Daily Endocrinology Research Analysis
Analyzed 89 papers and selected 3 impactful papers.
Summary
A pivotal JAMA randomized trial in adults with osteogenesis imperfecta found that teriparatide followed by zoledronic acid increased BMD but did not reduce fractures, underscoring the gap between density and bone quality. Innovative clinical physiology work in JCEM mapped neonatal HPA-axis steroid dynamics during cardiac procedures using high-frequency microdialysis and modeling. A mechanistic study in Autophagy uncovered an SQSTM1/p62–N-degron–RXRA axis linking autophagy to β-cell insulin secretion and systemic glucose homeostasis.
Research Themes
- Bone fragility: dissociation between BMD gains and fracture risk
- Age- and procedure-dependent HPA-axis steroid physiology in neonates
- Autophagy–N-degron control of RXRA linking β-cell function and glucose homeostasis
Selected Articles
1. Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta: A Randomized Clinical Trial.
In 349 evaluable adults with osteogenesis imperfecta, teriparatide for 2 years followed by a single zoledronic acid infusion did not reduce incident fractures versus standard care (HR 0.97, 95% CI 0.68–1.38) despite significantly greater increases in spine and hip BMD. Several quality-of-life measures favored the active regimen, and adverse events were similar.
Impact: This definitive multicenter RCT challenges the assumption that BMD gains translate into fewer fractures in OI, emphasizing bone quality as a primary determinant of fragility.
Clinical Implications: Therapeutic strategies in OI should prioritize improving bone material properties and microarchitecture beyond density. Clinicians should counsel patients that anabolic–antiresorptive sequencing may improve BMD and some QOL domains without proven fracture benefit.
Key Findings
- Incident fractures occurred in 36.9% (teriparatide→zoledronic acid) vs 36.4% (standard care); HR 0.97 (95% CI 0.68–1.38).
- Lumbar spine and total hip BMD increased significantly more with teriparatide followed by zoledronic acid.
- Several health-related quality-of-life measures favored the active regimen.
- Adverse events were similar between groups, supporting acceptable safety.
- Findings suggest bone quality rather than low BMD is central to fracture pathogenesis in OI.
Methodological Strengths
- Multicenter randomized design across 27 referral centers with blinded fracture adjudication
- Registered trial with comprehensive endpoints (fractures, BMD, turnover markers, QOL)
Limitations
- Open-label design may introduce performance bias
- Population largely type I OI; potential limitations in generalizability and event rate assumptions
Future Directions: Develop and test therapies targeting bone material properties and microarchitecture; incorporate imaging/biomarkers of bone quality and biomechanics into future OI trials.
IMPORTANCE: Osteogenesis imperfecta causes multiple fractures throughout life, causing substantial morbidity. OBJECTIVE: To determine whether the parathyroid hormone analogue teriparatide followed by zoledronic acid reduces the risk of fractures in adults with osteogenesis imperfecta. DESIGN, SETTING, AND PARTICIPANTS: Multicenter open-label, parallel-group, randomized clinical trial, conducted between May 17, 2017, and March 21, 2025, in adults attending one of 27 referral centers with a clinical diagnosis of osteogenesis imperfecta. Bone mineral density (BMD) was measured by dual x-ray absorptiometry and bone turnover by serum procollagen type 1 N-terminal propeptide and C-terminal telopeptide of type 1 collagen. Fractures were confirmed by skeletal imaging. Several measures of health-related quality of life were assessed. INTERVENTIONS: Those in the active group received 20 μg of teriparatide daily by subcutaneous injection for 2 years followed by an infusion of 5 mg of zoledronic acid. In the standard care group, bisphosphonates and other bone-targeted medicines could be used but teriparatide and other bone anabolic drugs were prohibited. MAIN OUTCOMES AND MEASURES: The primary end point was the number of participants with imaging-proven incident fractures adjudicated by reviewers blinded to treatment allocation.
2. The dynamic adrenal response of children to cardiac surgery and cardiac catheterisation.
Using high-frequency microdialysis and modeling, the study shows neonates have markedly higher interstitial free cortisol/cortisone exposure during cardiac surgery compared with older children or catheterization, likely driven by elevated 11β-HSD2 and reduced 11β-HSD1 activity. Low postoperative serum cortisol and CBG in neonates paradoxically coincide with high tissue free cortisol peaks.
Impact: The work provides a mechanistic, age-specific map of perioperative steroid physiology in children, addressing controversies about adrenal support in neonates undergoing cardiac surgery.
Clinical Implications: Perioperative steroid assessment should account for neonatal-specific free steroid dynamics; reliance on total serum cortisol alone may misjudge adrenal sufficiency. Protocols may need age-tailored thresholds and timing.
Key Findings
- Neonates undergoing surgery had higher interstitial free cortisol and cortisone AUC and peaks than catheterization patients and older surgical children.
- Elevated tissue cortisone in neonates is consistent with high 11β-HSD2 and reduced 11β-HSD1 activity, indicating distinct enzymatic programming.
