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Diabetes 54:32-40, 2005
© 2005 by the American Diabetes Association, Inc.

Increased Glucocorticoid Receptor and 11ß-Hydroxysteroid Dehydrogenase Type 1 Expression in Hepatocytes May Contribute to the Phenotype of Type 2 Diabetes in db/db Mice

Yanjun Liu1, Yuichi Nakagawa2, Ying Wang1, Reiko Sakurai1, Pinky V. Tripathi1, Kabirullah Lutfy1,3, and Theodore C. Friedman1

1 Division of Endocrinology, Charles R. Drew University of Medicine & Sciences, UCLA School of Medicine, Los Angeles, California
2 Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan
3 Department of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, California

Excess tissue glucocorticoid action may contribute to the hyperglycemia and insulin resistance associated with type 2 diabetes, but the associated mechanisms are poorly understood. 11ß-hydroxysteroid dehydrogenase type 1 (11ß-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 11ß-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 11ß-HSD1 in liver and insulin sensitivity and expression of PEPCK mRNA in db/db mice and db/+ controls. Increased expression of glucocorticoid receptor and 11ß-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 11ß-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, 11ß-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 11ß-HSD1 expression, whereas insulin did not affect the expression of 11ß-HSD1 and glucocorticoid receptor in primary hepatocytes. These findings suggest that activation of glucocorticoid receptor and 11ß-HSD1 expression within the liver may contribute to the development of type 2 diabetes in db/db mice.

Address correspondence and reprint requests to Yanjun Liu, MD, PhD, Charles R. Drew University of Medicine & Sciences, Division of Endocrinology, 1731 E. 120th St., Los Angeles, CA 90059. E-mail: dryanjunliu{at}hotmail.com


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