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Leucyl-beta-naphthylamide-splitting enzymes in the mammalian endocrine pancreas.

ABSTRACT: The proteolytic capacity of the endocrine pancreas in obese-hyperglycaemic mice was evaluated by using the chromogenic substrate l-leucyl-beta-naphthylamide (LNA). The analytical sensitivity obtained with this substrate in photometric and fluorimetric assays permitted quantitative determinations of C-N-bond-splitting activity in both crude islet homogenates and electrophoretic fractions thereof. The following observations were made: (1) The rate of LNA cleavage was maximal at about pH7 in islets as well as in acinar tissue. An apparent K(m) of 4x10(-5)-6x10(-5)m was calculated for both the endocrine and exocrine pancreas. (2) The level of LNA-splitting enzyme activity was of the same magnitude in the islets as in the liver, and significantly higher in the islets than in the exocrine pancreas. Starving the animals for 7 days did not affect the enzyme activity levels. (3) Two distinct LNA-splitting enzymes could be separated from the pancreatic islets by means of disc electrophoresis, the most rapidly migrating band representing the highest activity. Though similar electrophoresis patterns were obtained with acinar tissue and liver, only one enzyme could be demonstrated in serum. The data suggest that the beta-cells, in addition to being highly specialized for the production of a specific protein, contain a comparatively high capacity for protein catabolism.

SUBMITTER: Idahl LA

PROVIDER: S-EPMC1198482 | biostudies-other | 1968 Jan

REPOSITORIES: biostudies-other

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Project description:Transforming growth factor-beta (TGF-beta) superfamily signaling has been implicated in many developmental processes, including pancreatic development. Previous studies are conflicting with regard to an exact role for TGF-beta signaling in various aspects of pancreatic organogenesis. Here we have investigated the role of TGF-beta isoform signaling in embryonic pancreas differentiation and lineage selection. The TGF-beta isoform receptors (RI, RII and ALK1) were localized mainly to both the pancreatic epithelium and mesenchyme at early stages of development, but then with increasing age localized to the pancreatic islets and ducts. To determine the specific role of TGF-beta isoforms, we functionally inactivated TGF-beta signaling at different points in the signaling cascade. Disruption of TGF-beta signaling at the receptor level using mice overexpressing the dominant-negative TGF-beta type II receptor showed an increase in endocrine precursors and proliferating endocrine cells, with an abnormal accumulation of endocrine cells around the developing ducts of mid-late stage embryonic pancreas. This pattern suggested that TGF-beta isoform signaling may suppress the origination of secondary transition endocrine cells from the ducts. Secondly, TGF-beta isoform ligand inhibition with neutralizing antibody in pancreatic organ culture also led to an increase in the number of endocrine-positive cells. Thirdly, hybrid mix-and-match in vitro recombinations of transgenic pancreatic mesenchyme and wild-type epithelium also led to increased endocrine cell differentiation, but with different patterns depending on the directionality of the epithelial-mesenchymal signaling. Together these results suggest that TGF-beta signaling is important for restraining the growth and differentiation of pancreatic epithelial cells, particularly away from the endocrine lineage. Inhibition of TGF-beta signaling in the embryonic period may thus allow pancreatic epithelial cells to progress towards the endocrine lineage unchecked, particularly as part of the secondary transition of pancreatic endocrine cell development. TGF-beta RII in the ducts and islets may normally serve to downregulate the production of beta cells from embryonic ducts.

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Leucyl-beta-naphthylamide-splitting enzymes in the mammalian endocrine pancreas.

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