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Impaired Intestinal Proglucagon Processing in Mice Lacking Prohormone Convertase 1

Departments of Medical Physiology (R.U., C.F.D., J.J.H.) and Medical Anatomy (C.Ø.), the Panum Institute, University of Copenhagen, DK-2200 Copenhagen N., Denmark; and Department of Biochemistry and Molecular Biology (X.Z., D.F.S.), the Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Prof. Jens Juul Holst, Department of Medical Physiology, University of Copenhagen, the Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N., Denmark. E-mail: holst{at}mfi.ku.dk.

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 R⁷⁷ 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.

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