OR28-6 Short-Term Mifepristone Treatment Improves Hepatic and Adipose Tissue Insulin Sensitivity in Overweight and Obese Subjects with Glucose Intolerance

Abstract

Background: Increased tissue cortisol availability and enhanced glucocorticoid action have been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes. Objective: To test the hypothesis that blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance in overweight/obese subjects with glucose intolerance. Design: We conducted a randomized, placebo-controlled, double-blind, crossover trial of mifepristone (50 mg orally, every six hr) in overweight/obese subjects (BMI 25-37 kg/m2), with abnormal glucose tolerance (n=16, women=7). Participants (age:56 ± 8 yr) had prediabetes (n=12) or mild type 2 DM (n=4, A1c < 7%) on diet control or stable dose of metformin for 3 months (n=2). Mifepristone or placebo treatment for one week was followed by a 6-8-week washout and crossover to the other arm. At baseline, and after each treatment period, insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test (FSIVGTT) and an oral glucose tolerance test (OGTT). Whole body glucose disposal index of insulin sensitivity (SI) was derived using a Minimal model analysis. Adipose tissue-SI, which reflects insulin-induced free fatty acid (FFA) suppression, was estimated by the log-linear slope of FFA levels during the FSIVGTT. Matsuda index, oral glucose insulin sensitivity index (OGIS, ml/min/m2), and hepatic insulin resistance index (HIRI, mg/dL×µU/mL×105) were derived from OGTT. Adipo-IR, a surrogate measure of adipocyte insulin resistance, was calculated by multiplying fasting concentrations of FFA and insulin (mmol×pmol/L). Comparison of various post-treatment parameters was performed using crossover ANOVA. This analysis takes into account specific treatment arm, treatment order, and treatment effects. Thus, we explicitly tested for carryover effects in our crossover study. Results: GR blockade did not affect body weight (p=0.56) or fasting glucose (p=0.67), but significantly decreased fasting insulin levels when compared with placebo [mean (95%CI): -40.7 (-68.53 to -12.91), p=0.007]. Mifepristone administration for one week did not alter whole body glucose disposal indices of insulin sensitivity (FSIVGTT-Si: p=0.52, Matsuda Index: p=0.74; and OGIS: p=0.75). However, GR blockade reduced HIRI [-19.80 (-40.76 to 1.15), p=0.05], Adipo-IR [-15.54 (-31.47 to 0.37), p=0.04], and improved Adipose-SI [-19.75 (-31.41 to -8.08), p=0.003]. Conclusions: In patients with abnormal glucose tolerance, short-term GR blockade improved hepatic and adipose tissue insulin sensitivity without significantly altering whole-body insulin sensitivity. These findings suggest that GR may be a therapeutic target in insulin-resistant states. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.