RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 191
OP 200
DO 10.1124/jpet.104.081257
VO 314
IS 1
A1 Jacobson, Peer B.
A1 von Geldern, Thomas W.
A1 Öhman, Lars
A1 Österland, Marie
A1 Wang, Jiahong
A1 Zinker, Bradley
A1 Wilcox, Denise
A1 Nguyen, Phong T.
A1 Mika, Amanda
A1 Fung, Steven
A1 Fey, Thomas
A1 Goos-Nilsson, Annika
A1 Grynfarb, Marlena
A1 Barkhem, Tomas
A1 Marsh, Kennan
A1 Beno, David W. A.
A1 Nga-Nguyen, Bach
A1 Kym, Philip R.
A1 Link, James T.
A1 Tu, Noah
A1 Edgerton, Dale S.
A1 Cherrington, Alan
A1 Efendic, Suad
A1 Lane, Benjamin C.
A1 Opgenorth, Terry J.
YR 2005
UL http://jpet.aspetjournals.org/content/314/1/191.abstract
AB 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