Daily Endocrinology Research Analysis
Analyzed 30 papers and selected 3 impactful papers.
Summary
Analyzed 30 papers and selected 3 impactful articles.
Selected Articles
1. Phosphodiesterase ENPP2, which is co-upregulated in obese and pregnant mice, is essential for islet beta cell compensation during obesity.
Using single-cell transcriptomics and genetic perturbations, the authors identify ENPP2 as a pro-proliferative regulator of beta cells, necessary for obesity-induced compensation and enhanced in pregnancy. ENPP2 acts via the LPA–Akt/mTOR pathway (through LPA receptor 2), improves glucose-stimulated insulin secretion, and its deficiency impairs beta-cell adaptation in diet-induced obesity.
Impact: This work pinpoints an actionable, mechanistically defined node (ENPP2/LPA–mTOR) governing beta-cell mass and function, offering a translational target to slow diabetes progression. The integrated in vitro/in vivo validation elevates confidence for future intervention development.
Clinical Implications: Although preclinical, modulating ENPP2 or downstream LPA–LPAR2–Akt/mTOR signaling could be leveraged to preserve beta-cell mass in obesity and early type 2 diabetes. Hormonal co-regulation (estradiol/progesterone) may inform perinatal or sex-specific strategies.
Key Findings
- Single-cell RNA-seq showed proliferation as the dominant beta-cell compensation mechanism in obesity and pregnancy, with ENPP2 most increased in pregnancy beta cells.
- ENPP2 overexpression promoted beta-cell proliferation, reduced apoptosis, and enhanced high-glucose-stimulated insulin secretion in Min6 cells and Enpp2-transgenic mice.
- Global Enpp2 knockout on a high-fat diet led to insufficient beta-cell compensation during obesity.
- Mechanism involved LPA–LPAR2–Akt/mTOR signaling in beta cells.
- ENPP2 was reduced in diabetic mice and humans with T2D; estradiol and progesterone synergistically upregulated ENPP2.
Methodological Strengths
- Integrated single-cell RNA-seq with in vivo gain- and loss-of-function mouse models
- Convergent validation across cellular, animal, and human datasets
Limitations
- Preclinical models may not fully recapitulate human beta-cell biology
- Global knockout may introduce systemic effects beyond beta cells; beta cell–specific targeting was not isolated in vivo
Future Directions: Develop beta cell–targeted ENPP2/LPAR2 modulators, test pharmacologic activation of the LPA–mTOR axis, and conduct early-phase clinical trials for beta-cell preservation in high-risk metabolic states.
2. GLP-1 receptor agonist use during immune checkpoint inhibitor therapy is associated with mortality and Immune-Related adverse events across cancer types in People with type 2 Diabetes: A Target-Trial emulation.
In a propensity-matched target-trial emulation (n=5,806), GLP-1 RA use overlapping ICI initiation in adults with T2D and cancer was associated with substantially lower all-cause mortality (HR 0.55; NNT 5), fewer hospitalizations, and reduced composite irAEs. Ophthalmic safety signals (retinopathy progression and NAION) emerged, while hypoglycemia and AKI risks were lower.
Impact: This large, methodologically rigorous emulation suggests GLP-1 RAs may improve survival and immunotherapy tolerability in T2D patients with cancer, a high-priority clinical intersection. Findings are timely amid expanding GLP-1 RA use and immunotherapy indications.
Clinical Implications: Consider continuation or initiation of GLP-1 RAs at ICI start in eligible T2D patients after multidisciplinary review, with proactive ophthalmologic monitoring for retinopathy/NAION. Prospective trials are needed before guideline changes.
Key Findings
- All-cause mortality was lower with GLP-1 RA co-exposure at ICI start (HR 0.55, 95% CI 0.51–0.61; 36-month ARD −16.41%; NNT 5).
- Hospitalizations decreased (HR 0.76; ARD −7.06%; NNT 11) and composite irAEs were reduced (43.93% vs 51.51%; ARD −7.58%; NNT 11).
- Safety signals included higher diabetic retinopathy progression (HR 1.75; ARD +2.71%) and NAION (HR 1.51), while hypoglycemia, AKI, and dehydration/orthostasis were lower.
- Robustness supported by per-protocol, 90-day landmark, and semaglutide-only sensitivity analyses.
Methodological Strengths
- Target-trial emulation with new-user, active comparator, 1:1 propensity-score matching
- Large multi-center EHR network and multiple prespecified sensitivity analyses over 36 months
Limitations
- Observational design with potential residual confounding and channeling bias
- Heterogeneity in cancer types, ICI regimens, and unmeasured lifestyle/oncology variables
Future Directions: Conduct randomized and pragmatic trials testing GLP-1 RA strategies with ICI, mechanistic studies on immune modulation, and active surveillance for ocular adverse events.
3. Is FIB-4 the right tool for screening for liver fibrosis?
In primary care cohorts with external validation, FIB-4 demonstrated poor agreement with VCTE and low sensitivity for ≥F2 fibrosis in MASLD. Age-adjusted cut-offs (1.29 for ≤65 years; 1.72 for >65 years) improved sensitivity in older adults versus the 2.0 threshold but reduced specificity.
Impact: By challenging the widespread use of FIB-4 as a gatekeeper in MASLD, this study redirects diagnostic pathways toward more reliable non-invasive strategies and nuanced, age-specific thresholds.
Clinical Implications: Avoid relying on FIB-4 alone to rule out fibrosis in MASLD. Use VCTE or alternative biomarkers, and if using FIB-4, apply age-adjusted thresholds and consider confirmatory testing to mitigate false negatives.
Key Findings
- FIB-4 showed poor agreement with VCTE for fibrosis staging in MASLD (weighted κ=0.138, 95% CI 0.069–0.207).
- Proposed age-adjusted cut-offs: 1.29 (≤65 years) and 1.72 (>65 years) for ≥F2, with validation in Turkish primary care and Belgian T2DM cohorts.
- The 1.72 cut-off improved sensitivity versus 2.0 in older adults but reduced specificity, underscoring trade-offs.
Methodological Strengths
- Prospective primary care cohorts with external validation in distinct populations
- Use of VCTE as a standardized proxy reference and formal agreement metrics
Limitations
- VCTE is a proxy for histology and may introduce misclassification
- Generalizability beyond included regions and potential spectrum bias
Future Directions: Develop and validate multi-marker, age-aware algorithms combining FIB-4 with imaging/biomarkers; assess cost-effectiveness and workflow integration in diabetes and primary care clinics.