Blunting of the immediate-early gene and mitogenic response in hepatectomized type 1 diabetic animals

Abstract

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 type 1 diabetic BB rats, we have identified dramatic changes in the expression of primary or immediate-early growth response genes compared with normal animals. These include altered expression of insulin-regulated genes such as glucose-6-phosphatase (G-6-Pase), phosphoenolpyruvate 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 G-6-Pase, MKP-1, and PEPCK in the time 0 diabetic liver results in decreased induction after partial hepatectomy. Other genes, such as CL-6 and beta-actin, are induced at a lower level in the hepatectomized diabetic animals. The net effect is a blunting of the immediate-early gene response after 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.