Daily Endocrinology Research Analysis
A multicenter randomized trial (POInT) found that high-dose oral insulin did not prevent islet autoimmunity overall in genetically at-risk infants, though an INS genotype interaction suggests possible benefit in a selected subgroup. A large Nature Genetics meta-GWAS identified 179 novel hypothyroidism loci and developed a polygenic risk score that stratified progression risk, especially when combined with thyroid hormones and TPO antibodies. A prospective multicenter study showed stopping rhGH i
Summary
A multicenter randomized trial (POInT) found that high-dose oral insulin did not prevent islet autoimmunity overall in genetically at-risk infants, though an INS genotype interaction suggests possible benefit in a selected subgroup. A large Nature Genetics meta-GWAS identified 179 novel hypothyroidism loci and developed a polygenic risk score that stratified progression risk, especially when combined with thyroid hormones and TPO antibodies. A prospective multicenter study showed stopping rhGH in mid-puberty in adolescents with transient idiopathic GHD did not compromise near-adult height, supporting de-escalation of therapy.
Research Themes
- Primary prevention of type 1 diabetes and genotype-specific effects
- Genomic risk prediction and immune mechanisms in hypothyroidism
- De-escalation and optimization of growth hormone therapy in pediatric endocrinology
Selected Articles
1. Efficacy of once-daily, high-dose, oral insulin immunotherapy in children genetically at risk for type 1 diabetes (POInT): a European, randomised, placebo-controlled, primary prevention trial.
In genetically at-risk infants, daily high-dose oral insulin did not reduce the development of multiple islet autoantibodies or diabetes compared with placebo. A significant interaction with INS genotype suggested potential benefit on dysglycaemia/diabetes in carriers of susceptible alleles and possible harm in non-susceptible genotypes. Safety profiles were similar between groups.
Impact: This definitive, multicenter RCT informs the field that non–genotype-selected primary oral insulin is ineffective for preventing islet autoimmunity, while highlighting a plausible genotype-specific signal to guide next-generation prevention trials.
Clinical Implications: Oral insulin should not be used for primary prevention of islet autoimmunity in unselected genetically at-risk infants. Future prevention efforts may consider INS genotype stratification within clinical trials rather than routine practice.
Key Findings
- No overall prevention: primary outcome occurred in 10% (oral insulin) vs 9% (placebo), HR 1.12 (95% CI 0.76–1.67), p=0.57.
- INS genotype interaction: increased primary outcome in non-susceptible genotypes (HR 2.10) and protection from dysglycaemia/diabetes in susceptible genotypes (HR 0.38).
- Safety: hypoglycaemia was rare and comparable; adverse event rates were similar across groups; one death was adjudicated unrelated.
Methodological Strengths
- Randomized, double-masked, multicenter, placebo-controlled primary prevention design with trial registration.
- Rigorous longitudinal assessment of islet autoantibodies and glycaemic outcomes with predefined endpoints.
Limitations
- Primary endpoint focused on islet autoimmunity rather than clinical diabetes; genotype subgroup analyses may be underpowered.
- Generalizability beyond studied populations and adherence dynamics were not fully detailed.
Future Directions: Conduct genotype-selected (INS) prevention trials, explore alternative tolerogenic antigens or combinatorial strategies, and extend follow-up to overt diabetes to clarify clinical benefit.
