Glucocorticoids Fail to Cause Insulin Resistance in Human Subcutaneous Adipose Tissue In Vivo

• Published in: The journal of clinical endocrinology and metabolism Vol. 98; no. 4; pp. 1631 - 1640
• Main Authors: Hazlehurst, Jonathan M, Gathercole, Laura L, Nasiri, Maryam, Armstrong, Matthew J, Borrows, Sarah, Yu, Jinglei, Wagenmakers, Anton J. M, Stewart, Paul M, Tomlinson, Jeremy W
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.04.2013; Copyright by The Endocrine Society
• Subjects: Adult; Aged; Aged, 80 and over; Biological and medical sciences; Cells, Cultured; Cross-Over Studies; Double-Blind Method; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Glucocorticoids - administration & dosage; Glucocorticoids - pharmacology; Humans; Hydrocortisone - administration & dosage; Hydrocortisone - pharmacology; Infusion Pumps; Insulin - metabolism; Insulin Resistance - physiology; Male; Medical sciences; Middle Aged; Placebos; Subcutaneous Fat - drug effects; Subcutaneous Fat - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Obesity; Adipose tissue; Nutrition; Insulin human; Nutrition disorder; Metabolic diseases; Glucocorticoid; In vivo; Target tissue resistance; Cause; Insulin resistance; Subcutaneous tissue; Failure; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2012-3523

Context: It is widely believed that glucocorticoids cause insulin resistance in all tissues. We have previously demonstrated that glucocorticoids cause insulin sensitization in human adipose tissue in vitro and induce insulin resistance in skeletal muscle. Objective: Our aim was to determine whether glucocorticoids have tissue-specific effects on insulin sensitivity in vivo. Design: Fifteen healthy volunteers were recruited into a double-blind, randomized, placebo-controlled, crossover study, receiving both an overnight hydrocortisone and saline infusion. The tissue-specific actions of insulin were determined using paired 2-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis. Setting: The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom. Main Outcome Measures: The sensitivity of sc adipose tissue to insulin action was measured. Results: Hydrocortisone induced systemic insulin resistance but failed to cause sc adipose tissue insulin resistance as measured by suppression of adipose tissue lipolysis and enhanced insulin-stimulated pyruvate generation. In primary cultures of human hepatocytes, glucocorticoids increased insulin-stimulated p-ser473akt/protein kinase B. Similarly, glucocorticoids enhanced insulin-stimulated p-ser473akt/protein kinase B and increased Insulin receptor substrate 2 mRNA expression in sc, but not omental, intact human adipocytes, suggesting a depot-specificity of action. Conclusions: This study represents the first description of sc adipose insulin sensitization by glucocorticoids in vivo and demonstrates tissue-specific actions of glucocorticoids to modify insulin action. It defines an important advance in our understanding of the actions of both endogenous and exogenous glucocorticoids and may have implications for the development and targeting of future glucocorticoid therapies.