help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2110
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Duez, H.
Right arrow Articles by Lewis, G. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Duez, H.
Right arrow Articles by Lewis, G. F.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Related Collections
Right arrow Diabetes and Insulin
Right arrow Metabolism
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 5 1722-1729
Copyright © 2008 by The Endocrine Society

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

Hélène Duez, Benoît Lamarche, Kristine D. Uffelman, René Valéro, Linda Szeto, Simone Lemieux, Jeffrey S. Cohn and Gary F. Lewis

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.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Individuals with insulin resistance and type 2 diabetes have an increased risk of atherosclerotic cardiovascular disease (1). Dyslipidemia is a prominent feature of these conditions and may contribute to the increased risk of cardiovascular events (1, 2). Typical diabetic dyslipidemia is characterized by elevated plasma triglyceride-rich lipoproteins (TRL), low plasma high-density lipoprotein (HDL)-cholesterol concentration and increased numbers of small, dense low-density lipoprotein (LDL) particles (1). The elevation of TRL particles in insulin-resistant states is contributed to by both hepatic [apolipoprotein (apo)-B-100-containing] and intestinal (apoB-48-containing) lipoproteins in fasted and postprandial states (3, 4).

The thiazolidinedione (TZD) class of insulin-sensitizing agents, agonists of the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR)-{gamma}, are widely used for the treatment of type 2 diabetes (5). They improve insulin sensitivity and glycemic control in individuals with type 2 diabetes (6, 7). Although variable effects on plasma LDL-cholesterol concentration and LDL particle numbers have been reported, TZD treatment of humans with type 2 diabetes more consistently raises plasma HDL-cholesterol and increases LDL particle size (8). However, despite the potent insulin-sensitizing properties of TZDs and the link between insulin resistance and very low-density lipoprotein (VLDL) overproduction, the ability of these agents to lower plasma triglycerides is variable. There are well-documented differences between pioglitazone and rosiglitazone with respect to their effects on TRL, with pioglitazone having a modest triglyceride-lowering effect (8, 9, 10), and rosiglitazone having either no reduction or even a slight increase in plasma triglycerides (8, 11, 12). To examine the mechanism of effect of TZDs of TRL, it is necessary to go beyond the measurement of plasma lipoprotein and apolipoprotein concentrations and to determine the kinetics of TRL metabolism in vivo.

We have recently shown that diet-induced whole-body insulin resistance in the Syrian golden hamster was associated with mild hypertriglyceridemia and overproduction of both intestinal and hepatic TRL (13, 14). Using this model of insulin resistance-associated dyslipidemia, we demonstrated that rosiglitazone improved whole-body insulin sensitivity and insulin signaling, and partially reversed both hepatic and intestinal lipoprotein overproduction (15, 16, 17). This effect, however, may not be truly reflective of the effect of rosiglitazone treatment of humans with insulin resistance.

In the present study, we investigated the effect of rosiglitazone on steady-state fed TRL-apoB-48 and TRL-apoB-100 production and clearance rates in men with a broad range of homeostasis model assessment (HOMA) scores and plasma insulin concentrations. We specifically chose to examine nondiabetic individuals in this study to eliminate the potential confounding effect of rosiglitazone-induced improvements in glycemic control that occur in people with diabetes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and study design

