Weekly Endocrinology Research Analysis
This week’s endocrinology literature highlights durable progress on three fronts: adaptive immunotherapy dose-optimization that preserves beta-cell function in recent-onset type 1 diabetes (Lancet); discovery of a hepatocyte caspase‑8–YY1–meteorin axis driving MASH fibrosis, opening new anti-fibrotic targets (Nature Metabolism); and identification of a lysosomal LRRC8 anion channel program linking organelle pH to mTOR signaling and systemic insulin sensitivity (Science Advances). Together these
Summary
This week’s endocrinology literature highlights durable progress on three fronts: adaptive immunotherapy dose-optimization that preserves beta-cell function in recent-onset type 1 diabetes (Lancet); discovery of a hepatocyte caspase‑8–YY1–meteorin axis driving MASH fibrosis, opening new anti-fibrotic targets (Nature Metabolism); and identification of a lysosomal LRRC8 anion channel program linking organelle pH to mTOR signaling and systemic insulin sensitivity (Science Advances). Together these papers push therapeutic innovation (low-toxicity immune modulation, organelle-targeted drugs) and deepen mechanistic understanding that can be translated into biomarker-led trials.
Selected Articles
1. Minimum effective low dose of antithymocyte globulin in people aged 5-25 years with recent-onset stage 3 type 1 diabetes (MELD-ATG): a phase 2, multicentre, double-blind, randomised, placebo-controlled, adaptive dose-ranging trial.
An adaptive, multicentre, double‑blind RCT (n=117) tested ATG dose ranges in recent-onset type 1 diabetes and found that both 2.5 mg/kg and 0.5 mg/kg preserved stimulated C‑peptide at 12 months versus placebo. Importantly, the 0.5 mg/kg dose retained efficacy with markedly fewer immune-related adverse events, identifying a minimum effective, better-tolerated dose for disease‑modifying therapy.
Impact: First adaptive dose-ranging randomized evidence identifying a low, efficacious ATG dose with improved tolerability — a direct path toward phase‑3 testing of a disease-modifying immunotherapy in recent-onset type 1 diabetes.
Clinical Implications: 0.5 mg/kg ATG is a promising candidate for phase‑3 trials aiming to preserve beta-cell function with fewer AEs. Clinicians and trialists should prioritize early diagnosis windows (weeks from onset) and build safety monitoring for cytokine-release/serum-sickness mitigation.
Key Findings
- Both 2.5 mg/kg and 0.5 mg/kg ATG improved 12-month stimulated C‑peptide versus placebo (baseline-adjusted ln(AUC C‑peptide+1) differences 0.124 and 0.102).
- Adverse events were dose-dependent: cytokine release syndrome and serum sickness markedly higher at 2.5 mg/kg versus 0.5 mg/kg; 0.5 mg/kg offered a better tolerability profile.
- 0.5 mg/kg was identified as a minimum effective dose in people aged 5–25 within 3–9 weeks of diagnosis.
2. A non-apoptotic caspase-8-meteorin pathway in hepatocytes promotes MASH fibrosis.
This mechanistic study demonstrates that hepatocyte caspase‑8, via YY1, induces secretion of meteorin which activates hepatic stellate cells through c‑Kit–STAT3 to drive fibrosis in metabolic-dysfunction-associated steatohepatitis. Hepatocyte-specific caspase‑8 deletion reduced fibrosis without affecting apoptosis; meteorin manipulation (rescue/silencing) bidirectionally modulated fibrogenesis and meteorin was elevated in human MASH.
Impact: Identifies a druggable hepatocyte-to-stellate signaling axis (caspase‑8→YY1→meteorin→c‑Kit–STAT3) that dissociates apoptosis from fibrogenesis and provides genetic rescue/silencing proof-of-concept and human relevance — a paradigm shift in MASH biology and anti-fibrotic target discovery.
Clinical Implications: Meteorin levels could be developed as a biomarker for patient stratification, and therapeutic approaches targeting hepatocyte caspase‑8/YY1, meteorin itself, or downstream c‑Kit–STAT3 signaling warrant preclinical drug development and early-phase trials in MASH.
Key Findings
- Hepatic caspase‑8 expression correlates with fibrosis in human and mouse MASH.
- Hepatocyte-specific caspase‑8 deletion suppresses fibrosis and HSC activation without altering apoptosis.
- Caspase‑8–YY1 induces secreted meteorin which activates HSCs via c‑Kit–STAT3; meteorin manipulation bidirectionally affects fibrosis.
3. Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
This preclinical study identifies LRRC8 subunits on a subset of lysosomes in myotubes and shows LRRC8A controls lysosomal pH, size, and leucine-stimulated PI3K–AKT–mTOR signaling. A motif mutation in LRRC8A reproduced cellular signaling defects and knock‑in mice developed adiposity, glucose intolerance, and insulin resistance with reduced muscle glucose uptake and glycogen incorporation, revealing a lysosomal ion channel program that regulates systemic insulin sensitivity.
Impact: Bridges organelle biophysics and whole-body metabolism by implicating a lysosomal anion channel (LRRC8) in nutrient sensing and insulin sensitivity — a novel target class for metabolic disease therapeutics and biomarker development.
Clinical Implications: Supports early-stage drug discovery targeting LRRC8-dependent lysosomal function or trafficking motifs to modulate mTOR tone and improve insulin sensitivity; motivates validation of lysosomal pH–related biomarkers in humans with insulin resistance.
Key Findings
- Endogenous LRRC8 subunits localize to a subset of lysosomes and regulate lysosomal pH, size, and number.
- LRRC8A modulates leucine-stimulated mTOR signaling and lysosomal protein expression (LAMP2, P62, LC3B).
- LRRC8A motif-mutant knock-in mice show adiposity, impaired glucose tolerance, insulin resistance, and reduced muscle glucose uptake/glycogen incorporation.