Blunting of the immediate-early gene and mitogenic response in
insulin-deficient type 1 diabetic animals subjected to partial
hepatectomy.
Chin, Simon, Sylvia Ramirez, Linda Greenbaum, Ali Naji, and Rebecca
Taub.
Department of Genetics, Division of Gastroenterology and Nutrition,
Department of Pediatrics, Children's Hospital of Philadelphia,
Division of Gastroenterology, Department of Medicine, Department of
Surgery, Howard Hughes Medical Institute 5, University of
Pennsylvania School of Medicine, Philadelphia, PA 19104-6145
APStracts 2:0117E, 1995.
Studies suggest that liver regeneration is delayed in insulin
-deficient animals, but defining a role of insulin as a growth factor
in hepatic regeneration has remained elusive. By examining gene
expression of hepatectomized liver in Type1 diabetic BB rats, we have
identified dramatic changes in the expression of primary or
immediate-early growth response genes as compared to normal animals.
These include altered expression of insulin-regulated genes such as
glucose-6-phosphatase (G6Pase), phosphoenol pyruvate carboxykinase
(PEPCK), and [beta]-actin, and genes such as CL-6 and Map Kinase
Phosphatase-1 (MKP-1) that were previously unlinked to insulin action
in animals. Abnormal elevation of mRNAs encoding G6Pase, MKP-1, and
PEPCK in the time 0 diabetic liver results in decreased induction
following partial hepatectomy. Other genes such as CL-6 and [beta]
-actin are induced at a lower level in the hepatectomized diabetics.
The net effect is a blunting of the immediate-early gene response
following partial hepatectomy in diabetic animals. As determined by
DNA synthesis assays, the regenerative capacity of insulin-deficient
BB diabetic livers is reduced, and this defect is corrected at least
in part by insulin therapy. These findings suggest that because of
insulin deficiency, common intracellular signaling pathways that are
required for both metabolism and mitogenesis are aberrant in the Type
1 diabetic liver, and as a result, the regenerative response is
deficient.
Received 28 December 1994; accepted in final form 9 May 1995.
APS Manuscript Number E528-4.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 26 May 1995.