Seventeen healthy, normoglycemic men, aged 30–60 yr with a broad range of body weights (from 64.3 to 134.3 kg) and body mass index (from 20.0 to 41.6 kg/m2) participated in the study for determination of apoB-containing lipoprotein kinetics (see baseline characteristics in Table 1Go). Subjects were enrolled if their total plasma cholesterol was 5.5 mmol/liter or less, HDL-cholesterol 0.8 mmol/liter or greater, LDL-cholesterol 4.0 mmol/liter or less, and triglycerides 4.0 mmol/liter or less to exclude those with extreme dyslipidemia. No subject was taking medications and all had a normal 75-g oral glucose tolerance test performed immediately before enrollment in the study. Fasting insulin concentrations ranged from 21.0 to 151.0 pmol/liter. HOMA-IR as an index of insulin resistance was calculated as previously described (42) and ranged from 0.70 to 5.93 in the study subjects. The study was designed and conducted as a 12-wk, single-sequence, cross-over group design, with an initial 6-wk placebo treatment period followed by 6-wk rosiglitazone (8 mg/d) treatment period. Rosiglitazone and placebo tablets were supplied by GlaxoSmithKline Pharmaceuticals (Mississauga, Ontario, Canada). Participants were monitored weekly for weight, vital signs, and fasting blood glucose. Compliance with medications was assessed at the weekly visits by tablet counting and was determined to be greater than 98% for all subjects. All participants were nonsmokers and none had a previous history of cardiovascular disease or systemic illness. None had any surgical intervention within 6 months before the studies.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Demographic and biochemical (fasting plasma metabolites, hormones, and lipids) characteristics of subjects during the placebo (PL) and rosiglitazone (RSG) treatment periods

 
TRL apoB-containing lipoprotein kinetics studies

Kinetics studies for assessment of TRL-apoB metabolism were performed at the end of the 6-wk placebo treatment period and again at the end of the 6-wk rosiglitazone treatment period. Subjects were admitted to the Endocrine/Metabolic Diagnostic Center of the Toronto General Hospital at 1500 h after fasting from midnight the previous night. An iv line was placed in a superficial vein in each forearm, one for infusion and one for blood sampling, and a baseline fasting sample was drawn. Subjects were provided with a mixed meal (American Heart Association phase 1 diet) at approximately 1700 h, and at approximately 0700 h the following morning, subjects were instructed to begin ingesting 15 identical hourly volumes of a liquid food supplement called Boost (Mead Johnson Nutritionals, Ottawa, Ontario, Canada), each equivalent to one 15th of their total daily caloric needs, using the Harris Benedict equation to determine the total energy requirements (based on height, weight, age, and activity factors). Boost contains 20% of total calories from protein, 62% carbohydrate, and 18% fat (of the total energy derived from fat, 25% was polyunsaturated fatty acids, 65% monounsaturated fatty acids, and 13% saturated fatty acids). Three hours after starting to ingest Boost, subjects received a primed constant infusion (10 µmol/kg bolus followed by 10 µmol/kg·h for 12 h) of deuterium-labeled leucine (18) (L-[5,5,5-2H3]leucine; 98%, Cambridge Isotope Laboratories, Andover, MA) to enrich apoB-100 and apoB-48 in hepatic and intestinally derived lipoprotein particles, respectively, to calculate the production and clearance rates of the particles as previously described (19). Blood samples were collected at 1, 2, 3, 5, 7, 9, 10, 11, and 12 h.

The Research Ethics Board of the University Health Network, University of Toronto, approved the study, and all subjects gave written informed consent before their participation.

Sample processing

TRLs were isolated at each time point by centrifugation, and delipidated proteins were separated by preparative 3.3% SDS-PAGE and stained with Coomassie R-250. ApoB-100 and apoB-48 gel slices were excised, hydrolyzed and derivatized to allow for the determination of plasma leucine isotopic enrichment as previously described (18, 19, 20, 21). Enrichment of samples with deuterium-labeled leucine was measured by gas chromatography/mass spectrometry (Agilent 5973 GC/MS; Agilent Technologies Canada Inc., Mississauga, Ontario, Canada), and tracer to tracee ratios (corrected for background leucine in gel slices) were calculated from isotopic ratios for each sample as previously described (22).

Laboratory measurements

Triglycerides, cholesterol, and free fatty acids (FFAs) were determined using commercially available kits (Roche Diagnostics, Mannheim, Germany; Wako Industrials, Osaka, Japan). Plasma insulin concentrations were assayed by RIA using a human specific insulin kit (Linco Research, St. Louis, MO). Glucose was measured enzymatically using a Beckman Glucose Analyzer II (Beckman Instruments Corp., Fullerton, CA). Total apoB in plasma and TRL was measured by electroimmunoassay as previously described (23). ApoB-48 and apoB-100 mass in the TRL fraction was quantified using analytical SDS-PAGE as previously described (24). LDL size was determined on polyacrylamide gradient gels (4–16%) using molecular mass calibration markers (Pharmacia Biotech Inc., Uppsala, Sweden).

