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Dissociation between the Insulin-Sensitizing Effect of Rosiglitazone and Its Effect on Hepatic and Intestinal Lipoprotein Production

Departments of Medicine and Physiology (H.D., K.D.U., R.V., L.S., G.F.L.), Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada M5G 2C4; Institut des Nutraceutiques et Aliments Fonctionnels (B.L., S.L.), Université Laval, Québec, Canada G1K 7P4; and Clinical Research Institute of Montréal (J.S.C.), Montréal, Canada H2W 1R7

Address all correspondence and requests for reprints to: Dr. Gary F. Lewis, Toronto General Hospital, 200 Elizabeth Street, EN12-218, Toronto, Ontario, Canada M5G 2C4. E-mail: gary.lewis{at}uhn.on.ca.

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.