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.
Tumor-induced osteomalacia (TIO) is a rare disorder caused by a phosphaturic mesenchymal tumor (PMT) secreting fibroblast growth factor 23 (FGF23). The aim of this study was to analyze PMTs for their transcriptomic characteristics. We performed single-cell RNA (n = 3) alongside bulk RNA sequencing of PMTs (n = 5) and surrounding bone tissue (n = 4) obtained during tumor removal in 10 patients (age 44 (41;64), serum phosphate (Pi)- 0.54 (0.43; 0.59) mM/L, FGF23-113 (40; 205) pg/ml). We revealed a total of 22,449 cells divided into 13 different categories. We identified the heterogeneity of the PMT cell cluster and subsequently divided it into two tumor clusters 1 and 2 characterized by the deeper epithelial-mesenchymal phenotype transition, higher FGF23 expression as well as various SNP and CNV. We further identified tumor cell differentiation driving regulons ERG and EGR3, based on scoring by allele expression and velocity based pseudotime on a trajectory that may play a critical role in the tumorigenesis of PMTs. In both single-cell and bulk transcriptome analysis we found upregulation of vesicle-specific and exocytosis associated genes (SLC30A3, SYT1, STX1A and SNAP25) which most likely represent molecular mechanisms of active secretion in all PMT samples. We report transmembrane protein coding genes expressed in all PMTs specifically in tumor cell clusters (PHEX, ERBB4, PCDH7, LRRFIP2) which are suggested as potential diagnostic targets. We confirmed the presence of FN1-FGFR1 fusion genes and Klotho expression in most PMTs (6 out of 8). Conclusion: specific SNARE proteins gene upregulation along with transcriptional signatures of PMT offer new insights into its pathogenesis which may be further studied for diagnostic and therapeutic interventions.
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.
OBJECTIVE: Evidence on acute pancreatitis and pancreatic cancer with glucagon-like peptide-1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy is mixed, and no studies examined this risk directly across all commonly used classes of type 2 diabetes medications, particularly sodium-glucose cotransporter 2 inhibitors (SGLT2is) and sulfonylureas. METHODS: De-identified claims data from OptumLabs Data Warehouse and fee-for-service Medicare were used to emulate a target trial examining the risks of incident acute pancreatitis and pancreatic cancer among adults with type 2 diabetes and moderate cardiovascular risk. Propensity scores (estimated using the SuperLearner ensemble method) and inverse probability of treatment weighting emulated random treatment assignment to GLP-1RA, DPP-4i, SGLT2i, or sulfonylurea. RESULTS: The weighted study cohort included 388 262 patients starting GLP-1RA (N = 44 084), DPP-4i (N = 82 079), SGLT2i (N = 56 463), or a sulfonylurea (N = 205 636). SGLT2i was associated with a lower risk of acute pancreatitis compared with DPP-4i (hazard ratio [HR], 0.82; 95% CI, 0.68-0.98). Conversely, sulfonylurea was associated with a higher risk compared with GLP-1RA (HR, 1.28; 95% CI, 1.03-1.56) and SGLT2i (HR, 1.32; 95% CI, 1.12-1.57). There was no difference in acute pancreatitis risk between GLP-1RA and DPP-4i or GLP-1RA and SGLT2i. The risk of pancreatic cancer was lower with GLP-1RA compared with DPP-4i (HR, 0.56; 95% CI, 0.40-0.77). In contrast, risk was higher with SGLT2i and sulfonylurea compared with GLP-1RA (HR, 1.67; 95% CI, 1.12-2.49 and HR, 1.60; 95% CI, 1.17-2.19, respectively). CONCLUSION: GLP-1RA and DPP-4i therapy was not associated with increased risk of adverse pancreatic events. The lower risk of acute pancreatitis with SGLT2i therapy warrants further exploration.
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.
BACKGROUND & AIMS: Intermittent fasting (IF) is a popular nutritional strategy for weight control and improved metabolic health, however it is unclear which type of intermittent fasting is most effective. This randomized trial directly compared short-term alternate-day fasting (ADF) and time-restricted eating (TRE) with controls in adults with overweight or a high normal weight. The aim was to compare the effects of ADF and TRE versus controls regarding whole-body fat mass loss, weight control and cardiometabolic health. METHODS: In this 4-week, parallel-arm, randomized clinical trial (February 2021-May 2022), participants aged 18-40 years with a body mass index between 23 and 30 kg/m RESULTS: Seventy-six participants (mean [standard deviation (SD)] age, 29.6 [5.6] years; body mass index, 25.8 [2.2] kg/m CONCLUSIONS: In this randomized clinical trial, ADF was more effective in reducing energy intake than TRE which has subsequent effects on fat mass and body weight. Only ADF improved several cardiometabolic risk factors. REGISTRATION: https://clinicaltrials.gov/study/NCT04732130; Unique identifier: NCT04732130.