Analysis of lipoprotein production and clearance rates

Stable isotope enrichment curves for apoB-48 and apoB-100 were fitted to a three-compartment model using SAAM II computer software (SAAM II Institute, Seattle, WA) as previously described (22). Each subject was in steady state with respect to apoB-48 concentrations so fractional catabolic rate (FCR) was equivalent to fractional synthetic rate. Kinetic parameters were derived by analyzing individual enrichment curves and only those in which the coefficient of variation for apoB-48 or apoB-100 modeling was less than 25% were included. For this reason the apoB-48 kinetic results are reported in only 11 of the 17 study participants because only 11 subjects had acceptable TRL apoB-48 enrichment vs. time curves for both placebo and rosiglitazone-treated studies.

Production rates were derived using the FCR of the TRL apoB-100 and apoB-48 and multiplied by their pool sizes measured over the 12 h of the study per kilogram body weight, where pool size = plasma concentration (milligrams per deciliter) between time 3 h and time 12 h of the kinetic x plasma volume (0.045 liter/kg).

Details of the laboratory measurements, including the determination of TRL apoB-containing lipoprotein kinetics are included in the online data supplement, published as supplemental data on The Endocrine Society’s Journals Online Web site at http://jcem.endojournals.org.

Statistics

Results are presented as mean ± SEM. Paired t tests were used to compare patients during the placebo vs. rosiglitazone treatment period. ANOVA was used to analyze TRL-triglycerides (TG), TRL-apoB-100, and TRL-apoB-48 increase over the time. All analyses were performed with SPSS (version13; SPSS Inc., Chicago, IL). For all of the analyses, a P value < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Demographic characteristics and the effect of rosiglitazone treatment on anthropometric indices and insulin sensitivity (Table 1Go)

The clinical characteristics of subjects after the placebo and rosiglitazone treatment periods are given in Table 1Go. Rosiglitazone administration did not induce weight gain over the 6-wk treatment period. Waist circumference and body mass index were also not affected by rosiglitazone treatment (data not shown). As anticipated, rosiglitazone significantly decreased plasma insulin (P = 0.003) and glucose (P = 0.044). Accordingly, the HOMA-IR index was significantly reduced after rosiglitazone treatment (P = 0.002). There was no difference in FFA levels after rosiglitazone treatment. These data indicate that rosiglitazone administration improved insulin sensitivity, without a significant change in body fat.

Effect of rosiglitazone treatment on fasting plasma (Table 2Go) and TRL (Table 3Go) lipids and apolipoprotein B concentrations

As shown in Table 2Go, rosiglitazone treatment induced a significant increase in total plasma cholesterol (P = 0.003), apoB (P = 0.004), and triglycerides (P = 0.0006). HDL-cholesterol increased with rosiglitazone treatment (P = 0.035). No change was observed in plasma LDL-cholesterol concentration or LDL particle size after rosiglitazone treatment (P = 0.942).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Plasma lipids and apoB concentrations in the fasted state during the placebo (PL) and rosiglitazone (RSG) treatment periods

 

View this table:
[in this window]
[in a new window]

  		TABLE 3. Fasting TRL TG and apoB levels during the placebo (PL) and rosiglitazone (RSG) treatment periods

 
TRL composition was examined in more detail (Table 3Go). Fasting TRL-TGs were significantly elevated after rosiglitazone treatment (P = 0.007), and a parallel increase in TRL-apoB-48 (P < 0.001) and TRL apoB-100 (P = 0.005) was observed after rosiglitazone administration.

Effect of rosiglitazone on TRL-TG and TRL-apoB-48 and apoB-100 concentrations during liquid formula ingestion (Fig. 1Go)

Mean TRL-TG, TRL-apoB-100, and TRL-apoB-48 concentrations at fasting (0 h) and during the 15-h fat feeding study are illustrated in Fig. 1Go, A–C, respectively. TRL-TG in the fed state tended to be higher in rosiglitazone-treated patients. Similarly, both TRL-apoB-48 (mean fed state rosiglitazone, 0.93 ± 0.08 vs. placebo, 0.76 ± 0.07, P = 0.017) and TRL-apoB-100 (mean fed state rosiglitazone, 15.57 ± 0.90 vs. placebo, 13.71 ± 1.27, P = 0.029) were higher after rosiglitazone treatment.


