TY - JOUR
T1 - Effect of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog
AU - Edgerton, Dale S.
AU - Basu, Rita
AU - Ramnanan, Christopher J.
AU - Farmer, Tiffany D.
AU - Neal, Doss
AU - Scott, Melanie
AU - Jacobson, Peer
AU - Rizza, Robert A.
AU - Cherrington, Alan D.
PY - 2010/5
Y1 - 2010/5
N2 - 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.
AB - 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.
KW - Cortisol
KW - Endogenous glucose production
KW - Glucocorticoids
KW - Hepatic cortisol production
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U2 - 10.1152/ajpendo.00740.2009
DO - 10.1152/ajpendo.00740.2009
M3 - Article
C2 - 20159854
AN - SCOPUS:77950808186
SN - 0193-1849
VL - 298
SP - E1019-E1026
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 5
ER -