This study systematically demonstrates that Furin, rather than PC1/3, is responsible for proglucagon processing into GLP-1 in human α cells. It also reveals independent packaging of GLP-1 and glucagon in distinct secretory granules, providing novel insights for targeting Furin to regulate GLP-1 production.
Literature Overview
This article titled 'Furin may contribute to proglucagon processing and glucagon-like peptide-1 production in human alpha cells', published in Molecular Metabolism, reviews and summarizes the mechanisms of GLP-1 generation in human pancreatic α cells. It focuses on the expression, localization, and functional potential of processing enzymes Furin and PC1/3 for the precursor peptide proglucagon. The study further evaluates the impact of inflammatory cytokines and Akt activation on GLP-1 secretion, highlighting Furin's critical role in the regulated secretory system, which establishes a new theoretical foundation for GLP-1 research in diabetes.
Background Knowledge
Glucagon-like peptide-1 (GLP-1) is a key incretin regulating glucose homeostasis, typically secreted by intestinal L cells. Recent studies have identified GLP-1 production in human α cells, though its processing mechanisms remain incompletely understood. Conventional wisdom attributes GLP-1 generation to PC1/3 as the primary processing enzyme, but this study challenges that paradigm by demonstrating Furin's substitutional role in α cells. Given α cell dysfunction in diabetes pathogenesis, elucidating this GLP-1 generation mechanism may facilitate novel therapeutic strategies. Utilizing primary human islets and αTC1/9 cell models combined with qPCR, Western blot, and immunofluorescence, the research comprehensively analyzes convertase enzyme expression and localization while assessing Akt activation effects on processing pathways. This work provides mechanistic insights into α cell-derived GLP-1 function in diabetes and identifies Furin as a potential therapeutic target.
Research Methods and Experiments
The research team analyzed proglucagon and its processing enzymes (PC1/3, PC2, and Furin) in primary human α cells and αTC1/9 cells using qPCR, Western blot, and immunofluorescence microscopy. Cellular treatments with Akt activator SC-79 and inflammatory cytokines (IL-6 and SDF1α) evaluated their impact on GLP-1 secretion. Confocal microscopy assessed colocalization between processing enzymes and subcellular marker proteins to dissect processing environments.
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes Furin as the principal GLP-1 processing enzyme in human α cells, offering a new therapeutic target for diabetes treatment. Future research should investigate whether Furin dynamically regulates processing under metabolic stress or in diabetes models, and determine if Akt signaling enhances GLP-1 production through Furin localization or pathway modifications. As a broad-spectrum processing enzyme, Furin's functional variations across cell types warrant further exploration to optimize cell-specific regulatory strategies.
Conclusion
This work overturns the long-held belief that PC1/3 is essential for GLP-1 generation, systematically proving that Furin—not PC1/3—mediates proglucagon processing into GLP-1 in human α cells. GLP-1 and glucagon are independently packaged in different subcellular compartments yet respond similarly to secretion stimuli. These findings provide mechanistic foundations for targeted regulation of α cell GLP-1 production and establish Furin as a potential therapeutic target for diabetes. Future studies should validate Furin's functional role in diabetes models and explore its pharmacological targeting potential to enhance GLP-1 production and improve glucose homeostasis. The study also emphasizes the importance of primary human islets in mechanistic research, offering reliable models for translational medicine.