Figure 1
View larger version (16K):
[in this window]
[in a new window]

  		FIG. 1. TRL-TG, TRL-apoB-100, and TRL-apoB-48 concentrations over the time course of the kinetic study. TRL-TG (A), TRL-apoB-100 (B), and TR-apoB-48 (C) were measured throughout the 15-h study in subjects after the placebo period (empty squares) or after the rosiglitazone (RSG) treatment period (filled squares). Subjects began to ingest a liquid formula hourly at 0700 h (0 time), after an overnight fast. A primed, continuous infusion of deuterium-labeled leucine was started after 3 h of formula ingestion, and TRL-apoB kinetics parameters were calculated during the subsequent 12-h study period (time 3 to 15 h). Values are mean ± SEM for each group. The overall significance over the time as analyzed by ANOVA was P = 0.027 for TRL-apoB-100 and P < 0.001 for TRL-apoB-48.

 
Effect of rosiglitazone on hepatic and intestinal lipoprotein production and clearance rates (Fig. 2Go)

No significant changes in TRL-apoB-48 and TRL-apoB-100 production and clearance rates were observed after rosiglitazone treatment (Fig. 2Go). However, TRL-apoB-48 and TRL-apoB-100 production rates tended to slightly increase after rosiglitazone treatment [TRL-apoB-48 production rate (PR): rosiglitazone, 1.52 ± 0.21 mg/kg·d vs. placebo, 1.25 ± 0.26 mg/kg·d, P = 0.288 and TRL-apoB-100 PR: rosiglitazone, 28.93 ± 3.57 mg/kg·d vs. placebo, 26.68 ± 3.42 mg/kg·d, P = 0.410], whereas clearance rates tended to decrease (TRL-apoB-48 FCR: rosiglitazone, 3.80 ± 0.56 pool/d vs. placebo, 4.41 ± 0.92 pool/d, P = 0.665, and TRL-apoB-100 FCR: rosiglitazone, 4.21 ± 0.51 pool/d vs. placebo, 4.42 ± 0.42 pool/d, P = 0.645). However, the PR to FCR ratio was significantly increased after rosiglitazone treatment for both TRL-apoB-48 and TRL-apoB-100 (TRL-apoB-48: rosiglitazone, 0.43 ± 0.03 vs. placebo 0.34 ± 0.03, P = 0.048, and TRL-apoB-100: rosiglitazone, 7.0 ± 0.4 vs. placebo, 6.2 ± 0.6, P = 0.029).


Figure 2
View larger version (12K):
[in this window]
[in a new window]

  		FIG. 2. Effect of rosiglitazone (RSG) on TRL-apoB-48 and TRL-apoB-100 production and catabolic rates. TRL-apoB-100 (n = 17) and TRL-apoB-48 (n = 11) PRs (A) and FCRs (B) after 6 wk treatment with placebo or RSG. No statistically significant differences existed between placebo and RSG treatment periods.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we investigated the effect of 6-wk treatment with rosiglitazone on TRL metabolism in the fed state by modeling the stable isotope enrichment of protein (apoB-48 and apoB-100) moieties of TRL particles. We were thus able to examine both intestinally and hepatically derived TRL metabolism. We specifically chose to study nondiabetic individuals to exclude a potential confounding effect of improvements in glycemic control that would be anticipated to occur with rosiglitazone treatment of patients with type 2 diabetes. Because insulin resistance is associated with overproduction of TRL particles by both the intestine (22) and the liver (25), we hypothesized that the well-documented improvement in whole-body and hepatic insulin sensitivity with rosiglitazone would lower plasma TRL concentrations by reducing their production rates. Instead we found that, despite significant insulin sensitization in our subjects (reduction in plasma glucose, insulin, and consequently HOMA-IR), there was no reduction in either apoB48-containing or apoB-100-containing TRL production. In fact, we observed a small but significant increase in plasma TRL concentrations within the normal range, which can be explained by a tendency for rosiglitazone to increase TRL production and reduce particle clearance, as indicated by the significantly increased PR to FCR ratios for both apoB48-containing and apoB-100-containing TRL. Subjects with a wide range of insulin sensitivity were recruited in our study. It is interesting that rosiglitazone treatment does not improve TRL metabolism, even in subjects with the lowest pretreatment insulin sensitivity (i.e. those who were expected to benefit the most from insulin sensitization). Thus, our findings demonstrate that rosiglitazone does not reduce either hepatic or intestinal TRL production, despite improvement in whole-body insulin sensitivity, and rather suggests dissociation between its insulin-sensitizing properties and its effects on TRL metabolism.

