QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.081257v1 314/1/191    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jacobson, P. B. Articles by Opgenorth, T. J. Search for Related Content PubMed PubMed Citation Articles by Jacobson, P. B. Articles by Opgenorth, T. J.

ENDOCRINE AND REPRODUCTIVE

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

Abbott Laboratories, Chicago, Illinois (P.B.J., T.W.v.G., J.W., B.Z., D.W., P.T.N., A.M., S.F., T.F., K.M., D.W.A.B., B.N.-N., P.R.K., J.T.L., N.T., B.C.L., T.J.O.); Karo Bio, Huddinge, Sweden (L.Ö., M.Ö., A.G.-N., M.G., T.B.); Vanderbilt University, Nashville, Tennessee (D.S.E., A.C.); and Karolinska Institute, Stockholm, Sweden (S.E.)

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.

Address correspondence to: Dr. Peer B. Jacobson, Department of Metabolic Disease Research, Abbott Laboratories, R47M, AP10-111, 100 Abbott Park Rd., Abbott Park, IL 60064. E-mail: peer.b.jacobson{at}abbott.com

This article has been cited by other articles:

				J. W. Hill, Y. Xu, F. Preitner, M. Fukuda, Y.-R. Cho, J. Luo, N. Balthasar, R. Coppari, L. C. Cantley, B. B. Kahn, et al. Phosphatidyl Inositol 3-Kinase Signaling in Hypothalamic Proopiomelanocortin Neurons Contributes to the Regulation of Glucose Homeostasis Endocrinology, November 1, 2009; 150(11): 4874 - 4882. [Abstract] [Full Text] [PDF]

				M. Qatanani and M. A. Lazar Mechanisms of obesity-associated insulin resistance: many choices on the menu Genes & Dev., June 15, 2007; 21(12): 1443 - 1455. [Abstract] [Full Text] [PDF]

				D. Qi and B. Rodrigues Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E654 - E667. [Abstract] [Full Text] [PDF]

				P. D. van Poelje, S. C. Potter, V. C. Chandramouli, B. R. Landau, Q. Dang, and M. D. Erion Inhibition of Fructose 1,6-Bisphosphatase Reduces Excessive Endogenous Glucose Production and Attenuates Hyperglycemia in Zucker Diabetic Fatty Rats Diabetes, June 1, 2006; 55(6): 1747 - 1754. [Abstract] [Full Text] [PDF]