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.
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.
Liu
Yanjun
Y
Charles R. Drew University of Medicine and Sciences, Division of Endocrinology, UCLA School of Medicine, 1731 E. 120th St., Los Angeles, CA 90059, USA. dryanjunliu@hotmail.com
Nakagawa
Yuichi
Y
Wang
Ying
Y
Sakurai
Reiko
R
Tripathi
Pinky V
PV
Lutfy
Kabirullah
K
Friedman
Theodore C
TC
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology / Q000502:physiology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D015735:Mifepristone / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose