Weekly Endocrinology Research Analysis
This week featured high-impact translational advances across diabetes cell therapy, microbiome enzymology, and wound-healing biology. A pluripotent stem cell-derived islet reconstruction achieved full endocrine subtype composition and in vivo hypoglycemia protection, an AI pipeline mapped hundreds of thousands of microbial bile-acid enzymes and discovered a novel bile-acid skeleton, and mechanistic work revealed galectin-3/integrin α5β1 phase separation as a druggable pathway to restore diabetic
Summary
This week featured high-impact translational advances across diabetes cell therapy, microbiome enzymology, and wound-healing biology. A pluripotent stem cell-derived islet reconstruction achieved full endocrine subtype composition and in vivo hypoglycemia protection, an AI pipeline mapped hundreds of thousands of microbial bile-acid enzymes and discovered a novel bile-acid skeleton, and mechanistic work revealed galectin-3/integrin α5β1 phase separation as a druggable pathway to restore diabetic angiogenesis. Together these studies push toward safer beta-cell replacement, microbiome-informed metabolic interventions, and local therapies for diabetic complications.
Selected Articles
1. Reconstruction of endocrine subtype-complete human pluripotent stem cell-derived islets with capacity for hypoglycemia protection in vivo.
The authors engineered PSC-derived islets containing all five endocrine subtypes (α, β, δ, ε, γ) and demonstrated that reconstructed grafts not only reverse hyperglycemia but markedly reduce hypoglycemia exposure and restore counterregulatory responses during hypoglycemic clamps in diabetic mice.
Impact: First preclinical demonstration that restoring full endocrine cell composition in PSC-islets addresses a key safety barrier — hypoglycemia post–beta-cell replacement — advancing the field toward clinically safer cell therapies.
Clinical Implications: Supports development of PSC-islet products with calibrated endocrine subtype ratios and potency criteria to minimize post-transplant hypoglycemia risk; informs preclinical-to-clinical translation and trial design for beta-cell replacement.
Key Findings
- Engineered PSC-islets with α, β, δ, ε, and γ cells were robustly generated in vitro.
- In diabetic mice, reconstructed PSC-islets reduced hypoglycemia exposure (only 3% of readings <54 mg/dL) compared with 59% in non-reconstructed controls.
- Hypoglycemic clamp assays suggested restoration of counterregulatory responses in recipients of reconstructed PSC-islets.
2. Identification of gut microbial bile acid metabolic enzymes via an AI-assisted pipeline.
Using an AI-assisted workflow (BEAUT) the authors predicted over 600,000 candidate gut microbial bile-acid metabolic enzymes, published the HGBME database, and experimentally validated novel enzyme activities including ADS that produces a previously unreported skeleton bile acid (3-acetoDCA) which modulates microbial interactions.
Impact: Creates a broadly useful enzymatic map and publicly available resource that enables mechanistic linking of microbial bile-acid chemistry to host physiology and identifies novel enzymatic activities amenable to manipulation.
Clinical Implications: Provides foundational tools for microbiome-informed interventions that modulate bile-acid pools — potential future applications include metabolic disease modulation, cholestasis management, and targeted probiotics or small-molecule enzyme inhibitors.
Key Findings
- BEAUT AI workflow predicted >600,000 candidate microbial bile-acid enzymes compiled into the HGBME database.
- Experimentally validated new enzymes including MABH and ADS; ADS generates a novel C–C bond extended bile-acid (3-acetoDCA) that is widespread and modulates microbial ecology.
3. Galectin-3-integrin α5β1 phase separation disrupted by advanced glycation end-products impairs diabetic wound healing in rodents.
Galectin-3 binds integrin α5β1 and forms liquid–liquid phase-separated condensates that enhance FAK signaling and angiogenesis; advanced glycation end-products (AGEs) disrupt this interaction in diabetes. Topical recombinant galectin-3 delivered in hydrogels restored angiogenesis and accelerated wound healing in diabetic rodents without causing systemic insulin resistance and showed synergy with insulin.
Impact: Defines a phase-separation–based receptor mechanism for angiogenesis that is impaired in diabetes and provides an immediately translational local therapy concept (topical galectin-3) with in vivo efficacy and metabolic safety data.
Clinical Implications: Supports development of topical galectin-3 formulations (e.g., hydrogel delivery) as an adjunctive therapy for diabetic foot ulcers to restore angiogenesis and healing while minimizing systemic metabolic effects.
Key Findings
- Galectin-3 forms LLPS condensates with integrin α5β1, enhancing FAK phosphorylation and angiogenesis.
- AGEs bind galectin-3 and block its interaction with integrin α5β1, impairing angiogenesis in diabetic conditions.
- Topical recombinant galectin-3 hydrogel restores wound healing in diabetic rodent models without inducing systemic insulin resistance.