Effect of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog

Dale S. Edgerton, Rita Basu, Christopher J. Ramnanan, Tiffany D. Farmer, Doss Neal, Melanie Scott, Peer Jacobson, Robert A. Rizza, Alan D. Cherrington

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22 Scopus citations

Abstract

Edgerton DS, Basu R, Ramnanan CJ, Farmer TD, Neal D, Scott M, Jacobson P, Rizza RA, Cherrington AD. Effect of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog. Am J Physiol Endocrinol Metab 298: E1019 -E1026, 2010. First published February 16, 2010; doi:10.1152/ajpendo.00740.2009. - Inactive cortisone is converted to active cortisol within the liver by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11β-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11β-HSD1 inhibitor (compound 531) or placebo for 5 h. 11β-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11β-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11β-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes.

Original languageEnglish (US)
Pages (from-to)E1019-E1026
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume298
Issue number5
DOIs
StatePublished - May 1 2010

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Keywords

  • Cortisol
  • Endogenous glucose production
  • Glucocorticoids
  • Hepatic cortisol production

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Edgerton, D. S., Basu, R., Ramnanan, C. J., Farmer, T. D., Neal, D., Scott, M., Jacobson, P., Rizza, R. A., & Cherrington, A. D. (2010). Effect of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog. American Journal of Physiology - Endocrinology and Metabolism, 298(5), E1019-E1026. https://doi.org/10.1152/ajpendo.00740.2009