Furin may contribute to proglucagon processing and glucagon-like Peptide-1 production in human alpha cells

TL;DR

Human alpha cells produce GLP-1 and glucagon, with furin playing a key role in GLP-1 processing.

Contribution

Furin, not PC1/3, is identified as the primary enzyme for GLP-1 production in human alpha cells.

Findings

Furin is optimally positioned for proglucagon processing in human alpha cells.

GLP-1 and glucagon are packaged in separate secretory granules.

Akt activation increases GLP-1 production and alters trafficking dynamics.

Abstract

While glucagon-like peptide-1 (GLP-1) production has been previously documented in human alpha cells, the steps regulating its production and secretion are poorly characterized. We investigated the enzymes implicated in proglucagon processing, characterizing their expression and localization in primary human alpha cells and αTC1/9 cells.

Human alpha cells and αTC1/9 cells were maintained in control conditions or exposed to proinflammatory and Akt-activating stimuli to enhance GLP-1 levels. Proglucagon and convertase enzyme gene expression, protein content, and subcellular localization were evaluated by qPCR, Western Blot, and immunofluorescent microscopy, respectively.

Our data suggests that the canonical GLP-1-producing enzyme, Prohormone Convertase 1/3 (PC1/3), is poorly expressed and localized in alpha cells, while its homologue furin is optimally positioned for GLP-1 production. We also note that GLP-1 and glucagon processing occur in different subcellular compartments, creating two distinct pools of secretory granules which respond to similar secretory stimuli.

Our study suggests that furin, rather than PC1/3, is positioned to process proglucagon into GLP-1, and despite coming from the same precursor molecule, GLP-1 and glucagon are separately packaged in primary human alpha cells.

Graphical abstract created in BioRender. Koepke, J. (2025) https://BioRender.com/00jtutv.Image 1

•Human alpha cells produce GLP-1 and glucagon under native culture conditions.•Furin is well-positioned for proglucagon processing in human alpha cells.•GLP-1 and glucagon are packaged in separate secretory granules.•Akt activation increases GLP-1 production and alters TGN trafficking dynamics.

Human alpha cells produce GLP-1 and glucagon under native culture conditions.

Furin is well-positioned for proglucagon processing in human alpha cells.

GLP-1 and glucagon are packaged in separate secretory granules.

Akt activation increases GLP-1 production and alters TGN trafficking dynamics.

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