title: Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver.
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.
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom;
authors.forename: D P
authors.initials: DP
authors.lastname: Macfarlane
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom;
authors.forename: P J
authors.initials: PJ
authors.lastname: Raubenheimer
authors.affiliation: Scottish Universities Environmental Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom;
authors.forename: T
authors.initials: T
authors.lastname: Preston
authors.affiliation: SFC Brain Imaging Research Centre, University of Edinburgh, Edinburgh, Scotland, United Kingdom; and.
authors.forename: C D
authors.initials: CD
authors.lastname: Gray
authors.affiliation: SFC Brain Imaging Research Centre, University of Edinburgh, Edinburgh, Scotland, United Kingdom; and.
authors.forename: M E
authors.initials: ME
authors.lastname: Bastin
authors.affiliation: SFC Brain Imaging Research Centre, University of Edinburgh, Edinburgh, Scotland, United Kingdom; and.
authors.forename: I
authors.initials: I
authors.lastname: Marshall
authors.affiliation: University/MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
authors.forename: J P
authors.initials: JP
authors.lastname: Iredale
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom;
authors.forename: R
authors.initials: R
authors.lastname: Andrew
authors.affiliation: University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland, United Kingdom; b.walker@ed.ac.uk.
authors.forename: B R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005990:Glycerol / Q000097:blood; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007201:Indicator Dilution Techniques; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008797:Metyrapone / Q000627:therapeutic use; D008875:Middle Aged; D015735:Mifepristone / Q000627:therapeutic use*; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012606:Scotland; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D006727:Hormone Antagonists; D007328:Insulin; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D013252:Steroid 11-beta-Hydroxylase; D005990:Glycerol; D006854:Hydrocortisone; D008797:Metyrapone
keywords: Type 2 diabetes; fatty acid metabolism; glucocorticoids; nonalcoholic fatty liver disease
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