Daily Endocrinology Research Analysis
Three impactful endocrinology-related studies span genetics, metabolism, and clinical safety. A JBMR study identifies inactivating GNAS variants as a new genetic cause of multi-suture craniosynostosis, mechanistically linking impaired GPCR–cAMP signaling to dysregulated osteogenesis. A Gut multicenter cohort shows that admission gut microbiota predict postdischarge diabetes after acute pancreatitis with high accuracy. A large real-world pharmacovigilance screen finds TMP-SMX and metronidazole el
Summary
Three impactful endocrinology-related studies span genetics, metabolism, and clinical safety. A JBMR study identifies inactivating GNAS variants as a new genetic cause of multi-suture craniosynostosis, mechanistically linking impaired GPCR–cAMP signaling to dysregulated osteogenesis. A Gut multicenter cohort shows that admission gut microbiota predict postdischarge diabetes after acute pancreatitis with high accuracy. A large real-world pharmacovigilance screen finds TMP-SMX and metronidazole elevate severe hypoglycemia risk in older adults on sulfonylureas.
Research Themes
- GPCR signaling defects and skeletal/endocrine genetics
- Microbiome-based prediction of endocrine-metabolic outcomes
- Medication safety in diabetes management (drug–drug interactions)
Selected Articles
1. Inactivating GNAS variants impair GPCR signaling and cause multiple suture craniosynostosis in humans and zebrafish.
Germline inactivating GNAS variants were identified as a new cause of multi-suture craniosynostosis. Functional assays and zebrafish/MSC models show impaired G protein assembly and reduced cAMP signaling, relieving SMAD6 repression of RUNX2 and accelerating osteogenesis.
Impact: This study uncovers a novel genetic etiology and a coherent mechanistic pathway linking GPCR signaling defects to craniosynostosis, with implications for genetic diagnosis and pathway-targeted therapies.
Clinical Implications: Incorporate GNAS into craniosynostosis genetic testing panels and consider endocrine evaluation for possible hormone resistance. Mechanistic insights suggest potential for pathway-modulating therapies (e.g., cAMP/CREB or RUNX2/SMAD6 axis) in severe or refractory cases.
Key Findings
- Identified three de novo missense and one inherited splice-site GNAS variants in patients with multi-suture craniosynostosis.
- BRET assays showed impaired trimeric G protein assembly and reduced PTHR1 coupling; variants decreased basal and/or agonist-induced cAMP signaling.
- Zebrafish gnas inactivation and GNAS-deficient human mesenchymal stem cells recapitulated craniosynostosis and revealed CREB–SMAD6–RUNX2 pathway dysregulation driving osteogenesis.
Methodological Strengths
- Integrated human genetics with in vitro BRET functional assays and in vivo zebrafish models.
- Mechanistic dissection of downstream CREB–SMAD6–RUNX2 axis linking cAMP loss to osteogenic differentiation.
Limitations
- Number of affected individuals is limited; penetrance and phenotypic spectrum across populations remain to be defined.
- Translation of zebrafish and in vitro findings to human therapeutic interventions requires further validation.
Future Directions: Expand cohorts to define genotype–phenotype correlations and penetrance; assess therapeutic modulation of cAMP/CREB and RUNX2/SMAD6 signaling in preclinical craniosynostosis models.
2. Gut microbiota predict development of postdischarge diabetes mellitus in acute pancreatitis.
In a prospective multicenter cohort of acute pancreatitis, admission gut microbiome profiles predicted postdischarge diabetes with high accuracy (AUC up to 0.95) independent of traditional risk factors. Microbiome diversity also associated with mortality and recurrent pancreatitis.
Impact: Demonstrates a clinically actionable, early predictive tool for postdischarge diabetes using the admission microbiome in AP. This could enable precision surveillance and microbiome-targeted prevention strategies.
Clinical Implications: Consider microbiome-informed risk stratification after AP to target glucose monitoring, early endocrinology referral, and preventive interventions. Supports trials of microbiome modulation to prevent post-AP diabetes.
Key Findings
- Admission buccal and rectal microbiota profiles were associated with postdischarge outcomes including diabetes, mortality, and recurrent AP.
- An 11-species ridge regression classifier predicted postdischarge diabetes with AUC 0.948 (matched) and 0.862 (entire cohort), NPV 96%, and overall accuracy 95%.
- Predictive capacity was independent of AP severity, smoking, and alcohol, suggesting microbiome adds unique prognostic information.
Methodological Strengths
- Prospective multicenter design with long-term follow-up and combined 16S and metagenomic sequencing.
- Robust predictive modeling (ridge regression) with performance metrics and matched/entire cohort validation.
Limitations
- Moderate sample size; external validation in independent cohorts is needed.
- Causality cannot be inferred; interventional studies are required to test microbiome modulation effects.
Future Directions: External validation and randomized trials to test microbiome-targeted interventions for preventing post-AP diabetes; mechanistic studies linking taxa to beta-cell dysfunction.
3. Medications Associated with Increased Risk of Hypoglycemia in Older Adults on Sulfonylureas: A High-Throughput Case-Crossover-Based Screening Study.
Across three large US claims databases, a high-throughput case-crossover screen identified sulfamethoxazole/trimethoprim and metronidazole as associated with increased severe hypoglycemia among older adults on sulfonylureas after rigorous CCTC adjustment and FDR control.
Impact: Provides actionable medication safety signals for clinicians managing older adults on sulfonylureas, highlighting specific antibiotics that may precipitate severe hypoglycemia.
Clinical Implications: Avoid or closely monitor SU-treated older adults when prescribing TMP-SMX or metronidazole; consider alternative antibiotics and intensify glucose monitoring during and shortly after co-exposure.
Key Findings
- Among 1607 candidate drugs, TMP-SMX (CCTC OR 1.76; FDR q<0.01) and metronidazole (CCTC OR 2.17; FDR q=0.04) were linked to severe hypoglycemia with sulfonylureas.
- Insulin's apparent risk in CCO analysis attenuated after CCTC adjustment (CCTC OR 1.03), underscoring the importance of controlling for direct drug effects.
- Analytic approach controlled time-varying confounding and multiple testing (FDR 0.05) across three large databases (2003–2022).
Methodological Strengths
- Use of case-crossover with case-case time-control adjustment to mitigate time-varying confounding and direct drug effects.
- Replication across three national datasets and FDR control for multiple hypothesis testing.
Limitations
- Observational screening susceptible to residual confounding and exposure misclassification.
- Findings are hypothesis-generating and require pharmacoepidemiologic confirmation and mechanistic studies.
Future Directions: Confirmatory cohort/self-controlled studies quantifying absolute risk; drug–drug interaction mechanistic work (e.g., CYP2C9/transporters) and clinical decision support integration.