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.
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.
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.