scan

Stem cell-derived, fully-differentiated islets for type 1 diabetes

Reichman TW, Markmann JF, Odorico J, Witkowski P, Fung JJ, Wijkstrom M, et al., for the VX-880-101 FORWARD Study Group. N Engl J Med. 2025 Jun 20. doi: 10.1056/NEJMoa2506549. Online ahead of print.

Objective: Zimislecel (VX-880) is a treatment composed of allogeneic stem cell-derived, fully differentiated islets. This study reports interim data from a phase 1–2 study evaluating the effects of a single infusion of zimislecel in persons with type 1 diabetes who had recurrent severe hypoglycemic events and impaired awareness of hypoglycemia despite appropriate disease management.

Study Methodology and Results: VX-880-101 FORWARD (currently in phase 3) is an ongoing, open-label, 5-year study that is assessing the safety and efficacy of zimislecel. Persons 18–65 years of age who had type 1 diabetes with impaired awareness of hypoglycemia (defined by a reduced ability to perceive the onset of hypoglycemia), at least two severe hypoglycemic events in the previous year, and insulin dependence for at least 5 years were eligible. Part A was designed to assess the safety of zimislecel, and participants received zimislecel at a half dose of 0.4 × 10⁹ cells. Part B assessed safety and islet function, and part C further assessed safety and efficacy in additional participants, and a full dose of 0.8 × 10⁹ cells was infused. Induction immunosuppressive treatment was given before the infusion, and maintenance immunosuppressive treatment was given after the infusion.

The primary end point in part A was safety. The primary end point in part C was freedom from severe hypoglycemic events from day 90 through day 365 after zimislecel infusion, with a glycated hemoglobin level of <7% or a reduction of at least 1% point from baseline in the glycated hemoglobin level at one or more visits between day 180 and day 365. The secondary end points in part C were insulin independence at one or more visits between day 180 and day 365 after zimislecel infusion, a peak C-peptide level of at least 100 pmol/L during a 4-h mixed-meal tolerance test as assessed at each study visit, and safety.

Fourteen participants (2 in part A and 12 in parts B and C) who received zimislecel and completed at least 12 months of follow-up were included in the analyses. All participants had detectable fasting and stimulated C-peptide, suggesting islet engraftment. All 12 participants in parts B and C achieved the primary endpoint. At day 365, the mean reduction from baseline in the glycated hemoglobin level was 1.81% points. The mean time in the target glucose range improved to 93.3% (range, 79.5–96.9) at day 365. Ten of the 12 participants (83%) had insulin independence and were not using exogenous insulin at day 365. Two deaths occurred; one was due to serious cryptococcal meningitis following sinus surgery for base of skull injury, and the other was due to severe dementia with agitation due to the progression of preexisting neurocognitive impairment. Serious adverse events of neutropenia leading to extended hospitalization for observation occurred in three participants, and serious adverse events of acute kidney injury occurred in two participants.

Critical Review: This trial demonstrated that stem cell-derived islets engrafted, produced endogenous insulin, and restored the physiologic function of islets, leading to improved glycemic control, elimination of severe hypoglycemic events, and insulin independence in persons with type 1 diabetes. This is an important trial that explores a new source of beta-cell replacement therapy for patients with type 1 diabetes. Further investigation of this therapy in larger, longer studies involving diverse populations is warranted, with further analysis of safety in the long-term.

Phenotypic variation and pubertal outcomes in males and females with 46,XY partial gonadal dysgenesis

Tadokoro-Cuccaro R, Hughes IA, Cools M, van de Vijver K, Bilharinho de Mendonça B, Domenice S, et al. J Clin Endocrinol Metab. 2025 Apr 10: dgaf223. doi: 10.1210/clinem/dgaf223. Online ahead of print.

Objective: This study aimed to explore a large international dataset of patients to characterize clinical features of partial gonadal dysgenesis (PGD) using complete gonadal dysgenesis (CGD) as a comparator. The other aims of the study were to determine the outcome at puberty, including gonadal histology and function and the frequency of sex reassignment.

