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Hélène Duez, Benoît Lamarche, Kristine D. Uffelman, René Valéro, Linda Szeto, Simone Lemieux, Jeffrey S. Cohn, Gary F. Lewis, Dissociation between the Insulin-Sensitizing Effect of Rosiglitazone and Its Effect on Hepatic and Intestinal Lipoprotein Production, The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 5, 1 May 2008, Pages 1722–1729, https://doi.org/10.1210/jc.2007-2110
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Abstract
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.
