Weekly Endocrinology Research Analysis
This week’s endocrinology literature highlights mechanistic advances with clear translational potential and a phase‑3 randomized therapeutic win. High-resolution structural biology identified an adipocyte regulator (adipogenin) that stabilizes seipin to drive lipid droplet biogenesis, offering a new axis for lipid‑storage disorders. A peptide (spexin) was shown to bind ATP1A1 and restore β‑cell function in preclinical models, advancing beta‑cell–targeted therapeutic strategies. Finally, a phase‑
Summary
This week’s endocrinology literature highlights mechanistic advances with clear translational potential and a phase‑3 randomized therapeutic win. High-resolution structural biology identified an adipocyte regulator (adipogenin) that stabilizes seipin to drive lipid droplet biogenesis, offering a new axis for lipid‑storage disorders. A peptide (spexin) was shown to bind ATP1A1 and restore β‑cell function in preclinical models, advancing beta‑cell–targeted therapeutic strategies. Finally, a phase‑3 RCT found ropeginterferon alfa‑2b superior to anagrelide for hydroxyurea‑intolerant/refractory essential thrombocythaemia, providing high‑level evidence likely to change second‑line practice.
Selected Articles
1. Adipogenin promotes the development of lipid droplets by binding a dodecameric seipin complex.
High‑resolution cryo‑EM (≈3.0 Å) and in vivo models show adipogenin (Adig) selectively binds dodecameric seipin, bridging subunits to stabilize the complex and promote lipid droplet biogenesis; adipocyte‑specific Adig overexpression increases adiposity while deletion impairs triglyceride accumulation in brown fat.
Impact: Defines a concrete structural mechanism controlling lipid storage and nominates the Adig–seipin interface as a druggable axis for lipodystrophy/obesity research.
Clinical Implications: Although preclinical, targeting Adig–seipin could offer novel strategies to modulate adipose storage in disorders of lipid distribution; human genetic and safety data are needed before clinical translation.
Key Findings
- Cryo‑EM structure reveals mammalian seipin forms undecamers and dodecamers; Adig selectively binds dodecamers.
- Adig bridges and stabilizes adjacent seipin subunits, promoting lipid droplet biogenesis at multiple stages.
- Adipocyte‑specific Adig overexpression increases fat mass and lipid droplet size; Adig deletion impairs triglyceride accumulation in brown fat.
2. Peptide hormone spexin restores beta cell function and improves glycaemic control in mice via regulation of the sodium-potassium pump.
Preclinical studies demonstrate spexin increases glucose‑stimulated insulin secretion and β‑cell proliferation, improves glucose tolerance in diet and STZ models, and biochemically binds the Na+/K+‑ATPase α1 subunit (ATP1A1), inhibiting pump activity and inducing membrane depolarization—positioning spexin–ATP1A1 signaling as a beta‑cell therapeutic axis.
Impact: Identifies a defined molecular target (ATP1A1) and demonstrates in vivo beta‑cell efficacy, advancing peptide therapeutic strategies for diabetes.
Clinical Implications: Translational potential to develop spexin analogues or ATP1A1‑modulating agents to boost insulin secretion/β‑cell mass; human islet validation and careful safety profiling are required due to ATP1A1 ubiquity.
Key Findings
- Spexin increased glucose‑stimulated insulin secretion and β‑cell proliferation in mouse islets and in vivo.
- Improved glucose tolerance in HFD and HFD/STZ diabetic mouse models with elevated serum insulin.
- Pull‑down/MS and binding assays show spexin binds ATP1A1, inhibiting Na+/K+‑ATPase activity and causing membrane depolarization.
3. Ropeginterferon alfa-2b in hydroxyurea-intolerant or hydroxyurea-refractory essential thrombocythaemia (SURPASS ET): a multicentre, open-label, randomised, active-controlled, phase 3 study.
In 174 randomized HU‑intolerant/refractory ET patients, ropeginterferon alfa‑2b produced significantly higher durable modified ELN responses at months 9 and 12 (43% vs 6% with anagrelide) and fewer grade ≥3 and serious adverse events, signaling a superior second‑line option.
Impact: Provides high‑quality phase‑3 randomized evidence that will likely change second‑line management for HU‑intolerant/refractory ET and informs safety/tolerability considerations.
Clinical Implications: Clinicians managing HU‑intolerant/refractory ET should consider ropeginterferon alfa‑2b as a preferred second‑line option given superior durable responses and a favorable safety profile; longer follow‑up for thrombotic and molecular outcomes is needed.
Key Findings
- Durable modified ELN responses at months 9 and 12: 43% (ropeginterferon) vs 6% (anagrelide); difference statistically significant.
- Lower frequency of grade ≥3 treatment‑emergent adverse events and serious adverse events with ropeginterferon.
- Cerebral infarctions occurred only in the anagrelide arm; no treatment‑related deaths reported.