The effect of rosiglitazone on fasting plasma TGs is variable, with most studies reporting no change (26, 27, 28, 29) or an increase in plasma TGs (8, 11, 12). Several investigators have examined the effect of TZDs on postprandial TG metabolism. In patients with type 2 diabetes, rosiglitazone was reported to decrease TG levels after an oral fat load (30, 31), the latter also showing a reduction in TRL-TG. In contrast, James et al. (32) and Chappuis et al. (12) recently demonstrated an increase in fasting and postprandial TG levels and reported an increase of plasma apoB-48 concentration after a mixed meal in rosiglitazone-treated patients, compared with controls, and one of these studies (32) reported an increase of plasma apoB-48 concentration after a mixed meal in rosiglitazone-treated patients, compared with controls, a finding that is consistent with ours. Our results showing no reduction in either hepatic or intestinal TRL production and no increase in the clearance of the particles, despite ameliorated insulin sensitivity after rosiglitazone treatment, may explain the absence of robust TG-lowering in earlier studies.

The effect of pioglitazone, another member of the TZD class of insulin-sensitizing agents, on TRL metabolism was recently examined by Nagashima et al. (9) in patients with type 2 diabetes. Consistent with our findings, they also showed no reduction in hepatic VLDL production with pioglitazone treatment. In contrast to our results, in which there was a trend toward a reduction in TRL clearance with rosiglitazone treatment, pioglitazone lowered plasma TG by approximately 30% by stimulating VLDL-TG but not VLDL particle (i.e. apoB) clearance via a mechanism postulated to be due to increased LPL mass and decreased apoC-III (9). This effect may be attributed to partial PPAR{alpha} activation by pioglitazone (33), although an indirect effect on TRL clearance secondary to improved glycemic control cannot be excluded. More recently, pioglitazone treatment was reported to lower fasting and postprandial TG levels in patients with type 2 diabetes, independent of any change in LPL activity, and was associated with a significant decrease in hepatic lipase activity (10). The difference between the effect of rosiglitazone and pioglitazone on plasma TRL concentrations was recently confirmed in the first large-scale, prospective, double-blinded, head-to-head comparison study (8). It appears, therefore, that pioglitazone and rosiglitazone have common (insulin sensitizing) and distinct (lipid related effects) properties. The difference in effects on TRL metabolism appears to be confined to differences in the clearance of TRL triglycerides, whereas their effects on TRL production rates are similar.

