Endothelial IRE1α promotes thrombospondin-1 mRNA decay and supports metabolic stress adaptation of pancreatic islets.
Summary
Endothelial-specific IRE1α loss in high-fat diet-fed male mice caused glucose intolerance due to impaired insulin secretion, with blunted intra-islet angiogenesis and growth. IRE1α RNase activity degrades THBS1 mRNA in islet endothelium, relieving anti-angiogenic pressure and enabling adaptive islet vascularization.
Key Findings
- Endothelial IRE1α deletion in high-fat diet-fed male mice caused glucose intolerance with impaired insulin secretion.
- Loss of endothelial IRE1α blunted intra-islet angiogenesis and compensatory islet growth without affecting adiposity.
- IRE1α RNase activity decayed THBS1 mRNA in islet ECs, relieving anti-angiogenic signaling to support islet adaptation.
Clinical Implications
Targeting the endothelial IRE1α–THBS1 axis could enhance islet revascularization and beta-cell functional adaptation in obesity and type 2 diabetes, suggesting a vascular-centric adjunct to metabolic therapies.
Why It Matters
This study reveals a previously unrecognized endothelial ER-stress checkpoint that controls islet vascular support via THBS1 mRNA decay, linking vascular stress signaling to endocrine adaptation under obesity.
Limitations
- Preclinical mouse study; translatability to humans remains to be established.
- Experiments focused on male mice; potential sex differences were not addressed.
Future Directions
Test pharmacologic modulation of IRE1α–THBS1 signaling in vivo, assess sex-specific effects, and evaluate relevance in human islet endothelium and obesity-related diabetes.
Study Information
- Study Type
- Basic/mechanistic
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence in murine models with molecular pathway validation.
- Study Design
- OTHER