Glucocorticoid Excess Increases Hepatic 11β-HSD-1 Activity in Humans: Implications in Steroid-Induced Diabetes.

CONTEXT Animal studies indicate that glucocorticoids increase hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) expression and activity. OBJECTIVE Our goal was to determine whether glucocorticoid excess increases cortisol production in the liver via 11β-HSD-1 enzyme pathway in humans. DESIGN A total of 1 mg each [4-(13)C] cortisone and [9,12,12-(2)H3] cortisol were ingested, and [1,2,6,7-(3)H] cortisol was infused to measure C13 cortisol (derived from ingested [4-(13)C] cortisone) turnover using the triple tracer technique, whereas glucose turnover was measured using isotope dilution technique following [6-6(2)H2] glucose infusion during a saline clamp. SETTING This study took place at the Mayo Clinic Clinical Research Unit. PARTICIPANTS Thirty nondiabetic healthy subjects participated. INTERVENTION Subjects were randomized to hydrocortisone (n = 15) or placebo 50 mg twice daily (n = 15) for 1 week. OUTCOME MEASURES Hepatic cortisol production and endogenous glucose production were measured. RESULTS Plasma cortisol concentrations were higher throughout the study period in hydrocortisone group. Rates of appearance of C13 cortisol and hepatic C13 cortisol production were higher in hydrocortisone vs placebo group, indicating increased hepatic 11β-HSD-1 activity. Higher plasma cortisol and presumably higher intrahepatic cortisol was associated with impaired suppression of endogenous glucose production in hydrocortisone vs placebo group. CONCLUSION Chronic glucocorticoid excess increases intrahepatic cortisone to cortisol conversion via the 11β-HSD-1 pathway. The extent to which this causes or exacerbates steroid induced hepatic insulin resistance remains to be determined.

[1]  Zaki K Hassan-Smith,et al.  11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess , 2014, Proceedings of the National Academy of Sciences.

[2]  A. Basu,et al.  Hepatic 11β-hydroxysteroid dehydrogenase type 1 activity in obesity and type 2 diabetes using a novel triple tracer cortisol technique , 2014, Diabetologia.

[3]  T. Olsson,et al.  Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much? , 2014, Diabetologia.

[4]  C. Buettner,et al.  Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. , 2014, Endocrinology and metabolism clinics of North America.

[5]  M. Diamant,et al.  Steroid diabetes: from mechanism to treatment? , 2014, The Netherlands journal of medicine.

[6]  A. Poljak,et al.  Effects of Low-Dose Prednisolone on Hepatic and Peripheral Insulin Sensitivity, Insulin Secretion, and Abdominal Adiposity in Patients With Inflammatory Rheumatologic Disease , 2013, Diabetes Care.

[7]  B. Keevil,et al.  11-Dehydrocorticosterone causes metabolic syndrome, which is prevented when 11β-HSD1 is knocked out in livers of male mice. , 2013, Endocrinology.

[8]  M. Armstrong,et al.  Glucocorticoids fail to cause insulin resistance in human subcutaneous adipose tissue in vivo. , 2013, The Journal of clinical endocrinology and metabolism.

[9]  M. Rubio,et al.  Liver Upregulation of Genes Involved in Cortisol Production and Action Is Associated with Metabolic Syndrome in Morbidly Obese Patients , 2012, Obesity Surgery.

[10]  W. Lems,et al.  Glucose tolerance, insulin sensitivity and β-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids , 2011, Annals of the rheumatic diseases.

[11]  P. Pouwels,et al.  Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial , 2011, Diabetologia.

[12]  P. Hayes,et al.  Increased Whole-Body and Sustained Liver Cortisol Regeneration by 11β-Hydroxysteroid Dehydrogenase Type 1 in Obese Men With Type 2 Diabetes Provides a Target for Enzyme Inhibition , 2011, Diabetes.

[13]  M. Arrese,et al.  Overexpression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Hepatic and Visceral Adipose Tissue is Associated with Metabolic Disorders in Morbidly Obese Patients , 2010, Obesity surgery.