- Low postoperative serum cortisol and CBG in neonates coincided with high interstitial free cortisol peaks, highlighting discordance between serum and tissue measures.
- A mathematical model quantified age- and procedure-specific steroid dynamics.
Methodological Strengths
- High-frequency microdialysis (every 20 minutes up to 24 hours) capturing interstitial steroid kinetics
- Integration of hormonal panels with mechanistic mathematical modeling
Limitations
- Exact sample sizes and center-level heterogeneity not detailed in abstract
- Invasiveness of microdialysis may limit generalizability and routine clinical adoption
Future Directions: Validate age-tailored perioperative steroid thresholds in larger multicenter studies; explore noninvasive surrogates for tissue free steroid levels to guide neonatal adrenal support.
CONTEXT: The hypothalamic-pituitary-adrenal (HPA) axis is the key homeostatic system regulating the response to surgical stress. Imbalances in HPA axis hormones increase morbidity and mortality in children after cardiac surgery. Despite this, the physiology of the HPA axis in children undergoing cardiac surgery is poorly understood, leading to controversies in clinical practice. OBJECTIVE: To characterise dynamic HPA axis responses in children undergoing cardiac surgery and to determine age- and procedure-related differences in cortisol and cortisone physiology. METHODS: We recruited children (0-18 years) undergoing cardiac surgery with cardiopulmonary bypass or cardiac catheterisation. Tissue-free cortisol and cortisone were sampled every 20 minutes for up to 24 hours via microdialysis, alongside serum adrenocorticotropic hormone (ACTH), cortisol, cortisol-binding globulin (CBG), and inflammatory markers. We developed dynamic markers to quantify age- and procedure-dependent differences in hormonal responses and built a mathematical model to explain them. RESULTS: Neonates undergoing surgery showed higher free cortisol and cortisone AUC and peak concentrations than catheterisation patients. Neonates had higher peaks of cortisol and cortisone than older children undergoing surgery. The much higher tissue cortisone levels observed in neonates can be explained by enzymatic interconversion between cortisol and cortisone, likely due to persistent foetal high 11-βHSD2 activity and reduced 11-βHSD1 activity.Low post-operative blood cortisol and CBG values in neonates resulted in high free cortisol peaks in interstitial fluid during and after surgery. CONCLUSION: Neonates differ physiologically, with higher free cortisol levels that more readily diffuse into interstitial tissues, with implications for perioperative management.
3. The N-degron pathway regulates glucose and insulin homeostasis through the lysosomal degradation of RXRA/RXRα via SQSTM1/p62.
The study identifies an autophagy–N-degron axis in which SQSTM1/p62 targets RXRA for lysosomal degradation, maintaining β-cell mitochondrial respiration and insulin secretion. Under glucolipotoxic stress, RXRA escapes p62, suppressing respiration, reducing insulin secretion, and promoting lipogenesis, thereby linking protein quality control to glucose homeostasis.
Impact: This is a first-of-kind mechanistic link connecting the N-degron pathway, autophagic receptor p62, and RXRA turnover to β-cell function and systemic metabolism.
Clinical Implications: Targeting the p62–RXRA axis may preserve β-cell function under metabolic stress, suggesting novel therapeutic avenues for T2D beyond classical insulin sensitizers or secretagogues.
Key Findings
- SQSTM1/p62 sequesters RXRA and directs it to lysosomal degradation, sustaining β-cell respiration and insulin secretion.
- Under glucolipotoxicity, RXRA dissociates from p62, suppresses mitochondrial respiration, reduces insulin secretion, and induces lipogenesis.
- An N-degron–dependent mechanism governs RXRA turnover, linking protein degradation pathways to metabolic control.
- Reconstitution of SQSTM1-dependent RXRA degradation supports causality of the pathway.
Methodological Strengths
- Mechanistic dissection of protein turnover pathways with functional metabolic readouts
- Use of glucolipotoxic stress paradigms to model T2D-relevant β-cell dysfunction
Limitations
- Abstract does not detail the breadth of experimental systems or in vivo validation scope
- Translational relevance requires confirmation in human islets and animal models of diabetes
Future Directions: Validate the p62–RXRA axis in human islets and diabetic models; explore pharmacologic modulators of RXRA turnover to protect β-cell function.
Central to the pathogenesis of type 2 diabetes (T2D) is the failure in insulin secretion from pancreatic β-cells associated with insulin resistance. The nuclear receptor RXRA/RXRα (retinoid X receptor alpha) is a transcriptional regulator of insulin secretion and systemic glucose metabolism. Here, we show that the macroautophagic/autophagic receptor SQSTM1/p62 (sequestosome 1) sequesters RXRA for lysosomal degradation to modulate glucose metabolism and insulin secretion. Under glucolipotoxicity, RXRA is released from SQSTM1 to inhibit mitochondrial respiration and insulin secretion and to induce lipogenesis. SQSTM1-dependent degradation of RXRA was reconstituted