- Authors:
-
- Ugleholdt, Randi ;
- Zhu, Xiaorong ;
-
Deacon, Carolyn F
;
Close
0000-0003-2611-5642
Endocrinology and Metabolism, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet -
Ørskov, Cathrine
;
Close0000-0002-7762-2372
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Københavns Universitet - Steiner, Donald F ;
-
Holst, Jens J
Close0000-0001-6853-3805
Endocrinology and Metabolism, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet
- DOI:
- 10.1210/en.2003-0801
- Abstract:
- The neuroendocrine prohormone convertases 1 and 2 (PC1 and PC2) are expressed in endocrine intestinal L cells and pancreatic A cells, respectively, and colocalize with proglucagon in secretory granules. Mice lacking PC2 have multiple endocrinopathies and cannot process proglucagon to mature glucagon in the pancreas. Disruption of PC1 results in dwarfism and also multiple neuroendocrine peptide processing defects. This study compares the pancreatic and intestinal processing of proglucagon in mice lacking PC1 expression with that in age-matched wild-type controls. Because proglucagon was found to precipitate in acidic extracts, the intestinal processing profile was analyzed in both acidic and neutral extracts by gel filtration, HPLC, and RIA. Supporting a central role for PC2 in glucagon biosynthesis, we found normal processing of proglucagon to glucagon in the pancreas, whereas the intestinal proglucagon processing showed marked defects. Tissue proglucagon levels in null mice were elevated, and proglucagon processing to glicentin, oxyntomodulin, and glucagon-like peptide-1 and -2 (GLP-1 and GLP-2) was markedly decreased, indicating that PC1 is essential for the processing of all the intestinal proglucagon cleavage sites. This includes the monobasic site R(77) and, thereby, production of mature, biologically active GLP-1. We also found elevated glucagon levels, suggesting that factors other than PC1 that are capable of processing to mature glucagon are present in the secretory granules of the L cell. These findings strongly suggest that PC1 is essential for intestinal proglucagon processing in vivo and, thereby, plays an important role in production of the incretin hormone GLP-1 and the intestinotrophic hormone GLP-2.
- Type:
- Journal article
- Language:
- English
- Published in:
- Endocrinology, 2003, Vol 145, Issue 3, p. 1349-55
- Main Research Area:
- Medical science
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2003
- Scientific Level:
- Scientific
- ID:
- 52159210
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