Daily Endocrinology Research Analysis
Three impactful endocrinology studies stood out today: a mechanistically innovative preclinical study introducing a small-molecule strategy to downregulate the TSH receptor for Graves hyperthyroidism; a large multinational pediatric cohort showing that diabetic ketoacidosis (DKA) at type 1 diabetes onset predicts worse long-term glycemia but that automated insulin delivery attenuates this gap; and a large randomized trial ancillary analysis demonstrating no fracture risk reduction with cocoa ext
Summary
Three impactful endocrinology studies stood out today: a mechanistically innovative preclinical study introducing a small-molecule strategy to downregulate the TSH receptor for Graves hyperthyroidism; a large multinational pediatric cohort showing that diabetic ketoacidosis (DKA) at type 1 diabetes onset predicts worse long-term glycemia but that automated insulin delivery attenuates this gap; and a large randomized trial ancillary analysis demonstrating no fracture risk reduction with cocoa extract or multivitamin/multimineral supplements in older adults.
Research Themes
- Novel receptor downregulation strategy for autoimmune hyperthyroidism
- Long-term pediatric diabetes outcomes and impact of automated insulin delivery
- Evidence-based reassessment of supplements for fracture prevention
Selected Articles
1. Inhibition of TSH Receptor Expression by a Cyclotriazadisulfonamide as a Potential Treatment of Graves Hyperthyroidism.
The CADA analogue VGD040 selectively reduced TSH receptor surface expression, suppressed downstream signaling and thyroglobulin secretion in human thyrocytes, and lowered thyroid hormone secretion in mice without apparent toxicity. This establishes a first-in-class receptor downregulation approach as a potential pharmacotherapy for Graves hyperthyroidism.
Impact: Introduces a mechanistically novel, selective small-molecule strategy to reduce TSHR expression with in vivo efficacy, addressing an unmet need for non-ablative therapies in Graves hyperthyroidism.
Clinical Implications: If translated to humans, VGD040-like agents could offer a medical alternative to antithyroid drugs, radioiodine, or surgery by directly diminishing TSHR-mediated signaling, potentially with fewer systemic toxicities.
Key Findings
- VGD040 reduced TSHR surface expression in HEK-TSHR cells with selectivity over related glycoprotein hormone receptors.
- In human thyrocytes, VGD040 decreased cAMP production and thyroglobulin secretion by reducing TSHR surface expression.
- In BALB/c mice, VGD040 decreased thyroid hormone secretion in response to TSH without apparent toxicity at effective dose.
Methodological Strengths
- Multi-system validation across engineered cells, primary human thyrocytes, and in vivo mouse model
- Selectivity profiling against related glycoprotein hormone receptors with functional readouts (cAMP, Tg)
Limitations
- Preclinical study without human pharmacokinetic, safety, or efficacy data
- Long-term effects, immunogenicity, and off-target degradation risks remain uncharacterized
Future Directions: Advance to IND-enabling studies including GLP toxicology, pharmacokinetics, and ultimately phase 1 trials to assess safety, target engagement, and biomarkers (e.g., Tg, free T4) in Graves disease.
2. Association of Diabetic Ketoacidosis at Onset, Diabetes Technology Uptake, and Clinical Outcomes After 1 and 2 Years of Follow-up: A Collaborative Analysis of Pediatric Registries Involving 9,269 Children With Type 1 Diabetes From Nine Countries.
In 9,269 youths with type 1 diabetes, DKA at diagnosis predicted persistently higher HbA1c and higher BMI SDS at 1 and 2 years. Adoption of automated insulin delivery was associated with lower HbA1c and attenuated DKA-related glycemic differences over time.
Impact: Large, multinational pediatric data quantify the lasting metabolic penalty of DKA at onset and highlight AID as a modifiable factor that narrows disparities, informing prevention and early technology adoption strategies.
Clinical Implications: Preventing DKA at diagnosis remains critical; clinicians should consider early AID deployment in youth, particularly those presenting with DKA, to improve long-term glycemic outcomes.
Key Findings
- DKA at diagnosis occurred in 34.2% (severe DKA in 12.8%) among 9,269 youths with mean age 9.0 years.
- Adjusted mean HbA1c remained higher in severe DKA (7.41% at 1 year; 7.58% at 2 years) compared with nonsevere DKA and no DKA.
- Both DKA groups had higher BMI SDS than the no DKA group.
- Automated insulin delivery use was associated with lower HbA1c and moderated group differences over 2 years.
Methodological Strengths
- Large, multinational pediatric cohort with standardized outcomes and 2-year follow-up
- Adjusted analyses across clinically relevant subgroups, including technology adoption
Limitations
- Observational design limits causal inference; technology use not randomized
- Registry-based data may have heterogeneity in measurement and residual confounding
Future Directions: Prospective interventional studies to test early AID deployment post-diagnosis, and implementation research to reduce DKA at onset through education and access initiatives.
3. Effects of cocoa extract supplementation and multivitamin/multimineral supplements on self-reported fractures in the Cocoa Supplement and Multivitamins Outcomes Study randomized clinical trial.
In the COSMOS randomized trial ancillary analysis of 21,442 older adults, neither cocoa extract (500 mg/day flavanols) nor a daily multivitamin/multimineral supplement reduced self-reported clinical fractures over a median 3.6 years. These results do not support using these supplements to prevent fractures in community-dwelling older adults without targeted osteoporosis selection.
Impact: Provides high-quality randomized evidence countering common supplement practices for bone health, likely to influence clinical recommendations and public health messaging.
Clinical Implications: Clinicians should not recommend cocoa extract or generic multivitamin/multimineral supplements solely to prevent fractures in older adults; prioritize proven osteoporosis therapies and individualized calcium/vitamin D strategies.
Key Findings
- Among 21,442 older adults followed for a median 3.6 years, 2,083 clinical fractures occurred.
- Cocoa extract did not reduce total clinical fractures (aHR 1.03, 95% CI 0.95–1.12) or nonvertebral fractures (aHR 1.05, 95% CI 0.96–1.14).
- Multivitamin/multimineral supplementation did not reduce total clinical fractures (aHR 1.09, 95% CI 1.00–1.19), hip fractures (aHR 1.06, 95% CI 0.80–1.42), or nonvertebral fractures (aHR 1.10, 95% CI 1.00–1.20).
Methodological Strengths
- Large randomized, placebo-controlled, 2×2 factorial design with intention-to-treat analysis
- Long median follow-up and prespecified fracture outcomes across fracture sites
Limitations
- Fractures were self-reported; adjudication and vertebral morphometry were not detailed
- Participants were not selected for osteoporosis or high fracture risk; potential dilution of effects
Future Directions: Focus on targeted supplementation/therapy in high-risk populations, mechanistic biomarkers, and trials integrating pharmacotherapy with lifestyle to prevent fractures.