Daily Endocrinology Research Analysis
Analyzed 44 papers and selected 3 impactful papers.
Summary
Analyzed 44 papers and selected 3 impactful articles.
Selected Articles
1. Beta cell-derived cholecystokinin drives obesity-associated pancreatic adenocarcinoma development.
In obese mice, beta cell-derived cholecystokinin (CCK), not insulin, is a key driver of PDAC progression. Obesity expands immature β cells that reprogram via JNK/cJun to express CCK, reshaping peri-islet exocrine transcriptional states and fostering islet-proximal tumors.
Impact: This study reframes endocrine–exocrine signaling in pancreatic cancer by identifying β cell CCK as a bona fide driver of obesity-associated PDAC. It opens tractable targets (CCK or upstream JNK/cJun) to disrupt tumor–islet crosstalk.
Clinical Implications: Although preclinical, findings suggest that modulating β-cell CCK or its stress-activated induction could mitigate PDAC risk/progression in obesity. They also support biomarker development assessing islet CCK activity near tumors.
Key Findings
- Beta cell CCK expression is necessary and sufficient to drive obesity-associated PDAC progression in mice, outperforming insulin as a correlate of tumorigenesis.
- Obesity induces expansion of postnatal immature β cells that adopt CCK expression via stress-responsive JNK/cJun signaling.
- CCK-dependent remodeling of peri-islet exocrine transcriptional states enhances islet-proximal tumor formation.
Methodological Strengths
- Integrated single-cell RNA-seq with archetypal/trajectory analyses and in vivo lineage tracing
- Convergent genetic and functional perturbations demonstrating necessity and sufficiency of β-cell CCK
Limitations
- Preclinical mouse-focused evidence; limited direct validation in human PDAC tissues
- Potential context-specificity to obesity-associated tumorigenesis
Future Directions: Validate β-cell CCK axis in human PDAC, define therapeutic windows to target CCK or JNK/cJun without impairing islet function, and test combinatorial strategies with standard PDAC therapies.
Pancreatic endocrine-exocrine crosstalk plays a key role in normal physiology and disease and can be altered by host metabolic states, such as obesity. Classically, endocrine islet beta (β) cell secretion of insulin is thought to promote the development of obesity-associated pancreatic adenocarcinoma (PDAC), an exocrine cell-derived tumor. Here, we show that β cell expression of the peptide hormone cholecystokinin (CCK) is necessary and sufficient for obesity-associated PDAC progression in mice and that CCK expression - rather than insulin - correlates strongly with enhanced tumorigenesis. Single-cell RNA-sequencing, in silico latent-space archetypal and trajectory analysis, and experimental lineage tracing in vivo reveal that obesity induces the expansion of postnatal immature β cells, which adapt to express CCK via stress-responsive JNK/cJun signaling. Finally, obesity perturbs CCK-dependent peri-islet exocrine cell transcriptional states and enhances islet-proximal tumor formation. These results define endocrine-exocrine CCK signaling as a bona fide driver of obesity-associated PDAC development and uncover avenues to target the endocrine pancreas to subvert exocrine tumorigenesis.
2. An extracellular vesicle-mediated mitochondrial transfer network critical for testosterone synthesis.
Leydig cells maintain mitochondrial homeostasis via an extracellular vesicle-mediated transfer network with testicular macrophages. Defective mitochondria are exported in vesicles and cleared by CD206-expressing macrophages, a mechanism essential for sustaining testosterone synthesis.
Impact: This work uncovers a fundamental mitochondrial quality-control pathway in the testis, redefining how steroidogenic capacity is preserved despite sustained metabolic stress.
Clinical Implications: Insights into Leydig cell–macrophage mitochondrial crosstalk suggest new targets for male infertility and hypogonadism, potentially enabling therapies that bolster steroidogenesis without cytotoxicity.
Key Findings
- Identification of a mitochondrial transfer network between Leydig cells and distinct testicular macrophage subpopulations.
- Leydig cells export defective mitochondria within extracellular vesicles.
- CD206-expressing macrophages eliminate these vesicle-encapsulated dysfunctional mitochondria, supporting steroidogenic function.
Methodological Strengths
- In vivo identification of intercellular organelle transfer via extracellular vesicles
- Cell-type-specific dissection of macrophage subpopulations engaged in mitochondrial clearance
Limitations
- Abstract indicates mechanistic pathway but provides limited quantitative data in the summary provided
- Translational validation in human testis and clinical phenotypes remains to be established
Future Directions: Quantify the dynamics and regulation of mitochondrial cargo loading into EVs, define macrophage receptors and effectors (including CD206 pathways), and test therapeutic modulation in models of hypogonadism.
