High circulating levels of RBP4 and mRNA levels of aP2, PGC‐1α and UCP‐2 predict improvement in insulin sensitivity following pioglitazone treatment of drug‐naïve type 2 diabetic subjects

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Abstract
Context. High levels of circulating retinol‐binding protein 4 (RBP4) and baseline expression of adipogenic genes correlate with subsequent improvement in insulin sensitivity following Thiazolidinedione (TZD) treatment. Objective. The aim was to identify baseline characteristics and early changes related to TZD treatment that could predict a good treatment response. Design. Subjects were examined with oral glucose tolerance test, intravenous glucose tolerance test, hyperinsulinaemic euglycaemic clamp, body composition and standard blood sampling at baseline and after 4 and 12 weeks treatment. Subcutaneous adipose tissue biopsies were taken from the abdominal region at baseline, after 3 days and 4 weeks treatment to examine the gene expression profile. Setting. Research laboratory in a University hospital. Participants. Ten newly diagnosed and previously untreated type 2 diabetic subjects were treated with pioglitazone for 3 months. Main outcome measures. Baseline characteristics and early changes related to TZD treatment that could predict the response after 3 months. Results. Pioglitazone improved insulin sensitivity after 4 weeks combined with lower glucose and insulin levels without any change in BMI. It was accompanied by lower circulating resistin and plasminogen activator inhibitor‐1 levels rapidly increased levels of circulating total and high molecular weight adiponectin as well as adiponectin and adipocyte fatty acid‐binding protein (aP2) mRNA expression in the adipose tissue. High levels of circulating RBP4 at baseline and adipose tissue expression of aP2, proliferator‐activated receptor‐gamma coactivator 1 alpha (PGC‐1α) and uncoupling protein 2 (UCP‐2) predicted a good treatment response measured as improvement in insulin‐stimulated whole‐body glucose uptake after 3 months. Conclusions. Circulating levels of RBP4 as an index of insulin sensitivity and mRNA levels of adipogenic genes correlate with the subsequent improvement in insulin sensitivity following TZD treatment.