Endocrinology Research Analysis
August’s endocrinology research converged on mechanistic targets and translational tools across metabolic and reproductive axes. Functional genomics linked DENND1A regulatory activity to androgen excess in PCOS, while autophagy–SNARE dysfunction (G3BP1) and immunometabolic targeting (ACLY) refined therapeutic strategies for MASLD/MASH and MASH‑HCC. A large randomized trial indicated SADI‑S yields superior two‑year weight loss vs RYGB, and fluorescent dual GLP1R/GIPR agonist probes enabled direct
Summary
August’s endocrinology research converged on mechanistic targets and translational tools across metabolic and reproductive axes. Functional genomics linked DENND1A regulatory activity to androgen excess in PCOS, while autophagy–SNARE dysfunction (G3BP1) and immunometabolic targeting (ACLY) refined therapeutic strategies for MASLD/MASH and MASH‑HCC. A large randomized trial indicated SADI‑S yields superior two‑year weight loss vs RYGB, and fluorescent dual GLP1R/GIPR agonist probes enabled direct tissue mapping to optimize incretin therapeutics. Living comparative evidence for T2D pharmacotherapy and microbiome‑derived peptides rounded out a month emphasizing actionable biology and practice‑facing data.
Selected Articles
1. Gene regulatory activity associated with polycystic ovary syndrome revealed DENND1A-dependent testosterone production.
Using massively parallel reporter assays and CRISPR-based epigenome editing, the authors fine-mapped regulatory elements at PCOS GWAS loci (including DENND1A) and showed that upregulation of endogenous DENND1A in an adrenal cell model raises testosterone, linking noncoding regulatory variation to a core PCOS endophenotype.
Impact: Provides one of the first functional causal links from GWAS-identified regulatory variants to androgen excess in PCOS, enabling mechanistic target identification for future therapies.
Clinical Implications: Improved causal variant mapping may permit genetic risk stratification and inform development of DENND1A‑targeted or regulator-focused interventions to reduce hyperandrogenism in PCOS.
Key Findings
- Functional genomics identified regulatory elements at DENND1A and other PCOS loci.
- CRISPR-based perturbation increasing endogenous DENND1A elevated testosterone in an adrenal model.
- Bridges noncoding regulatory variation to a core endocrine phenotype.
2. Efficacy and safety of single-anastomosis duodeno-ileal bypass with sleeve gastrectomy versus Roux-en-Y gastric bypass in France (SADISLEEVE): results of a randomised, open-label, superiority trial at 2 years of follow-up.
In a multicentre French RCT (n=381), SADI‑S produced superior weight loss at 2 years compared with RYGB with a similar safety profile, providing the first large randomized evidence favoring SADI‑S for mid-term outcomes.
Impact: Head-to-head randomized evidence likely to influence bariatric surgical decision-making and guidelines by showing superior mid-term efficacy without excess harm.
Clinical Implications: SADI‑S can be considered for patients prioritizing greater weight loss with careful long‑term nutritional surveillance given its malabsorptive component.
Key Findings
- 381 patients randomized across 22 centers with ITT analysis.
- SADI‑S achieved superior 2‑year weight loss vs RYGB with comparable safety.
- First large RCT to support SADI‑S superiority in mid-term weight outcomes.
3. Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain.
Lipidated and non‑lipidated fluorescent dual GLP1R/GIPR agonist probes (daLUXendins) retained potent dual agonism, labeling rodent and human islet cells and GLP1R‑rich brain regions in vivo, enabling direct tissue‑level mapping of incretin engagement.
Impact: First-in-class molecular tools to visualize dual agonist target engagement, directly informing dose optimization, safety profiling, and next-generation incretin drug design.
Clinical Implications: Facilitates preclinical target validation and off-target safety assessments for GLP1R/GIPR dual agonists; supports translational studies guiding dosing, tissue exposure, and patient selection.
Key Findings
- Developed lipidated and non‑lipidated daLUXendin probes with potent GLP1R/GIPR dual agonism.
- Robust in vivo labeling of rodent and human islet cells (β>α=δ) and GLP1R‑enriched brain regions.
- Reduces receptor‑selectivity bias and enables direct mapping of incretin engagement.
4. ACLY inhibition promotes tumour immunity and suppresses liver cancer.
ACLY inhibition reprograms the immunosuppressive microenvironment in MASH‑driven hepatocellular carcinoma, enhancing anti‑tumor immunity and suppressing tumor growth in preclinical models, nominating ACLY as an actionable immunometabolic target.
Impact: Positions ACLY as a high‑value immunometabolic node with translational potential to convert non‑inflamed MASH‑HCC into an immunoresponsive state.
Clinical Implications: Supports testing ACLY inhibitors to enhance immunotherapy efficacy in patients with MASH‑HCC, potentially expanding options for a treatment‑resistant subgroup.
Key Findings
- ACLY inhibition enhanced anti‑tumor immunity within immunosuppressive MASH‑HCC models.
- ACLY targeting suppressed liver cancer growth in preclinical systems.
- Frames ACLY as an actionable immunometabolic therapeutic node.
5. Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.
Human MASLD/MASH samples and hepatocyte-specific G3BP1 knockout mice show that reduced G3BP1 impairs autophagosome–lysosome fusion (via STX17/VAMP8), prevents TFE3 nuclear translocation, and increases de novo lipogenesis, worsening steatosis and steatohepatitis.
Impact: Identifies a G3BP1–STX17/VAMP8–TFE3 autophagy–transcriptional axis linking autophagy dysfunction to hepatic lipogenesis and steatohepatitis, nominating a druggable node.
Clinical Implications: Supports preclinical development of agents restoring G3BP1 function or autophagosome–lysosome fusion and biomarker strategies along the G3BP1/TFE3 pathway.
Key Findings
- Reduced hepatic G3BP1 in human MASLD/MASH.
- Hepatocyte-specific G3BP1 knockout worsened steatosis and steatohepatitis.
- G3BP1 promotes autophagosome–lysosome fusion via STX17/VAMP8 and enables TFE3 nuclear translocation.