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 [(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.
Footnotes
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Financial support for A-348441 research completed at Vanderbilt University was paid for by Abbott Laboratories.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.081257.
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ABBREVIATIONS: PEPCK, phosphoenolpyruvate carboxykinase; GR, glucocorticoid receptor; GIR, glucose infusion rate; RU-486, RU-38486 (mifepristone); HbA1c, glycosylated hemoglobin; HPA, hypothalamic pituitary adrenal; LSGRA, liver-selective glucocorticoid receptor antagonist; 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; HGO, hepatic glucose output; HPMC, hydroxypropylmethylcellulose; TAT, tyrosine aminotransferase; RT-PCR, reverse transcription-polymerase chain reaction; RPC, rat prednisolone challenge; ACTH, adrenocorticotropic hormone; DHT, delayed-type hypersensitivity; DNFB, 2,4-dinitrofluorobenzene; q.d., once daily.
- Received November 24, 2004.
- Accepted March 21, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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