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

Edgerton DS, Basu R, Ramnanan CJ, Farmer TD, Neal D, Scott M, Jacobson P, Rizza RA, Cherrington AD. Effect of 11 beta-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 11 beta-hydroxysteroid dehydrogenase-1 (11 beta-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 11 beta-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 11 beta-HSD1 inhibitor (compound 531) or placebo for 5 h. 11 beta-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 11 beta-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11 beta-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes.