Objective: We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. For this purpose, we determined the effects of rosiglitazone (8 mg/d) on postprandial leukocyte counts and pro-inflammatory cytokines (IL-6 and IL-8) in patients with type 2 diabetes.Methods and results: A randomized, 8-week, cross-over, placebo-controlled, double-blind clinical trial was performed in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. During placebo treatment, blood leukocytes increased to a maximum 6-h postprandially, due to significant increases in neutrophils and lymphocytes. Concomitant postprandial increases were observed for IL-6 and IL-8, the major chemokines responsible for leukocyte recruitment. Rosiglitazone reduced the incremental area under the curves (dAUCs) for IL-6 (-63%, p < 0.01) and IL-8 (-16%, p < 0.05). The dAUC for leukocytes decreased with 37% (p < 0.05), due to a specific reduction of neutrophils (-39%, p < 0.05).Conclusions: Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. Since inflammation is a major force driving atherosclerosis, and man lives in a postprandial period most part of the day, a reduced inflammatory response after a meal may delay progression of atherosclerosis.Condensed abstract: We postulated that in type 2 diabetes, the postprandial phase is a pro-inflammatory state that can be modulated by PPAR-gamma agonists. Rosiglitazone attenuated the postprandial increases of neutrophils, IL-6 and IL-8 in patients with type 2 diabetes. These effects may contribute to cardiovascular risk reduction. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVES We investigated functional and structural markers of atherosclerosis in human immunodeficiency virus (HIV)-infected patients in relation to the presence of the metabolic syndrome (MS).BACKGROUND Antiretroviral combination therapy in HIV has been associated with cardiovascular risk factors that cluster in the MS.METHODS Thirty-seven HIV-infected patients underwent assessment of flow-mediated vasodilation (FMD), aortic pulse-wave velocity (PWV), and carotid intima-media thickness (IMT). Age-matched type 2 diabetic patients (n = 13) and healthy controls (n = 14) served as reference groups.RESULTS Fifteen HIV-infected patients (41%) fulfilled the National Cholesterol Education Program criteria of the MS. The FMD was similarly impaired in HIV-infected patients without the MS (MS- group) and the diabetic patients (5.1 +/- 0.4% and 4.9 +/- 0.6%, respectively) compared with controls (8.8 +/- 0.7%). The HTV-infected patients with the MS (MS+ group) had even more impaired FMD (2.5 +/- 0.3%). Carotid IMT was similarly increased in the MS+ group and the diabetic patients compared with the other groups. Aortic PWV was increased in the diabetic patients only. In HIV-infected patients, FMD was related to metabolic parameters, whereas aortic PWV and IMT were related to parameters of HIV infection, time on antiretroviral combination therapy, inflammatory (C-reactive protein and leukocytes) and metabolic parameters.CONCLUSIONS The data of the present study suggest an increased cardiovascular risk in HIV-infected patients, even in the absence of clustering of metabolic risk variables. The presence of the MS in HIV is associated with even more advanced atherosclerotic changes. Presumably, both HIV infection and antiretroviral therapy may promote atherosclerosis through mechanisms involving endothelial cells, either directly or indirectly via metabolic risk factors.

Background: The use of antiretroviral combination therapy in HIV has been associated with lipodystrophy and cardiovascular risk factors.Objective: To compare the effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone and metformin for treating HIV lipodystrophy.Design: An open, randomized, 6-month clinical trial.Setting: University Medical Center, Utrecht, the Netherlands.Patients: 39 HIV-infected men with lipodystrophy.Intervention: Rosiglitazone, 8 mg/d, or metformin, 2 mg/d.Measurements: insulin sensitivity estimated by the oral glucose tolerance test, subcutaneous and visceral abdominal fat measured by single-slice computed tomography, endothelial function measured by flow-mediated vasodilation, and fasting plasma measurements. