Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver

Macfarlane, D.P., Raubenheimer, P.J., Preston, T. , Gray, C.D., Bastin, M.E., Marshall, I., Iredale, J.P., Andrew, R. and Walker, B.R. (2014) Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver. American Journal of Physiology: Gastrointestinal and Liver Physiology, 307(7), G760-G768. (doi: 10.1152/ajpgi.00030.2014) (PMID:25104497) (PMCID:PMC4187063)

Abstract

To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU·m −2·min−1) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Preston, Professor Tom
• Authors: Macfarlane, D.P., Raubenheimer, P.J., Preston, T., Gray, C.D., Bastin, M.E., Marshall, I., Iredale, J.P., Andrew, R., and Walker, B.R.
• College/School: College of Science and Engineering > Scottish Universities Environmental Research Centre
• Journal Name: American Journal of Physiology: Gastrointestinal and Liver Physiology
• Publisher: American Physiological Society
• ISSN: 0193-1857
• ISSN (Online): 1522-1547
• Copyright Holders: Copyright © 2014 The American Physiological Society
• First Published: First published in AJP: Gastrointestinal and Liver Physiology 307(7):G760-G768
• Publisher Policy: Reproduced under a Creative Commons License