[14]  R. Rizza,et al.  Basu R, Basu A, Grudzien M, Jung P, Jacobson P, Johnson M, Singh R, Sarr M, Rizza RA. Liver is the site of splanchnic cortisol production in obese nondiabetic humans. Diabetes 2009;58:39-45 , 2009 .

[15]  M. Žarković,et al.  Glucocorticoid effect on insulin sensitivity: A time frame , 2008, Journal of endocrinological investigation.

[16]  P. Jacobson,et al.  Liver-selective glucocorticoid receptor antagonism decreases glucose production and increases glucose disposal, ameliorating insulin resistance. , 2007, Metabolism: clinical and experimental.

[17]  T. Uzu,et al.  Glucocorticoid-Induced Diabetes Mellitus: Prevalence and Risk Factors in Primary Renal Diseases , 2006, Nephron Clinical Practice.

[18]  B. Walker,et al.  Acute in vivo regulation of 11beta-hydroxysteroid dehydrogenase type 1 activity by insulin and intralipid infusions in humans. , 2006, The Journal of clinical endocrinology and metabolism.

[19]  J. K. Oeser,et al.  The glucose-6-phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements. , 2005, Molecular endocrinology.

[20]  S. Lightman,et al.  Why is the management of glucocorticoid deficiency still controversial: a review of the literature , 2005, Clinical endocrinology.

[21]  R. Rizza,et al.  Obesity and type 2 diabetes impair insulin-induced suppression of glycogenolysis as well as gluconeogenesis. , 2005, Diabetes.

[22]  C. Cobelli,et al.  0021-972X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(7):3919–3926 Printed in U.S.A. Copyright © 2005 by The Endocrine Society doi: 10.1210/jc.2004-2390 Obesity and Type 2 Diabetes Do Not Alter Splanchnic Cortisol Production in Human , 2005 .

[23]  B. Walker,et al.  The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. , 2005, Diabetes.

[24]  C. Cobelli,et al.  Splanchnic cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11-beta hydroxysteroid dehydrogenase (11beta-hsd) type 1 pathway. , 2004, Diabetes.

[25]  J. Seckl,et al.  Metabolic syndrome without obesity: Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Flier,et al.  Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. , 2003, The Journal of clinical investigation.

[27]  V. Giusti,et al.  Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers. , 2002, Obesity research.

[28]  Robert L. Taylor,et al.  Validation of a high-throughput liquid chromatography-tandem mass spectrometry method for urinary cortisol and cortisone. , 2002, Clinical chemistry.

[29]  J. Hux,et al.  Quantification of the risk of corticosteroid-induced diabetes mellitus among the elderly , 2002, Journal of general internal medicine.

[30]  J. Flier,et al.  A Transgenic Model of Visceral Obesity and the Metabolic Syndrome , 2001, Science.

[31]  E. Jéquier,et al.  Effects of glucocorticoids on hepatic sensitivity to insulin and glucagon in man. , 2000, Clinical nutrition.

[32]  M. Jensen,et al.  Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism: evidence for a defect in hepatic glucokinase activity. , 2000, Diabetes.

[33]  Edwards,et al.  11 b-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress , 1997 .

[34]  B. Ahrén,et al.  Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women. , 1996, The Journal of clinical endocrinology and metabolism.

[35]  C. Edwards,et al.  11 beta-hydroxysteroid dehydrogenase type 1 expression in 2S FAZA hepatoma cells is hormonally regulated: a model system for the study of hepatic glucocorticoid metabolism. , 1996, The Biochemical journal.

[36]  C. Edwards,et al.  11 beta-hydroxysteroid dehydrogenase is an exclusive 11 beta- reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. , 1995, Endocrinology.

[37]  M. Vranic,et al.  The diabetogenic effects of glucocorticoids are more pronounced in low- than in high-insulin responders. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Yergey,et al.  Cortisol production rates measured by liquid chromatography/mass spectrometry , 1990, Steroids.

[39]  N. Kraus-Friedmann.  Hormonal regulation of hepatic gluconeogenesis. , 1984, Physiological reviews.

[40]  L. Mandarino,et al.  Cortisol-induced insulin resistance in man: impaired suppression of glucose production and stimulation of glucose utilization due to a postreceptor detect of insulin action. , 1982, The Journal of clinical endocrinology and metabolism.