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.
Graves hyperthyroidism (GH) is a condition in which autoantibodies chronically activate the thyrotropin (TSH) receptor (TSHR). TSHR is one of the few G protein-coupled receptors (GPCRs) predicted to have a signal peptide, making it a potential target for cyclotriazadisulfonamide (CADA) compounds. We sought to determine whether a small-molecule drug that selectively induces nascent protein degradation could decrease TSHR expression in vitro and in vivo at therapeutically relevant levels. We tested several CADA compounds for their ability to reduce TSHR surface expression in HEK 293 cells overexpressing human TSHR (HEK-TSHR cells) using flow cytometry. Inhibition of downstream cAMP production and thyroglobulin (Tg) secretion were measured in HEK-TSHR and human thyrocytes, respectively. Follow-up studies in VGD040-treated BALB/c mice assessed plasma levels of free T4 in response to TSH stimulation. Among a number of CADA analogues, VGD040 decreased TSHR at the surface of HEK-TSHR cells. VGD040 was found to be selective toward TSHR compared to similar glycoprotein hormone receptors. In human thyrocytes, reduction of TSHR surface expression by VGD040 decreased cyclic adenosine monophosphate production and Tg secretion. Most important, VGD040 decreased TH secretion in mice without apparent toxicity at the effective dose studied. VGD040 is an important new lead with potential for developing safe drug treatments for GH.
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.
OBJECTIVE: This study examined the association between diabetic ketoacidosis (DKA) at type 1 diabetes diagnosis and long-term glycemic outcomes, insulin requirements, BMI SD score (SDS), and diabetes technology uptake in youth. RESEARCH DESIGN AND METHODS: Data were from nine countries (Austria, Czechia, Germany, Italy, Luxembourg, New Zealand, Slovenia, Switzerland, and U.S. [Colorado]), including youth (0.5-15.9 years) diagnosed with type 1 diabetes in 2019-2020 and followed for 2 years thereafter. Participants were divided into three groups: no DKA, nonsevere, and severe DKA at diagnosis. HbA1c, insulin requirements, BMI SDS, and use of technology, including automated insulin delivery (AID), were assessed. RESULTS: The analysis included 9,269 individuals (54.8% males, mean age 9.0 years). DKA at diagnosis was observed in 34.2% of participants and severe DKA in 12.8%. After 1 year, adjusted mean HbA1c was higher in the severe DKA group (7.41%) compared with nonsevere DKA (7.23%, P = 0.001) and no DKA groups (7.14, P < 0.001), and this difference persisted after 2 years (7.58% vs. 7.38% [P < 0.001] and vs. 7.32% [P < 0.001]). Higher BMI SDS was observed in both DKA groups compared with no DKA. The use of AID was associated with lower HbA1c levels compared with other treatment modalities and moderated differences between DKA groups after 2 years of follow-up (P = 0.072). CONCLUSIONS: Severe and nonsevere DKA at type 1 diabetes diagnosis were both associated with persistently higher HbA1c and higher BMI SDS. AID use diminishes the association of DKA at diagnosis and higher HbA1c over time.
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.
Osteoporosis is a major public health problem among older adults. Forty percent of older US adults take multivitamin/multimineral (MVM) supplementation. The effects of MVM supplementation on fractures are unclear. Preclinical and observational studies suggest that MVM and flavanols may have beneficial effects on bone. We conducted an ancillary study to Cocoa Supplement and Multivitamin Outcomes Study (COSMOS; NCT05232669) designed to investigate incident fracture and injurious falls in 21 442 COSMOS participants (12 666 females aged ≥65 yr and 8776 males aged ≥60 yr) randomized in a 2 × 2 factorial design to 1 of 4 intervention groups: cocoa extract + MVM, cocoa extract + MVM placebo, cocoa extract placebo + MVM, or double placebo. The daily cocoa extract supplement contained 500 mg/d flavanols and 80 mg/d (-)-epicatechin (Mars Edge); the daily MVM supplement was Centrum Silver (Haleon). The median (interquartile range) duration of the intervention was 3.6 (3.2-4.2) yr. Annually, participants self-reported incident fractures. In intention-to-treat analyses, we examined the effects of cocoa extract and MVM on the primary outcomes of total clinical fracture (hip, upper leg, forearm/wrist, pelvis, upper arm/shoulder, spine, knee, or other), hip fracture, and nonvertebral fracture, and secondary outcomes of clinical spine, forearm/wrist, major osteoporotic, and pelvic fracture using Cox proportional hazards models. During the intervention period, 2083 incident clinical fractures occurred. Compared with placebo, cocoa extract was not significantly associated with lower risk of incident clinical fracture (adjusted hazard ratio [aHR] 1.03, 95% CI 0.95-1.12) or nonvertebral fracture (aHR 1.05, 95% CI 0.96-1.14). MVM supplementation was not associated with lower risk of total clinical fracture (aHR 1.09, 95% CI 1.00-1.19), hip fracture (aHR 1.06, 95% CI 0.80-1.42), or nonvertebral fracture (aHR 1.10, 95% CI 1.00-1.20). These findings do not support the use of cocoa extract or MVM to decrease fracture risk in older individuals not selected for pre-existing osteoporosis. Osteoporosis is a major public health problem among older adults. Some studies suggest that flavanols, which are present in large quantities in cocoa, may have beneficial effects on bone. Multivitamin/multimineral (MVM) supplementation, taken by 40% of the US population, may also have beneficial effects on bone. We conducted an ancillary study to the COSMOS clinical trial. The COSMOS trial assigned 21 442 participants (12 666 females aged ≥65 yr and 8776 males aged ≥60 yr) to receive 2 of 4 study pills: cocoa extract + MVM, cocoa extract + MVM placebo, cocoa extract placebo + MVM, or double placebo. After accounting for age, race/ethnicity, and sex, compared with placebo, cocoa extract supplementation was not significantly associated with the risk of clinical fractures. MVM supplementation also did not reduce risk of total clinical, hip, or nonvertebral fracture. In this large study of older men and women, cocoa extract compared with placebo supplementation given for an average of 3.6 yr did not significantly affect the risk of fractures. Similarly, MVM supplement (vs placebo) did not reduce the risk of clinical fracture in older community-dwelling persons. MVM may have other health benefits, including helping to ensure adequate intake of calcium and vitamin D.