Study Methodology and Results: This was a retrospective study which collected data from the International-Differences in Sex Development (I-DSD) registry and 2 additional centers. Clinical, biochemical, radiological, genetic, and histological data were collated. Patients were assigned into three categories: CGD, PGD assigned female (PGDf), and PGD assigned male (PGDm) at birth. A total of 310 patients were included in the final analysis (CGD = 100, PGDf = 107, and PGDm = 103).

The individuals with CGD presented at the age 15.0 (8.4–17.9) years, with the majority (62.5%) complaining of delayed puberty. In contrast, individuals with PGD presented at a younger age (PGDf 1.3 [0.1–13.9] years; PGDm 0.5 [0.1–4.0] years) due to atypical genitalia in all patients with PGDm and 62.1% in PGDf. Delayed puberty was the presenting feature in 17.9% of PGDf patients, and it was associated with virilization in 8.4%. A high frequency of comorbidities was reported in all categories, with no significant differences between the groups (CGD 38.0%, PGDf 33.0%, and PGDm 33.3%). Examples of neurodiversity were the most frequent (CGD 28.9%, PGDf 21.3%, and PGDm 26.3%). The next most frequent group of comorbidities was renal disorders, including Wilms’ tumor, congenital proteinuria, and structural anomalies (CGD 23.7%, PGDf 12.8%, and PGDm 31.6%). There was no significant difference in basal serum testosterone levels in individuals with PGDm and PGDf. The follicle-stimulating hormone (FSH) levels were similar between PGDf and PGDm and above the reference range in all individuals with CGD, and 67.9% in PGDf and 64.7% in PGDm. Genetic screening was performed in 78.7% of the cohort and identified the likely genetic cause in 42.3%. The most frequent gene alterations in CGD were SRY (23.6%; n = 21/89) and WT1 (9.0%; n = 8/89). In PGD, alterations in NR5A1 were the most frequent finding (PGDf: 42.2%; n = 35/83; PGDm: 25.6%; n = 20/78). About 80% of PGDm with at least one retained gonad had spontaneous puberty (n = 36/45). Bilateral gonadectomy was performed in 93.6% of individuals with CGD (n = 88/94), and 75% (n = 75/100) of the individuals with PGDf, at ages 16.0 [13.1–18.3] years and 6.5 [1.6–15.1] years, respectively. Gonadal malignancy or premalignancy (germ cell neoplasia in situ) was reported in 33.7% (n = 28/83) in CGD, 19.7% (n = 13/66) in PGDf, and 8.8% (n = 3/34) in PGDm (CGD vs. PGDf, P = 0.066; CGD vs. PGDm, P = 0.005).

Critical Review: This is an important study that provides detailed characteristics of a large cohort of 46,XY PGD individuals and highlights the wide spectrum of this condition. It highlights that many PGD patients with preserved gonads have the potential to develop puberty spontaneously, though further study is needed to determine the risk of developing gonadal tumors.

Growth hormone excess in children with neurofibromatosis and optic pathway glioma, an underdiagnosed condition: experience with long-acting treatment

Casano-Sancho P, Molina PX, Valls A, Hector S. Eur J Endocrinol. 2025 Jun 4: lvaf113. doi: 10.1093/ejendo/lvaf113. Online ahead of print.

Objective: The objective of this study was to describe the prevalence of high levels of growth hormone (GH) in a cohort of pediatric neurofibromatosis type 1 (NF-1) patients and to report the results of administering long-acting somatostatin analogs (SSA) to children with NF-1, optic pathway glioma (OPG), and high GH levels.

Study Methodology and Results: This study describes seven NF-1 children with OPG and excess GH (GHE) who were treated with long-acting SSA (octreotide-long-acting release [LAR]). The diagnosis of NF-1 was made according to the criteria established by the National Institutes of Health Consensus Development Conference. The diagnosis of GHE was established based on the following criteria: Accelerated physical growth, high levels of insulin-like growth factor 1 (IGF-1 >1 standard deviation [SD]), and the absence of GH suppression during the glucose tolerance test (<1 ng/dL).

