Context Insulin resistance is associated with blunted sympathetic nervous system (SNS) response to carbohydrate ingestion which may contribute to postprandial hypotension and impaired body weight homeostasis. Objective This study was conducted to examine the effects of pharmacological insulin sensitization on whole-body norepinephrine kinetics during a standard 75-g oral glucose tolerance test (OGTT) in obese, insulin resistant subjects with metabolic syndrome. Methods Un-medicated individuals (n = 42, mean age 56 ± 0.8 yrs, body mass index 34 ± 0.6 kg/m2) were randomised to 12-weeks pioglitazone (PIO, 15 mg for 6 weeks, then 30 mg daily) or placebo using a double-blind, parallel group design. Whole-body norepinephrine kinetics (arterial norepinephrine concentration, calculated spillover and clearance rates), spontaneous cardiac baroreflex sensitivity, heart rate and blood pressure were measured at times 0, 30, 60, 90 and 120 minutes during OGTT. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M) and Matsuda index. Results PIO increased clamp derived glucose utilisation by 35% (P < 0.001) and there were concurrent reductions in inflammatory status and plasma triglycerides (P < 0.05). Fasting norepinephrine kinetic parameters were unaltered. PIO treatment was associated with lower plasma insulin incursions, greater reduction in diastolic blood pressure and enhanced baroreflex sensitivity during OGTT (P all < 0.05). The overall norepinephrine spillover response (AUC0-120) increased significantly in the PIO group (group × time interaction, P = 0.04), with greatest increment at 30 minutes post-glucose (101 ± 38 ng/min at baseline versus 241 ± 48 ng/min post treatment, P = 0.04) and correlated with percent improvement in M. Conclusions PIO enhances the early postprandial SNS response to carbohydrate ingestion.