G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells.
Summary
This translational study shows that G6PC2 in pancreatic α cells determines the glucose set point for glucagon secretion. By linking genetic variation at G6PC2 to α-cell glucose sensing, it provides a mechanistic basis for hyperglucagonemia in type 2 diabetes and a potential therapeutic target.
Key Findings
- G6PC2 in pancreatic α cells defines the glucose set point for glucagon secretion.
- Genetic variation at G6PC2 is mechanistically linked to α-cell glucose sensing and glucagon output.
- Findings provide a pathophysiologic basis for hyperglucagonemia observed in T2D.
Clinical Implications
Pharmacologic modulation of G6PC2 or downstream α-cell glucose-sensing pathways may reduce inappropriate glucagon secretion in T2D, complementing insulin-centric therapies.
Why It Matters
Defining an α-cell-intrinsic glucose set point through G6PC2 reframes glucagon dysregulation in T2D and opens a tractable molecular target. This can redirect therapeutic strategies beyond β-cell centric approaches.
Limitations
- Mechanistic findings require validation in larger human cohorts and clinical contexts
- Therapeutic modulation of G6PC2 needs safety and efficacy evaluation
Future Directions
Test pharmacologic/biologic modulators of G6PC2 in α cells, validate genetic-physiology links in human islets and patients with T2D, and evaluate impact on fasting/postprandial glucagon.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- IV - Preclinical/translational mechanistic evidence linking gene function to α-cell physiology
- Study Design
- OTHER