The first two patients were initially treated with short-acting SSA, which involved a single subcutaneous dose daily (1.5 µg/kg/day). After confirming efficacy and tolerability, the treatment regimen was changed to intramuscular long-acting SSA (Octreotide-LAR) (10 mg/28 days) and these and subsequent patients were treated with octreotide-LAR. After 3 months, six out of seven patients showed normalization of IGF-1 levels and growth velocity. Except for mild diarrhea, no other adverse events were observed among patients. Treatment could be withdrawn in all seven patients after 19.9 ± 4.6 months. One year after treatment, long-acting SSA (Octreotide-LAR) was discontinued; the median growth velocity was −0.08 ± 1.34 SD.

Critical Review: This is an interesting study which highlights the relatively unknown phenomenon of GH excess in children with NF-1-associated OPGs. The authors also report that treatment with long-acting SSA is an effective and safe option to normalize growth rates and IGF-1 levels. However, long-term effects on growth patterns and tumor stabilization need further elucidation in prospective follow-up studies.

Efficacy and safety of automated insulin delivery in children aged 2–6 years: An open-label, multicenter, randomized, and crossover trial

Battelino T, Kuusela S, Shetty A, Rabbone I, Cherubini V, Campbell F; LENNY study group. Lancet Diabetes Endocrinol. 2025 Jun 18:S2213-8587(25)00091-9. doi: 10.1016/S2213-8587(25)00091-9. Online ahead of print.

Objective: The objective of this study was to investigate the efficacy and safety of the MiniMed 780G system in children aged 2–6 years with a total daily insulin dose of at least 6 U.

Study Methodology and Results: This was a prospective, open-label, multicenter, and randomized crossover study, involving children with type 1 diabetes aged 2–6 years requiring at least 6 units (U) of insulin a day. Participants underwent a 2-week run-in phase in manual+suspend before low (SBL) mode, followed by the 26-week study phase. After run-in, participants were randomly assigned to a sequence comprising 12 weeks in auto mode, a 2-week washout, and 12 weeks in manual+SBL mode (auto mode-manual mode (AM-MM) sequence), or to the reverse order sequence (MM-AM). The primary endpoint was the adjusted between-treatment difference for auto mode versus manual+SBL mode in the percentage of time in range (TIR) (70–180 mg/dL). Secondary endpoints were the adjusted between-treatment difference in mean hemoglobin A1C (HbA1c) at the end of each 12-week period, assessed for non-inferiority with an absolute margin of 0.4% points, mean TIR, assessed for superiority, and mean HbA1c at the end of each 12-week period, assessed for superiority. The study randomized 98 participants, with 50 allocated to sequence AM-MM and 48 to sequence MM-AM. Mean TIR was 58.1% (SD 14.3) during the run-in phase, 68.3% (6.9) during auto mode, and 58.3% (12.5) during manual+SBL mode (model adjusted between-treatment difference during the study phase for auto mode versus manual+SBL mode, 9.9% points [95% CI 8.0– 11.7%]; non-inferiority met for the primary endpoint with superiority for auto mode). Mean HbA1c was 7.53% (SD 0.96; 58.8 mmol/mol [10.5]) at baseline and during the run-in phase, 7.00% (0.53; 53.0 mmol/mol [5.8]) during auto mode, and 7.61% (0.91; 59.7 mmol/mol [9.9]) during manual+SBL mode (between-treatment difference –0.61% points [95% CI –0.76 to –0.46]; non-inferiority met with superiority for auto mode). Mean TBR (<70 mg/dL) was 3.5% (SD 2.2) during the run-in phase, 4.6% (2.2) during auto mode, and 3.5% (2.1) during manual+SBL mode. Mean TBR (<54 mg/dL) was 0.7% (1.0) during the run-in phase, 0.9 (0.8) during auto mode, and 0.7% (0.8) during manual+SBL mode. Mean TITR (70–140 mg/dL) was 36.8% (11.8) during run-in, 47.8% (5.8) during auto mode, and 36.5% (10.4) during manual+SBL mode. The mean total daily insulin dose was similar between the auto mode and manual+SBL mode periods (15.2 U [SD 5.0] and 15.0 U [4.5], respectively). No severe hypoglycemic events were reported. Nine serious adverse events were reported, including five events in the auto mode period (one of the events was an episode of diabetic ketoacidosis following an acute viral bronchiolitis), two in the manual+SBL mode period, one during the washout period, and one during the run-in phase. None of the serious adverse events were deemed to be related to the device or procedure, and only one (the event of diabetic ketoacidosis) was related to diabetes.

