BACKGROUND: Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. CONCLUSION: Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism. Copyright Published by Oxford University Press on behalf of the Endocrine Society 2021. METHODS: We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. RESULTS: Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 +/- 32.9 vs 42.8 +/- 23.9; P = 0.002) and reduced adipo-IR (49.9 +/- 45.9 vs 65.5 +/- 43.8; P = 0.004), and HIRI (50.2 +/- 38.7 vs 70.0 +/- 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or beta-cell glucose sensitivity.