GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.
Summary
Following GLP-1RA stimulation, endosomal GLP-1R engages ER tether VAPB and the AKAP SPHKAP at ER–mitochondria contact sites to create a localized cAMP/PKA signaling hub. This PKA-RIα condensate modifies MICOS phosphorylation, drives mitochondrial remodeling, and improves β-cell insulin secretion and stress survival.
Key Findings
- Endosomal GLP-1R associates with ER tether VAPB at ER–mitochondria contact sites after GLP-1RA stimulation.
- GLP-1R engages SPHKAP to form a PKA-RIα condensate, creating ERMCS-localized cAMP/PKA signaling.
- MICOS phosphorylation and mitochondrial remodeling ensue, enhancing β-cell insulin secretion and stress survival.
- SPHKAP, linked to T2D/adiposity GWAS signals, functions as a crucial AKAP scaffold in this pathway.
Clinical Implications
Supports that GLP-1RAs may preserve β-cell function by organizing localized cAMP/PKA signaling at ER–mitochondria interfaces; SPHKAP/VAPB complexes may be novel drug targets to enhance β-cell resilience in T2D.
Why It Matters
Identifies an endosomal–ER–mitochondria signaling axis linking GLP-1R activation to mitochondrial remodeling and β-cell functional adaptation via SPHKAP, a GWAS-implicated scaffold. This mechanistic insight can inform next-generation incretin therapies and β-cell protective strategies.
Limitations
- Preclinical mechanistic work; no randomized clinical validation
- Quantitative causal contribution in vivo across disease stages remains to be defined
Future Directions
Test whether targeting SPHKAP/VAPB complexes enhances β-cell survival and function in vivo and whether ERMCS-localized PKA signaling can be pharmacologically modulated to potentiate GLP-1RA efficacy.
Study Information
- Study Type
- Basic/Mechanistic Research
- Research Domain
- Pathophysiology/Treatment
- Evidence Level
- III - Controlled preclinical experimental evidence across multiple model systems
- Study Design
- OTHER