Critical Review: This trial demonstrated that the use of the MiniMed 780 G system was safe and efficacious in a cohort of young children between the ages of 2 and 6 years. These important findings add to the existing evidence on the safety and efficacy of hybrid closed-loop systems in this vulnerable population and, pending regulatory approval, will increase the options for young children and caregivers to choose their preferred hybrid closed-loop system. One persistent challenge in young children which has not yet been addressed is the optimal management of those children with a low total daily insulin dose. Future research should explore the safety and efficacy of hybrid closed-loop systems with diluted insulin in young children with a low total daily insulin dose.

Maturity-onset diabetes of the young (MODY) in a racially/ethnically diverse pediatric population

Relan S, Alarcon G, Guffey D, Minard CG, Fang ME, Timmons K, et al. J Clin Endocrinol Metab. 2025 Jun 24:dgaf360. doi: 10.1210/clinem/dgaf360. Online ahead of print.

Objective: The objective of this study was to identify the clinical characteristics of a racially and/or ethnically diverse pediatric population with maturity-onset diabetes of the young (MODY).

Study Methodology and Results: This was a retrospective cohort review which used the Texas Children’s Hospital (Houston, Texas) electronic medical records Population Health registry to systematically identify individuals between 6 months and 21 years of age with genetic confirmation of MODY. The genetic testing was performed based on the clinician’s index of suspicion for MODY and performed in one of six CAP/CLIA-certified diagnostic laboratories. Only cases with pathogenic/likely pathogenic variants were analyzed in this study. The study included 50 genetically confirmed cases of MODY. Glucokinase (GCK)-MODY was found to be the most common MODY type, accounting for 60% (n = 30) of all patients with MODY, followed by Hepatocyte nuclear factor- 1 alpha (HNF1α)-MODY (16%; n = 8), HNF1B-MODY (18%; n = 9), and HNF4A-MODY (4%; n = 2). More than half of the patients were of race/ethnicity other than non-Hispanic White (NHW) (32% [n = 16] Hispanic and 20% [n = 10] African Americans, Lebanese, Asians, and others). NHW comprised only 48% (n = 24) of the cohort. The median age of diabetes diagnosis was 9.7 years for the entire cohort, 14.4 years for HNF4A MODY, 7.5 years for GCK-MODY, 12 years for HNF1A-MODY, and 9 years for HNF1B-MODY. HbA1c at the time of diabetes diagnosis was 6.3% (45 mmol/mol) for the entire cohort. It was significantly higher in patients with HNF4A-MODY (7.0%), HNF1A-MODY (6.8%), and HNF1B-MODY (6.7%), than in those with GCK-MODY (6.1%) (P = 0.005). Positive parental history was absent in 24% (n = 12) of MODY patients, none of the patients with HNF4A-MODY, 23.3% (n = 7) with GCK-MODY2, 33.3% (n = 3) with HNF1B-MODY, 12.5% (n = 1) with 1 HNF1A-MODY, and 100% (n = 1) with dual molecular diagnosis. Overweight or obesity were present in 22.4% (n = 11) of participants, in addition, 12% (n = 6) of patients had acanthosis Nigerians. Features of metabolic syndrome, such as dyslipidemia and hypertension, were found in 30% (n = 15) of study participants. About 8% (n = 4) of patients had positive islet autoantibodies. Of note, these four patients were positive for a single autoantibody and, in three of the cases, at low titers. Two patients with GCK-MODY and one patient with HNF1A-MODY had a coexisting autoimmune disease, such as Hashimoto thyroiditis or vitiligo. After genetic confirmation of MODY, 25 individuals required diabetes treatment. Of these, 48% (12/25) were treated with insulin. The overall proportion of patients on insulin decreased from 36% (n = 18) to 24% (n = 12). Of note out of the 50 reported cases reported, only 34% (n = 17) would have met current ADA guidelines for molecular testing.

Critical Review: This is an important study which demonstrated that in a real world, racially/ethnically diverse population of children from the US with MODY, characteristics consistent with either T1D or T2D, and lack of parental history of diabetes were prevalent. Thus, the current clinical guidelines to consider diagnosis of MODY may not apply to a racially diverse pediatric population.