Effect of 11 beta-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog.
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.
Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 710 Robinson Research Bldg., Nashville, TN 37232-0615, USA. dale.edgerton@vanderbilt.edu
Dale S
DS
Edgerton
Rita
R
Basu
Christopher J
CJ
Ramnanan
Tiffany D
TD
Farmer
Doss
D
Neal
Melanie
M
Scott
Peer
P
Jacobson
Robert A
RA
Rizza
Alan D
AD
Cherrington
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000704:Analysis of Variance; D000818:Animals; D004285:Dogs; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006854:Hydrocortisone / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011897:Random Allocation; D013004:Somatostatin / Q000494:pharmacology
D007328:Insulin; D013004:Somatostatin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose; D006854:Hydrocortisone