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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on March 22, 2005; DOI: 10.1124/jpet.104.081257

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Received for publication November 30, 2004.
Revised February 22, 2005.
Accepted for publication March 21, 2005.

Hepatic Glucocorticoid Receptor Antagonism is Sufficient to Reduce Elevated Hepatic Glucose Output and Improve Glucose Control in Animal Models of Type 2 Diabetes

Peer B. Jacobson 1*, Thomas W. von Geldern 1, Lars Ohman 2, Marie Osterlund 2, Jiahong Wang 1, Bradley Zinker 1, Denise Wilcox 1, Phong T. Nguyen 1, Amanda Mika 1, Steven Fung 1, Thomas Fey 1, Annika Goos-Nilsson 2, Marlena Grynfarb 2, Tomas Barkhem 2, Philip R. Kym 1, Noah Tu 1, James T. Link 1, Kennan Marsh 1, David W. A. Beno 1, Bach-Nga Nguyen 1, Benjamin C. Lane 1, Dale S. Edgerton 3, Alan Cherrington 3, Suad Efendic 4, Terry J. Opgenorth 1

1 Abbott Laboratories 2 Karo Bio 3 Vanderbilt University 4 Karolinska Institute

* Address correspondence to: E-mail: peer.b.jacobson{at}abbott.com

Abstract

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 represents the first LSGRA with significant anti-diabetic 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 co-administered 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 (HPA) axis, or on other measured glucocorticoid-induced extra-hepatic 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.


Key words: HGO, HPA, antagonist, diabetes, glucocorticoid, liver


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