title: Dissociation between the insulin-sensitizing effect of rosiglitazone and its effect on hepatic and intestinal lipoprotein production.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a 12-wk, single-sequence, cross-over study of rosiglitazone vs. placebo for 6 wk.
  
  
  METHODS
  Participants included 17 nondiabetic men with a broad range of insulin sensitivity.
  
  
  METHODS
  INTERVENTION included rosiglitazone 8 mg/d vs. placebo for 6 wk.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Departments of Medicine and Physiology, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada.
authors.forename: Hélène
authors.initials: H
authors.lastname: Duez
authors.forename: Benoît
authors.initials: B
authors.lastname: Lamarche
authors.forename: Kristine D
authors.initials: KD
authors.lastname: Uffelman
authors.forename: René
authors.initials: R
authors.lastname: Valéro
authors.forename: Linda
authors.initials: L
authors.lastname: Szeto
authors.forename: Simone
authors.initials: S
authors.lastname: Lemieux
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Cohn
authors.forename: Gary F
authors.initials: GF
authors.lastname: Lewis
mesh_terms: D000328:Adult; D053299:Apolipoprotein B-100 / Q000096:biosynthesis; D053283:Apolipoprotein B-48 / Q000096:biosynthesis; D018592:Cross-Over Studies; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008074:Lipoproteins / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014280:Triglycerides / Q000096:biosynthesis*
chemical_list: D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D008074:Lipoproteins; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone