Context: Despite its potent, well documented insulin sensitizing effects, rosiglitazone (RSG) does not effectively ameliorate the hypertriglyceridemia of insulin-resistant or diabetic individuals and has even been shown to slightly but significantly increase triglyceride-rich lipoproteins (TRL) in some studies. The mechanism of this effect is currently not known.

Objective: We investigated the effect of RSG treatment on TRL metabolism.

Design: 12-week, single-sequence, crossover study, rosiglitazone vs placebo for 6 weeks.

Participants: 17 non-diabetic men with a broad range of insulin sensitivity.

Intervention: Rosiglitazone 8mg/day vs placebo for 6 weeks.

Main outcome measure: TRL metabolism (concentration, production and catabolic rates) was assessed in a constant fed state with a 12-hour primed constant infusion of [D3]-L-leucine and multicompartmental modeling.

Results: RSG treatment resulted in significant insulin sensitization with no change in body weight. Fasting plasma triglyceride (TG) concentration, however, was higher with RSG vs placebo (p=0.0006), as were fasting and fed TRL-TG, TRL-apoB-48 and TRL-apoB-100 (fed TRLapoB-48: 0.93±0.08 vs 0.76±0.07 mg/dl, p=0.017 and fed TRL-apoB-100: 15.57±0.90 vs 13.71±1.27 mg/dl, p=0.029). This small but significant increase in plasma TRL concentration was explained by a tendency for RSG to increase TRL production while reducing particle clearance, as indicated by the significantly increased production/clearance ratios for both apoB48-containing (0.43±0.03 vs 0.34±0.03, p=0.048) and apoB-100-containing (7.0± 0.4 vs 6.2±0.6, p=0.029) TRL.

Conclusion: These data indicate dissociation between the insulin-sensitizing effects of RSG and absence of anticipated reductions in production rates of apoB-100- and apoB-48-containing-TRL particles, which may explain the absence of TG-lowering seen in humans treated with this agent.