Daily Endocrinology Research Analysis
Today's top endocrinology papers span pharmacovigilance, rare-tumor pathophysiology, and diet-based metabolic interventions. A target trial emulation across major glucose-lowering drug classes clarifies pancreatic safety signals; single-cell and bulk transcriptomics of FGF23-producing tumors uncovers a vesicle/exocytosis program underlying phosphate-wasting; and a randomized trial shows alternate-day fasting outperforms time-restricted eating for short-term fat loss and risk factors.
Summary
Today's top endocrinology papers span pharmacovigilance, rare-tumor pathophysiology, and diet-based metabolic interventions. A target trial emulation across major glucose-lowering drug classes clarifies pancreatic safety signals; single-cell and bulk transcriptomics of FGF23-producing tumors uncovers a vesicle/exocytosis program underlying phosphate-wasting; and a randomized trial shows alternate-day fasting outperforms time-restricted eating for short-term fat loss and risk factors.
Research Themes
- Drug safety and pancreatic outcomes across type 2 diabetes therapies
- Molecular mechanisms of FGF23 hypersecretion in tumor-induced osteomalacia
- Intermittent fasting strategies for fat loss and cardiometabolic health
Selected Articles
1. Integrating single-cell and bulk transcriptome analysis of fibroblast growth factor 23 (FGF23)-producing mesenchymal tumors reveals molecular basis of its secretory phenotype.
By integrating single-cell and bulk transcriptomics from 10 patients with phosphaturic mesenchymal tumors, the authors define tumor heterogeneity and a conserved vesicle/exocytosis program that likely drives FGF23 hypersecretion. They also highlight membrane proteins (PHEX, ERBB4, PCDH7, LRRFIP2) as candidate diagnostic targets and confirm FN1-FGFR1 fusions and Klotho expression in most tumors.
Impact: This study provides mechanistic insight into the secretory phenotype of FGF23-producing tumors, a key pathophysiologic driver of tumor-induced osteomalacia, and proposes actionable diagnostic targets.
Clinical Implications: The identification of a conserved exocytosis program and tumor-specific membrane targets may inform development of diagnostic assays (e.g., immunohistochemistry, molecular panels) and eventually guide targeted interventions in TIO.
Key Findings
- Single-cell and bulk RNA-seq from 10 patients resolved 22,449 cells into 13 clusters and two PMT tumor subclusters with higher FGF23 expression and EMT features.
- Upregulation of vesicle/exocytosis genes (SLC30A3, SYT1, STX1A, SNAP25) suggests a conserved SNARE-mediated secretory mechanism across PMTs.
- Tumor cell regulons ERG and EGR3 were implicated in differentiation trajectories; FN1-FGFR1 fusions and Klotho expression were present in most tumors.
- Transmembrane proteins (PHEX, ERBB4, PCDH7, LRRFIP2) were consistently expressed in tumor clusters, representing candidate diagnostic targets.
Methodological Strengths
- Integrated single-cell and bulk transcriptomics on patient-derived tumors with cell-state and trajectory analyses
- Cross-validation of findings across modalities (scRNA-seq, bulk RNA-seq) including CNV/SNP inference and regulon analysis
Limitations
- Small sample size and descriptive nature limit generalizability and causal inference
- Functional validation of candidate genes and pathways was not performed in vivo
Future Directions: Validate candidate membrane targets and SNARE/exocytosis nodes functionally; develop diagnostic assays; explore targeted therapeutics to modulate FGF23 secretion.
2. Comparative Risk of Adverse Pancreatic Events With GLP-1 Receptor Agonists, SGLT2 Inhibitors, DPP4 Inhibitors, and Sulfonylureas Among Adults With Type 2 Diabetes at Moderate Cardiovascular Disease Risk.
In a target trial emulation of 388,262 adults with type 2 diabetes at moderate CVD risk, GLP-1RAs and DPP-4is were not linked to higher pancreatic risks. SGLT2is had lower acute pancreatitis risk than DPP-4is, while sulfonylureas had higher pancreatitis risk than GLP-1RAs and SGLT2is; GLP-1RAs were associated with lower pancreatic cancer risk versus DPP-4is.
Impact: This large, methodologically rigorous comparative effectiveness study directly contrasts pancreatic outcomes across four major drug classes, informing ongoing safety debates and clinical decision-making.
Clinical Implications: Findings support the pancreatic safety of GLP-1RAs and DPP-4is and suggest SGLT2is may carry lower acute pancreatitis risk than DPP-4is, whereas sulfonylureas may confer higher risk. These data aid shared decision-making, especially for patients with pancreatobiliary concerns.
Key Findings
- Weighted cohort of 388,262 new users across GLP-1RA, DPP-4i, SGLT2i, and sulfonylurea with SuperLearner-based propensity weighting.
- SGLT2i associated with lower acute pancreatitis risk vs DPP-4i (HR 0.82; 95% CI 0.68-0.98).
- Sulfonylurea associated with higher acute pancreatitis risk vs GLP-1RA (HR 1.28; 95% CI 1.03-1.56) and vs SGLT2i (HR 1.32; 95% CI 1.12-1.57).
- GLP-1RA associated with lower pancreatic cancer risk vs DPP-4i (HR 0.56; 95% CI 0.40-0.77); no difference in acute pancreatitis between GLP-1RA and DPP-4i or GLP-1RA and SGLT2i.
Methodological Strengths
- Target trial emulation with advanced propensity weighting (SuperLearner) and IPTW across multiple drug classes
- Large, real-world datasets from OptumLabs and Medicare with class-level head-to-head comparisons
Limitations
- Residual confounding and misclassification inherent to claims data cannot be fully excluded
- Follow-up duration and some clinical covariates (e.g., imaging, laboratory detail) are limited in administrative data
Future Directions: Prospective pharmacovigilance and mechanistic studies to clarify class-specific pancreatic risks, and subgroup analyses in high-risk patients.
3. Alternate-day fasting elicits larger changes in fat mass than time-restricted eating in adults without obesity - A randomized clinical trial.
In a 4-week randomized, parallel-arm trial (n=76; BMI 23–30 kg/m²), alternate-day fasting reduced energy intake more than time-restricted eating, leading to greater reductions in fat mass and body weight. Only alternate-day fasting improved several cardiometabolic risk markers over the short intervention.
Impact: This registered randomized clinical trial provides head-to-head evidence comparing two widely used intermittent fasting strategies, informing diet-based management of metabolic risk.
Clinical Implications: For short-term fat loss and cardiometabolic improvement in adults without obesity, alternate-day fasting may outperform time-restricted eating; clinicians should individualize based on tolerability, adherence, and patient goals.
Key Findings
- Alternate-day fasting produced larger reductions in energy intake than time-restricted eating over 4 weeks.
- Greater decreases in whole-body fat mass and body weight were observed with alternate-day fasting.
- Only alternate-day fasting improved several cardiometabolic risk factors during the intervention.
- Trial was registered (NCT04732130) and used a randomized, parallel-arm design with a control.
Methodological Strengths
- Randomized, parallel-arm design with trial registration
- Direct head-to-head comparison of two popular intermittent fasting regimens against control
Limitations
- Short intervention duration (4 weeks) limits assessment of sustainability and long-term outcomes
- Young, non-obese cohort limits generalizability to older or obese populations; blinding not feasible
Future Directions: Longer trials in diverse populations to assess durability, safety, and clinical endpoints, and mechanistic studies on adherence, appetite regulation, and metabolic flexibility.