Insulin sensitization by a variety of methods, including weight reduction and exercise, is associated with reductions in VLDL secretion and plasma TRL concentrations (34, 35, 36), which is why we were surprised that rosiglitazone did not effectively reduce TRL secretion. VLDL secretion is, to a large extent, driven by the increased FFA flux to liver that characterizes insulin resistance and type 2 diabetes (37). FFA lowering has been demonstrated in some human studies secondary to an improvement of insulin sensitivity in muscle and/or adipose tissue (28, 30, 38, 39). In the present study, however, rosiglitazone treatment failed to decrease fasting plasma FFA concentration, although we cannot exclude the possibility that it may have resulted in lower postprandial FFA flux to the liver. The fact that our subjects were not diabetic, or the short period of treatment might explain the difference from the above-mentioned studies. A reduction of FFA flux to the liver would be anticipated to decrease TRL production, which was not the case in the present study. The significant increase in plasma total cholesterol levels, and possibly in plasma VLDL-cholesterol, indicates that failure to decrease hepatic cholesterol with rosiglitazone may contribute to the VLDL oversecretion as well. We did not measure liver fat in the present study, but the anticipated reduction in liver fat content would be another factor expected to reduce VLDL secretion. It may be postulated that a direct effect of rosiglitazone in stimulating hepatic lipogenesis might have counteracted the other insulin-sensitizing effects of rosiglitazone. To the best of our knowledge, no previous study has addressed whether TZD treatment results in direct stimulation of hepatic de novo lipogenesis. This could occur through a PPAR{gamma}-LXR-sterol regulatory element-binding protein-1c-mediated mechanism (40) or a PPAR{gamma}2-dependent but LXR/sterol regulatory element-binding protein-1c-independent mechanism as recently demonstrated in a mouse model of insulin resistance- and steatosis-associated dyslipidemia (41) or by other yet unknown direct effects of rosiglitazone on TRL particle biogenesis and TRL-lipid clearance. The mechanism accounting for the puzzling dissociation between the hepatic and whole-body insulin-sensitizing effects of rosiglitazone and TRL metabolism requires further investigation.

In conclusion, we have demonstrated that, despite a significant improvement in insulin sensitivity, rosiglitazone does not improve fasting and postprandial lipemia in men with a broad range of insulin sensitivity. Our observations highlight the fact that not all clinical effects of PPAR{gamma} agonists, such as the TZDs, can be anticipated according to the insulin-sensitizing effects of these drugs, which is but one of many downstream effects of PPAR{gamma} activation.


   Acknowledgments
 
We are indebted to Patricia Harley, R.N., for her assistance with subject recruitment and conducting the clinical protocol.


   Footnotes
 
This work was supported by the Canadian Institutes for Health Research (MOP-43839), Glaxosmithkline Canada, and the Heart and Stroke Foundation of Canada. G.F.L. holds a Canada Research Chair in Diabetes and is a Career Investigator of the Heart and Stroke Foundation of Canada. B.L. holds a Canada Research Chair in Nutrition and Cardiovascular Health. H.D. is the recipient of a Postdoctoral Fellowship Award from the Heart and Stroke Foundation of Canada.

Present address for J.S.C.: Heart Research Institute, Nutrition and Metabolism Group, Camperdown, Sydney, New South Wales 2050, Australia.

Disclosure statement: G.F.L. received a grant from GlaxoSmithKline, which provided funding in part for this study. All other authors have nothing to disclose.

First Published Online February 19, 2008

Abbreviations: Apo, Apolipoprotein; FCR, fractional catabolic rate; FFA, free fatty acid; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment-insulin resistance; LDL, low-density lipoprotein; PPAR, peroxisome proliferator-activated receptor; PR, production rate; TG, triglyceride; TRL, triglyceride-rich lipoprotein; TZD, thiazolidinedione; VLDL, very low-density lipoprotein.

Received September 20, 2007.

