Increased glucocorticoid receptor and 11{beta}-hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 1; pp. 32 - 40
• Main Authors: Liu, Yanjun, Nakagawa, Yuichi, Wang, Ying, Sakurai, Reiko, Tripathi, Pinky V, Lutfy, Kabirullah, Friedman, Theodore C
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01-01-2005
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1 - genetics; 11-beta-Hydroxysteroid Dehydrogenase Type 1 - metabolism; Animals; Body fat; Care and treatment; Causes of; Cells, Cultured; Corticosteroids; Cushing syndrome; Dehydrogenases; Diabetes; Diabetes Mellitus, Type 2 - genetics; Gene Expression Regulation - drug effects; Glucocorticoids; Glucose; Glucose - pharmacology; Health aspects; Hepatocytes - enzymology; Hepatocytes - physiology; Hyperglycemia; Insulin resistance; Laboratory animals; Liver; Male; Metabolism; Mice; Mice, Obese; Mifepristone - pharmacology; Obesity; Phenotype; Physiological aspects; Receptors, Glucocorticoid - antagonists & inhibitors; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; RNA, Messenger - genetics; Transcription, Genetic - drug effects; Type 2 diabetes; Japan; California
• ISSN: 0012-1797; 1939-327X

Excess tissue glucocorticoid action may contribute to the hyperglycemia and insulin resistance associated with type 2 diabetes, but the associated mechanisms are poorly understood. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts inactive 11-dehydrocorticosterone into active corticosterone, thus amplifying glucocorticoid receptor-mediated tissue glucocorticoid action, particularly in the liver. To examine the role of tissue glucocorticoid action in type 2 diabetes, we analyzed expression of glucocorticoid receptor and 11beta-HSD1 and their regulation by endogenous hormones in vivo and in vitro in hepatocytes from db/db mice (a model of type 2 diabetes). We observed positive relations between expression of both glucocorticoid receptor and 11beta-HSD1 in liver and insulin sensitivity and expression of PEPCK mRNA in db/db mice and db/+ controls. Increased expression of glucocorticoid receptor and 11beta-HSD1 in the liver of db/db mice was correlated with elevated circulating levels of corticosterone, insulin, and blood glu-cose. Treatment of db/db mice with glucocorticoid antagonist RU486 reversed the increases in the expression of glucocorticoid receptor and 11beta-HSD1 within the liver and attenuated the phenotype of type 2 diabetes. Addition of corticosterone to db/db mouse primary hepatocytes activated expression of glucocorticoid receptor, 11beta-HSD1, and PEPCK, and these effects were abolished by RU486. Incubation of primary hepatocytes with increasing concentrations of glucose caused dose-dependent increases in glucocorticoid receptor and 11beta-HSD1 expression, whereas insulin did not affect the expression of 11beta-HSD1 and glucocorticoid receptor in primary hepatocytes. These findings suggest that activation of glucocorticoid receptor and 11beta-HSD1 expression within the liver may contribute to the development of type 2 diabetes in db/db mice.