Impaired intestinal proglucagon processing in mice lacking prohormone convertase 1

Area of Science:

• Neuroendocrinology
• Molecular Biology
• Gastroenterology

Background:

• Prohormone convertases 1 and 2 (PC1 and PC2) process neuroendocrine prohormones.
• PC1 and PC2 are found in intestinal L cells and pancreatic A cells, respectively, colocalizing with proglucagon.
• Mice lacking PC2 exhibit endocrinopathies and impaired pancreatic glucagon processing; PC1 deficiency causes dwarfism and peptide processing defects.

Purpose of the Study:

• To compare intestinal and pancreatic proglucagon processing in mice lacking PC1 versus wild-type controls.
• To investigate the role of PC1 in the processing of intestinal proglucagon and the production of key peptides like GLP-1 and GLP-2.

Main Methods:

• Analysis of proglucagon processing in acidic and neutral intestinal extracts.
• Techniques used include gel filtration, High-Performance Liquid Chromatography (HPLC), and Radioimmunoassay (RIA).
• Comparison of proglucagon processing in PC1-deficient mice and age-matched wild-type controls.

Main Results:

• Normal proglucagon to glucagon processing in the pancreas of PC1-deficient mice, confirming PC2's role.
• Marked defects in intestinal proglucagon processing in PC1-deficient mice, with elevated tissue proglucagon levels.
• Significantly decreased processing of proglucagon to glicentin, oxyntomodulin, GLP-1, and GLP-2 in the intestine, indicating PC1's essential role in these cleavages.

Conclusions:

• PC1 is essential for in vivo intestinal proglucagon processing, including cleavage at the monobasic site R(77).
• PC1 deficiency impairs the production of mature, biologically active glucagon-like peptide-1 (GLP-1) and GLP-2.
• Elevated glucagon levels in PC1-deficient mice suggest alternative processing pathways for glucagon in L cell secretory granules.