Accepted February 12, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Ginsberg HN 2000 Insulin resistance and cardiovascular disease. J Clin Invest 106:453–458[Medline]
  2. Lewis GF, Steiner G 1996 Hypertriglyceridemia and its metabolic consequences as a risk factor for atherosclerotic cardiovascular disease in non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 12:37–56[CrossRef][Medline]
  3. Schaefer EJ, McNamara JR, Shah PK, Nakajima K, Cupples LA, Ordovas JM, Wilson PW; Framingham Offspring Study 2002 Elevated remnant-like particle cholesterol and triglyceride levels in diabetic men and women in the Framingham Offspring Study. Diabetes Care 25:989–994[Abstract/Free Full Text]
  4. Taskinen MR 2003 Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 46:733–749[CrossRef][Medline]
  5. Staels B, Fruchart JC 2005 Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 54:2460–2470[Abstract/Free Full Text]
  6. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefèbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive investigators 2005 Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366:1279–1289[CrossRef][Medline]
  7. Sidhu JS, Kaposzta Z, Markus HS, Kaski JC 2004 Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol 24:930–934[Abstract/Free Full Text]
  8. Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJ; GLAI Study Investigators 2005 A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 28:1547–1554[Abstract/Free Full Text]
  9. Nagashima K, Lopez C, Donovan D, Ngai C, Fontanez N, Bensadoun A, Fruchart-Najib J, Holleran S, Cohn JS, Ramakrishnan R, Ginsberg HN 2005 Effects of the PPAR{gamma} agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J Clin Invest 115:1323–1332[CrossRef][Medline]
  10. Majali KA, Cooper MB, Staels B, Luc G, Taskinen MR, Betteridge DJ 2006 The effect of sensitisation to insulin with pioglitazone on fasting and postprandial lipid metabolism, lipoprotein modification by lipases, and lipid transfer activities in type 2 diabetic patients. Diabetologia 1–11
  11. Nolan JJ, Jones NP, Patwardhan R, Deacon LF 2000 Rosiglitazone taken once daily provides effective glycaemic control in patients with type 2 diabetes mellitus. Diabet Med 17:287–294[CrossRef][Medline]
  12. Chappuis B, Braun M, Stettler C, Allemann S, Diem P, Lumb PJ, Wierzbicki AS, James R, Christ ER 2007 Differential effect of pioglitazone (PGZ) and rosiglitazone (RGZ) on postprandial glucose and lipid metabolism in patients with type 2 diabetes mellitus: a prospective, randomized crossover study. Diabetes Metab Res Rev 23:392–399[CrossRef][Medline]
  13. Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, Lewis GF, Adeli K 2000 Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem 275:8416–8425[Abstract/Free Full Text]
  14. Haidari M, Leung N, Mahbub F, Uffelman KD, Kohen-Avramoglu R, Lewis GF, Adeli K 2002 Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction. J Biol Chem 277:31646–31655[Abstract/Free Full Text]
  15. Carpentier A, Taghibiglou C, Leung N, Szeto L, Van Iderstine SC, Uffelman KD, Buckingham R, Adeli K, Lewis GF 2002 Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem 277:28795–28802[Abstract/Free Full Text]
  16. Leung N, Naples M, Uffelman K, Szeto L, Adeli K, Lewis GF 2004 Rosiglitazone improves intestinal lipoprotein overproduction in the fat-fed Syrian Golden hamster, an animal model of nutritionally-induced insulin resistance. Atherosclerosis 174:235–241[Medline]
  17. Lewis GF, Uffelman K, Naples M, Szeto L, Haidari M, Adeli K 2005 Intestinal lipoprotein overproduction, a newly recognized component of insulin resistance, is ameliorated by the insulin sensitizer rosiglitazone: studies in the fructose-fed Syrian golden hamster. Endocrinology 146:247–255[Abstract/Free Full Text]
  18. Cohn JS, Wagner DA, Cohn SD, Millar JS, Schaefer EJ 1990 Measurement of very low density and low density lipoprotein apolipoprotein (Apo) B-100 and high density lipoprotein Apo A-I production in human subjects using deuterated leucine. Effect of fasting and feeding. J Clin Invest 85:804–811[Medline]
  19. Batal R, Tremblay M, Barrett PH, Jacques H, Fredenrich A, Mamer O, Davignon J, Cohn JS 2000 Plasma kinetics of apoC-III and apoE in normolipidemic and hypertriglyceridemic subjects. J Lipid Res 41:706–718[Abstract/Free Full Text]
  20. Batal R, Tremblay M, Krimbou L, Mamer O, Davignon J, Genest Jr J, Cohn JS 1998 Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not proapoA-I. Arterioscler Thromb Vasc Biol 18:655–664[Abstract/Free Full Text]