BACKGROUND: Type 1 diabetes begins with autoimmunity against pancreatic islet antigens, including insulin. The aim of the Primary Oral Insulin Trial (POInT) was to evaluate the efficacy and safety of daily high-dose oral insulin to prevent the development of islet autoantibodies and diabetes. METHODS: In this randomised, controlled, primary prevention trial, genetic screening in seven obstetric and paediatric clinics in Germany, Poland, Sweden, Belgium, and the UK identified newborns with a greater than 10% risk of developing islet autoimmunity. Eligible infants aged 4-7 months were randomly assigned in a 1:1 ratio to receive insulin manufactured from human zinc-insulin crystals administered orally at a once-daily dose of 7·5 mg for 2 months, increasing to 22·5 mg for 2 months and 67·5 mg until age 3 years, or placebo. Participants were randomly assigned via a web-based application and were stratified by site. The primary outcome was the development of two or more islet autoantibodies or diabetes assessed throughout follow-up until a maximum age of 6·5 years. A secondary outcome was the development of dysglycaemia or diabetes. Islet autoantibodies were measured in samples collected at baseline and during study visits conducted at outpatient clinics at 2, 4, and 8 months after randomisation, at age 18 months, and every 6 months thereafter. All participants and their family members, investigators of the study, and laboratory personnel remained masked to treatment allocation during the whole study. All randomly assigned participants who correctly fulfilled eligibility criteria and had not reached the primary outcome at the baseline visit (modified intention-to-treat) were included in the primary analysis. All participants who received at least one dose of study drug were included in the safety analysis. POInT is registered with ClinicalTrials.gov (NCT03364868) and is complete. FINDINGS: Of 241 977 screened newborns, 2750 (1·14%) had an elevated genetic risk of developing islet autoimmunity and 1050 (38·2%) of the eligible infants (531 males [51%], 519 females [49%]), were assigned to oral insulin or placebo between Feb 7, 2018, and March 24, 2021. Two participants in the oral insulin group and none in the placebo group were excluded from the modified intention-to-treat analysis. The primary outcome developed in 52 (10%) participants in the insulin group and 46 (9%) in the placebo group (hazard ratio 1·12 [95% CI 0·76-1·67], p=0·57). An interaction between treatment and the INS rs1004446 genotype was observed, with an increase in the primary outcome in participants in the insulin group carrying non-susceptible INS genotypes compared with the placebo group (2·10 [1·08-4·09]) and protection against diabetes or dysglycaemia in participants in the insulin group carrying susceptible INS genotypes compared with the placebo group (0·38 [0·17-0·86]). Blood glucose values less than 50 mg/dL were observed in two (0·03%) of 7210 measurements in the insulin group and six (0·08%) of 7070 measurements in the placebo group. Of 10 252 reported adverse events, 5076 (49·5%) occurred in 507 (96·0%) of 528 participants in the oral insulin group and 5176 (50·5%) occurred in 500 (95·8%) of 522 participants in the placebo group. One death occurred in the oral insulin group and was unrelated to the study drug following independent review. INTERPRETATION: There was no evidence that high-dose, daily oral insulin prevents the development of islet autoantibodies. Further studies are needed to assess the benefit of primary oral insulin therapy for preventing diabetes in INS genotype-selected infants. FUNDING: Leona M and Harry B Helmsley Charitable Trust.
2. Genome-wide association study and polygenic risk prediction of hypothyroidism.
A meta-GWAS identified 350 hypothyroidism loci (179 novel), implicating immune pathways and hematopoietic regulation. A PRS built from >115,000 cases improved prediction when combined with thyroid hormones and TPO antibodies and stratified progression risk among subclinical hypothyroidism.
Impact: This study substantially expands the genetic architecture of hypothyroidism and provides a clinically actionable PRS framework that enhances risk prediction beyond conventional biomarkers.
Clinical Implications: PRS could support earlier identification and monitoring of individuals at higher risk of hypothyroidism and progression from subclinical disease, guiding targeted surveillance and tailored treatment thresholds once validated across populations.
Key Findings
- Identified 350 hypothyroidism loci, including 179 novel; 29 linked through TSH.
- Prioritized 259 putative causal genes enriched in immune-related functions and hematopoietic regulation.
- PRS combined with thyroid hormones and TPO antibodies yielded highest predictive accuracy and stratified progression in subclinical hypothyroidism.
Methodological Strengths
- Very large-scale meta-analysis integrating hypothyroidism, TSH, and FT4 datasets with multiple gene-mapping strategies.
- Development and evaluation of PRS including demonstration of progression risk stratification in subclinical disease.
Limitations
- Likely Eurocentric ancestry composition limits generalizability; heterogeneity across cohorts may persist.
- Clinical utility of PRS requires external validation, calibration, and cost-effectiveness assessment across diverse populations.
Future Directions: Validate PRS across ancestries, integrate into clinical workflows with decision thresholds, and functionally characterize prioritized genes and pathways to identify therapeutic targets.
We performed a genome-wide meta-analysis of hypothyroidism (113,393 cases and 1,065,268 controls), free thyroxine (191,449 individuals) and thyroid-stimulating hormone (482,873 individuals). We identified 350 loci associated with hypothyroidism, including 179 not previously reported, 29 of which were linked through thyroid-stimulating hormone. We found that many hypothyroidism risk loci regulate blood cell counts and the circulating inflammasome, and through multiple gene-mapping strategies, we prioritized 259 putative causal genes enriched in immune-related functions. We developed a polygenic risk score (PRS) based on more than 115,000 hypothyroidism cases to address diagnostic challenges in individuals with or at risk of thyroid hormone deficiency. We show that the highest predictive accuracy for hypothyroidism was achieved when combining the PRS with thyroid hormones and thyroid-peroxidase autoantibodies, and that the PRS was able to stratify risk of progression among individuals with subclinical hypothyroidism. These findings demonstrate the potential for a hypothyroidism PRS to support the prediction of disease progression and onset in thyroid hormone deficiency.
3. Growth Hormone Withdrawal in Mid-Puberty: No Impact on Near Adult Height in Adolescents with Transient Idiopathic GHD.
In adolescents with transient IIGHD who normalized GH secretion at mid-puberty, discontinuing rhGH did not adversely affect near adult height or total pubertal growth compared with continuation. Findings support shortening rhGH treatment duration after confirmatory retesting.
Impact: Provides prospective multicenter evidence to de-escalate GH therapy without compromising final height, directly informing clinical decision-making and resource allocation.
Clinical Implications: In adolescents with childhood IIGHD who retest GH-sufficient at mid-puberty, clinicians can consider stopping rhGH without jeopardizing near-adult height, reducing treatment burden and costs; protocols should include standardized retesting and follow-up.
Key Findings
- Primary outcome (NAH-SDS minus TH-SDS) did not differ between continuation and discontinuation (−0.17 vs −0.18; P=0.96).
- Near adult height SDS, total pubertal growth, and predicted vs attained height gain were similar between groups.
- High completion (99%) and multicenter prospective design support the robustness of findings.
Methodological Strengths
- Prospective multicenter design with predefined outcomes and standardized retesting criteria.
- Pragmatic patient-preference allocation reflecting real-world decision-making and high completion rate.
Limitations
- Non-randomized allocation introduces potential selection bias and residual confounding.
- Generalizability limited to adolescents with IIGHD who normalize GH on retesting; assay thresholds may vary across centers.
Future Directions: Randomized trials or advanced causal inference designs to confirm findings; evaluate long-term metabolic, bone, and quality-of-life outcomes and cost-effectiveness of de-escalation strategies.
CONTEXT: In children with idiopathic isolated growth hormone deficiency (IIGHD), GH secretion often normalizes by near adult height (NAH). Whether rhGH treatment can be safely discontinued earlier remains unclear. OBJECTIVE: To investigate if withdrawing rhGH treatment from mid-puberty onwards had no negative effect on attained NAH in adolescents who, after retesting, were no longer GH deficient. DESIGN: Prospective multicenter patient preference study (2017-2024) with follow-up until NAH (SEENEZ GH Study). SETTING: Pediatric endocrinology departments in multiple centers. PATIENTS OR OTHER PARTICIPANTS: 127 adolescents (95 male, 75%) with childhood IIGHD (GH peak 1.7-10 µg/L) who tested GH sufficient (GH peak >6.7 µg/L) at mid-puberty. 44 continued rhGH (GHcont), 83 discontinued (GHstop). 99% of patients completed the study. INTERVENTIONS: RhGH treatment continuation vs discontinuation from mid-puberty until NAH. MAIN OUTCOME MEASURES: Primary: NAH-SDS minus target height (TH)-SDS. Secondary: NAH-SDS, total pubertal growth (TPG), and predicted vs attained height gain. RESULTS: Mean (SD) NAH-SDS minus TH-SDS was -0.17 (0.60) in the GHcont and -0.18 (0.62) in the GHstop group (P=.96). Mean NAH-SDS was -0.91 (0.76) (GHcont) vs -0.78 (0.76) (GHstop) (P=.35). Mean (SD) TPG (from start of puberty) in males was 27.5 cm (7.0; GHcont) vs 25.9 cm (6.2; GHstop) (P =.25) and in females 20.5 cm (5.7; GHcont) vs 20.9 cm (7.6; GHstop) (P = .90). Predicted vs attained height gain based on the prediction model did not differ between groups. CONCLUSIONS: In adolescents with transient IIGHD, rhGH treatment can be stopped at mid-puberty. These findings support reducing rhGH treatment duration, lowering patient burden and healthcare costs.