Weekly Endocrinology Research Analysis
This week’s endocrinology literature highlights mechanistic genomics, impactful surgical outcomes, and novel molecular tools. A functional genomics study links DENND1A regulatory variation to androgen excess in PCOS, providing a causal bridge from GWAS to phenotype. A large multicentre randomized trial in The Lancet shows SADI-S yields superior 2‑year weight loss versus Roux‑en‑Y with comparable safety, influencing bariatric practice. Advanced molecular probes (fluorescent dual GLP1R/GIPR agonis
Summary
This week’s endocrinology literature highlights mechanistic genomics, impactful surgical outcomes, and novel molecular tools. A functional genomics study links DENND1A regulatory variation to androgen excess in PCOS, providing a causal bridge from GWAS to phenotype. A large multicentre randomized trial in The Lancet shows SADI-S yields superior 2‑year weight loss versus Roux‑en‑Y with comparable safety, influencing bariatric practice. Advanced molecular probes (fluorescent dual GLP1R/GIPR agonists) enable direct mapping of incretin targets across pancreas and brain, accelerating rational incretin therapeutic design.
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 (reporter assays + CRISPR epigenome editing) identified regulatory elements at DENND1A and other PCOS loci.
- Perturbation increasing endogenous DENND1A expression in an adrenal model elevated testosterone production, linking regulation to 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. The trial used intention‑to‑treat analysis across 22 bariatric centers and provides the first large randomized evidence favoring SADI‑S for mid-term weight outcomes.
Impact: First large randomized head‑to‑head trial suggesting SADI‑S may outperform RYGB for weight loss at 2 years without increased short‑term harm — likely to influence surgical decision‑making and guideline updates.
Clinical Implications: SADI‑S should be considered as a preferred option for selected patients seeking greater weight loss, with careful long‑term nutritional monitoring given its malabsorptive component.
Key Findings
- 381 patients randomized across 22 centers (SADI‑S 190; RYGB 191) with ITT analysis.
- SADI‑S achieved superior 2‑year weight loss versus RYGB with comparable safety profiles over follow‑up.
3. Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain.
The authors developed lipidated and non‑lipidated fluorescent dual GLP1R/GIPR agonist probes (daLUXendins) that retain potent dual‑agonism and label rodent and human islet cells (β>α=δ) and GLP1R‑rich brain regions in vivo, reducing receptor‑selectivity bias and enabling tissue‑level mapping of incretin engagement.
Impact: Introduces first‑in‑class molecular tools that directly map dual‑agonist tissue targets — a key enabling advance for optimizing dosing, safety profiling, and next‑generation incretin drug design.
Clinical Implications: These probes can guide preclinical target validation, off‑target safety assessment, and translational studies that inform dosing and design of GLP1R/GIPR dual agonists; eventual clinical translation could refine patient selection and adverse‑event monitoring.
Key Findings
- Developed daLUXendin probes (lipidated and non‑lipidated) with potent GLP1R/GIPR dual agonism.
- Probes robustly label rodent and human islet cells (β cells > α = δ) and GLP1R‑enriched brain regions in vivo.