  21. Tremblay AJ, Lamarche B, Ruel I, Hogue JC, Bergeron J, Gagné C, Couture P 2004 Lack of evidence for reduced plasma apo B48 catabolism in patients with heterozygous familial hypercholesterolemia carrying the same null LDL receptor gene mutation. Atherosclerosis 172:367–373[CrossRef][Medline]
  22. Duez H, Lamarche B, Uffelman K, Valero R, Cohn J, Lewis GF 2006 Hyperinsulinemia is associated with increased production rate of intestinal apoB-48-containing lipoproteins in humans. Arterioscler Thromb Vasc Biol 26:1357–1363[Abstract/Free Full Text]
  23. Reardon MF, Poapst ME, Uffelman KD, Steiner G 1981 Improved method for quantitation of B apoprotein in plasma lipoproteins by electroimmunoassay. Clin Chem 27:892–895[Abstract/Free Full Text]
  24. Karpe F, Hamsten A, Uffelman K, Steiner G 1996 Apolipoprotein B-48. Methods Enzymol 263:95–104[Medline]
  25. Taskinen MR 2005 Type 2 diabetes as a lipid disorder. Curr Mol Med 5:297–308[CrossRef][Medline]
  26. Patel J, Anderson RJ, Rappaport EB 1999 Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diabetes Obes Metab 1:165–172[CrossRef][Medline]
  27. Fonseca V, Rosenstock J, Patwardhan R, Salzman A 2000 Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 283:1695–1702[Abstract/Free Full Text]
  28. Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J 2001 A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 24:1226–1232[Abstract/Free Full Text]
  29. Samaha FK, Szapary PO, Iqbal N, Williams MM, Bloedon LT, Kochar A, Wolfe ML, Rader DJ 2006 Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome. Arterioscler Thromb Vasc Biol 26:624–630[Abstract/Free Full Text]
  30. Tan GD, Fielding BA, Currie JM, Humphreys SM, Désage M, Frayn KN, Laville M, Vidal H, Karpe F 2005 The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes. Diabetologia 48:83–95[CrossRef][Medline]
  31. van Wijk JP, de Koning EJ, Castro CM, Rabelink TJ 2005 Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes. Diabetes Care 28:844–849[Abstract/Free Full Text]
  32. James AP, Watts GF, Mamo JC 2005 The effect of metformin and rosiglitazone on postprandial lipid metabolism in obese insulin-resistant subjects. Diabetes Obes Metab 7:381–389[CrossRef][Medline]
  33. Sakamoto J, Kimura H, Moriyama S, Odaka H, Momose Y, Sugiyama Y, Sawada H 2000 Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 278:704–711[CrossRef][Medline]
  34. Ginsberg HN, Le NA, Gibson JC 1985 Regulation of the production and catabolism of plasma low density lipoproteins in hypertriglyceridemic subjects. Effect of weight loss. J Clin Invest 75:614–623[Medline]
  35. Riches FM, Watts GF, Hua J, Stewart GR, Naoumova RP, Barrett PH 1999 Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men. J Clin Endocrinol Metab 84:2854–2861[Abstract/Free Full Text]
  36. Alam S, Stolinski M, Pentecost C, Boroujerdi MA, Jones RH, Sonksen PH, Umpleby AM 2004 The effect of a six-month exercise program on very low-density lipoprotein apolipoprotein B secretion in type 2 diabetes. J Clin Endocrinol Metab 89:688–694[Abstract/Free Full Text]
  37. Lewis GF 1997 Fatty acid regulation of very low density lipoprotein production. Curr Opin Lipidol 8:146–153[Medline]
  38. Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF 2002 The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51:797–802[Abstract/Free Full Text]
  39. Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM 2006 Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes 55:2277–2285[Abstract/Free Full Text]
  40. Li AC, Glass CK 2004 PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res 45:2161–2173[Abstract/Free Full Text]
  41. Zhang YL, Hernandez-Ono A, Siri P, Weisberg S, Conlon D, Graham MJ, Crooke RM, Huang LS, Ginsberg HN 2006 Aberrant hepatic expression of PPAR{gamma}2 stimulates hepatic lipogenesis in a mouse model of obesity, insulin resistance, dyslipidemia, and hepatic steatosis. J Biol Chem 281:37603–37615[Abstract/Free Full Text]
  42. Levy JC, Matthews DR, Hermans MP1998 Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 21:2191–2192




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Duez, H.
Right arrow Articles by Lewis, G. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Duez, H.
Right arrow Articles by Lewis, G. F.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Related Collections
Right arrow Diabetes and Insulin
Right arrow Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals