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Submitted on July 17, 2003
Accepted on March 10, 2004
Molecular Biology of the Cell I, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.; Molecular Genetics and Neurophysiology, FRE2401, Collège de France, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France.; Center for Neurobiology and Behaviour, Columbia University, New York, USA; Division of Metabolic and Endocrine Diseases, University Children's Hospital, 69120 Heidelberg, Germany
* To whom correspondence should be addressed. E-mail: g.schuetz{at}dkfz.de.
Hepatic glucose production by gluconeogenesis is the main source of glucose during fasting and contributes significantly to the hyperglycemia in diabetes mellitus. Accordingly, glucose metabolism is tightly controlled by a variety of hormones including insulin, epinephrin, glucagon and glucocorticoids (GC) acting on various cell types. GC effects are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor, which in the liver and kidney controls gluconeogenesis by induction of gluconeogenic enzymes. To specifically study the contribution of GC on liver carbohydrate metabolism, we generated mice with an inactivation of the GR gene exclusively in hepatocytes using the Cre/loxP technology. Half of the mutant mice die within the first two days after birth most likely due to hypoglycemia. Adult mice have normal blood sugar under basal conditions but show hypoglycemia after prolonged starvation due to reduced expression of genes involved in gluconeogenesis. We further demonstrate that absence of GR in hepatocytes limits the development of hyperglycemia in streptozotocin-induced diabetes mellitus probably due to impaired induction of gluconeogenesis. These findings show the essential role of glucocorticoid receptor function in liver glucose metabolism during fasting and in diabetic mice and indicate that liver-specific glucocorticoid antagonists could be beneficial in control of the diabetic hyperglycemia.
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