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Research ArticleENDOCRINE 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

Peer B. Jacobson, Thomas W. von Geldern, Lars Öhman, Marie Österland, Jiahong Wang, Bradley Zinker, Denise Wilcox, Phong T. Nguyen, Amanda Mika, Steven Fung, Thomas Fey, Annika Goos-Nilsson, Marlena Grynfarb, Tomas Barkhem, Kennan Marsh, David W. A. Beno, Bach Nga-Nguyen, Philip R. Kym, James T. Link, Noah Tu, Dale S. Edgerton, Alan Cherrington, Suad Efendic, Benjamin C. Lane and Terry J. Opgenorth
Journal of Pharmacology and Experimental Therapeutics July 2005, 314 (1) 191-200; DOI: https://doi.org/10.1124/jpet.104.081257
Peer B. Jacobson
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Thomas W. von Geldern
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Lars Öhman
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Marie Österland
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Jiahong Wang
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Bradley Zinker
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Denise Wilcox
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Phong T. Nguyen
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Amanda Mika
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Steven Fung
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Thomas Fey
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Annika Goos-Nilsson
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Marlena Grynfarb
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Tomas Barkhem
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Kennan Marsh
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David W. A. Beno
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Bach Nga-Nguyen
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Philip R. Kym
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James T. Link
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Noah Tu
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Dale S. Edgerton
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Alan Cherrington
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Suad Efendic
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Benjamin C. Lane
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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

  • Financial support for A-348441 research completed at Vanderbilt University was paid for by Abbott Laboratories.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.104.081257.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 384 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 384, Issue 2
1 Feb 2023
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Research ArticleENDOCRINE 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

Peer B. Jacobson, Thomas W. von Geldern, Lars Öhman, Marie Österland, Jiahong Wang, Bradley Zinker, Denise Wilcox, Phong T. Nguyen, Amanda Mika, Steven Fung, Thomas Fey, Annika Goos-Nilsson, Marlena Grynfarb, Tomas Barkhem, Kennan Marsh, David W. A. Beno, Bach Nga-Nguyen, Philip R. Kym, James T. Link, Noah Tu, Dale S. Edgerton, Alan Cherrington, Suad Efendic, Benjamin C. Lane and Terry J. Opgenorth
Journal of Pharmacology and Experimental Therapeutics July 1, 2005, 314 (1) 191-200; DOI: https://doi.org/10.1124/jpet.104.081257

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Research ArticleENDOCRINE 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

Peer B. Jacobson, Thomas W. von Geldern, Lars Öhman, Marie Österland, Jiahong Wang, Bradley Zinker, Denise Wilcox, Phong T. Nguyen, Amanda Mika, Steven Fung, Thomas Fey, Annika Goos-Nilsson, Marlena Grynfarb, Tomas Barkhem, Kennan Marsh, David W. A. Beno, Bach Nga-Nguyen, Philip R. Kym, James T. Link, Noah Tu, Dale S. Edgerton, Alan Cherrington, Suad Efendic, Benjamin C. Lane and Terry J. Opgenorth
Journal of Pharmacology and Experimental Therapeutics July 1, 2005, 314 (1) 191-200; DOI: https://doi.org/10.1124/jpet.104.081257
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