Testosterone production by testicular Leydig cells (LCs) in male mammals is energetically demanding and prone to mitochondrial damage. Despite these challenges, LCs exhibit remarkable longevity and minimal turnover, suggesting the existence of specialized mechanisms that maintain LC mitochondrial homeostasis under such constrains. Here we identify a mitochondrial transfer network between LCs and different testicular macrophage (tMac) subpopulations. Leydig cells release extracellular vesicles containing defective mitochondria, which are eliminated by CD206
3. Comparative safety of sulfonylurea therapies on cardiovascular and severe hypoglycemia outcomes among adults with type 2 diabetes and moderate cardiovascular risk: a target trial emulation.
In a 314,699-patient target trial emulation, glimepiride had the lowest 1-year MACE risk, while glipizide minimized severe hypoglycemia risk. Glyburide was associated with higher MACE and hypoglycemia versus comparators.
Impact: This large, methodologically rigorous emulation provides actionable, within-class safety differentiation among sulfonylureas, guiding treatment where SUs remain in use.
Clinical Implications: When selecting a sulfonylurea for T2D with moderate CV risk, glimepiride may be preferred for lower MACE, whereas glipizide may be favored if minimizing severe hypoglycemia is paramount.
Key Findings
- Glimepiride users had the lowest 1-year MACE incidence (2.5%) versus glipizide (2.7%) and glyburide (2.8%).
- Compared with glimepiride, MACE risk was higher with glyburide (HR 1.10, 95% CI 1.05–1.16) and glipizide (HR 1.05, 95% CI 1.03–1.07).
- Severe hypoglycemia risk was lowest with glipizide (HR 0.82 vs glimepiride) and highest with glyburide (HR 1.43 vs glipizide).
Methodological Strengths
- Target trial emulation with IPTW using super learner propensity models across two large claims datasets
- Very large sample size enabling precise comparative safety estimates
Limitations
- Observational design subject to residual confounding and misclassification from claims data
- Findings may not generalize to high CV-risk populations or non-U.S. healthcare settings
Future Directions: Prospective head-to-head trials of sulfonylureas, dose–response analyses, and subgroup evaluations (e.g., CKD, elderly) to refine individualized SU selection.
INTRODUCTION: To examine within-class sulfonylurea safety, we compared risks of major adverse cardiovascular events (MACE) and severe hypoglycemia among adults with type 2 diabetes (T2D) and moderate cardiovascular risk following sulfonylurea initiation. RESEARCH DESIGN AND METHODS: We conducted a target trial emulation including adults ≥21 years old with T2D and moderate cardiovascular risk who initiated glimepiride, glipizide or glyburide between 2014 and 2021, using claims data from Optum Labs Data Warehouse and the Medicare fee-for-service 100% sample. Study outcomes were MACE (primary), expanded MACE and its components and emergency department or hospital encounters for hypoglycemia, ascertained during follow-up through 2022. Inverse probability of treatment weighting (IPTW) was applied using propensity scores estimated using the super learner ensemble, and outcomes were examined using IPTW Cox proportional hazards models. RESULTS: The weighted study cohort comprised 314 699 patients (mean age 66.9 years, 52.0% men, 76.6% non-Hispanic white). At 1 year, MACE was experienced by 2.5%, 2.7% and 2.8% of patients starting glimepiride, glipizide and glyburide, respectively. Compared with glimepiride, glyburide and glipizide were associated with higher risk of MACE (HR 1.10, 95% CI 1.05 to 1.16 for glyburide; HR 1.05, 95% CI 1.03 to 1.07 for glipizide). At 1 year, severe hypoglycemia was experienced by 0.3%, 0.3% and 0.4% of patients starting glimepiride, glipizide and glyburide, respectively. Glyburide was associated with a greater risk of severe hypoglycemia compared with glipizide (HR 1.43, 95% CI 1.23 to 1.65), while glipizide was associated with a lower risk compared with glimepiride (HR 0.82, 95% CI 0.77 to 0.87). CONCLUSIONS: Among adults with T2D and moderate cardiovascular risk, glimepiride was associated with lowest risk of MACE and glipizide with lowest risk of severe hypoglycemia. These results can help inform treatment selection if sulfonylureas are used for glucose-lowering.