This study systematically demonstrates that Furin, rather than PC1/3, is responsible for proglucagon processing to GLP-1 in human α cells, and reveals that GLP-1 and glucagon are independently packaged in distinct secretory granules. These findings provide novel insights for targeting Furin to regulate GLP-1 production in diabetes therapy.
Literature Overview
The article 'Furin may contribute to proglucagon processing and glucagon-like peptide-1 production in human alpha cells' published in Molecular Metabolism investigates the mechanisms of GLP-1 generation in human pancreatic α cells. It focuses on the expression, localization, and functional potential of proglucagon-processing enzymes Furin and PC1/3. The study further evaluates the impact of inflammatory cytokines and Akt activation on GLP-1 secretion, highlighting Furin's critical role in the regulatory secretory pathway and establishing a new theoretical foundation for GLP-1 research in diabetes.
Background Knowledge
Glucagon-like peptide-1 (GLP-1) is a key incretin hormone regulating glucose homeostasis, traditionally believed to be secreted exclusively by intestinal L cells. Recent discoveries show human α cells also produce GLP-1, though its processing mechanisms remain unclear. Conventional understanding implicated PC1/3 as the primary processing enzyme, but this study challenges that paradigm by identifying Furin as the key enzyme substituting for PC1/3 in α cells. Given α cell dysfunction in diabetes pathogenesis, clarifying their GLP-1 production mechanisms could enable novel therapeutic strategies. Using primary human islets and αTC1/9 cell models combined with qPCR, Western blot, and immunofluorescence techniques, the research systematically analyzed convertase enzyme expression/localization and Akt activation effects on processing pathways, providing mechanistic insights into α cell GLP-1 function in diabetes and suggesting Furin as a potential therapeutic target.
Research Methods and Experiments
The team analyzed proglucagon and its processing enzymes (PC1/3, PC2, Furin) in primary human α cells and αTC1/9 cells through qPCR, Western blot, and immunofluorescence microscopy. They also treated cells with Akt activator SC-79 and inflammatory factors IL-6/SDF1α to assess impacts on GLP-1 secretion. Confocal microscopy examined enzyme colocalization with subcellular markers to elucidate processing environments.
Key Conclusions and Perspectives
Research Significance and Prospects
This work identifies Furin as the principal GLP-1 processing enzyme in human α cells, offering a novel target for modulating α cell GLP-1 production in diabetes treatment. Future studies should investigate whether Furin undergoes dynamic regulation under metabolic stress or diabetes models, and explore if Akt signaling enhances GLP-1 generation through Furin localization or processing pathway modulation. Additionally, as a broad-spectrum processing enzyme, further research into Furin's functional differences across cell types could optimize cell-specific therapeutic strategies.
Conclusion
This study overturns the long-held belief that PC1/3 is critical for GLP-1 generation, establishing Furin as the primary proglucagon-processing enzyme in human α cells. It also demonstrates that GLP-1 and glucagon are independently packaged in distinct subcellular compartments despite similar secretory responses. These findings provide mechanistic foundations for targeted regulation of α cell GLP-1 production and suggest Furin as a potential therapeutic target for diabetes. Future research should validate Furin's function in diabetes models and explore its pharmacological potential for enhancing GLP-1 production and glucose homeostasis. The study emphasizes the importance of primary human islets as reliable models for mechanistic research, offering critical support for translational medicine.
