Dissociation between the insulin-sensitizing effect of rosiglitazone and its effect on hepatic and intestinal lipoprotein production.

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

This was a 12-wk, single-sequence, cross-over study of rosiglitazone vs. placebo for 6 wk.

PARTICIPANTS

Participants included 17 nondiabetic men with a broad range of insulin sensitivity.

INTERVENTION

INTERVENTION included rosiglitazone 8 mg/d vs. placebo for 6 wk.

MAIN OUTCOME MEASURE

TRL metabolism (concentration, production and catabolic rates) was assessed in a constant fed state with a 12-h 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 TRL-apoB-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 and reduce particle clearance, as indicated by the significantly increased production to clearance ratios for both apoB-48-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.