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

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.

• Authors: Hélène Duez, Benoît Lamarche, Kristine D Uffelman, René Valéro, Linda Szeto, Simone Lemieux, Jeffrey S Cohn, Gary F Lewis
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 93 Issue 5 Pg. 1722-9 (May 2008) ISSN: 0021-972X [Print] United States
• PMID: 18285418 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein B-100
• Apolipoprotein B-48
• Fatty Acids, Nonesterified
• Hypoglycemic Agents
• Insulin
• Lipoproteins
• Thiazolidinediones
• Triglycerides
• Rosiglitazone

Topics

• Adult
• Apolipoprotein B-100 (biosynthesis)
• Apolipoprotein B-48 (biosynthesis)
• Cross-Over Studies
• Fatty Acids, Nonesterified (blood)
• Humans
• Hypoglycemic Agents (pharmacology)
• Insulin (blood)
• Intestinal Mucosa (metabolism)
• Lipoproteins (biosynthesis)
• Liver (metabolism)
• Male
• Middle Aged
• Rosiglitazone
• Thiazolidinediones (pharmacology)
• Triglycerides (biosynthesis)