TY - JOUR T1 - Hepatic Glucocorticoid Receptor Antagonism Is Sufficient to Reduce Elevated Hepatic Glucose Output and Improve Glucose Control in Animal Models of Type 2 Diabetes JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 191 LP - 200 DO - 10.1124/jpet.104.081257 VL - 314 IS - 1 AU - Peer B. Jacobson AU - Thomas W. von Geldern AU - Lars Öhman AU - Marie Österland AU - Jiahong Wang AU - Bradley Zinker AU - Denise Wilcox AU - Phong T. Nguyen AU - Amanda Mika AU - Steven Fung AU - Thomas Fey AU - Annika Goos-Nilsson AU - Marlena Grynfarb AU - Tomas Barkhem AU - Kennan Marsh AU - David W. A. Beno AU - Bach Nga-Nguyen AU - Philip R. Kym AU - James T. Link AU - Noah Tu AU - Dale S. Edgerton AU - Alan Cherrington AU - Suad Efendic AU - Benjamin C. Lane AU - Terry J. Opgenorth Y1 - 2005/07/01 UR - http://jpet.aspetjournals.org/content/314/1/191.abstract N2 - Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes. The American Society for Pharmacology and Experimental Therapeutics ER -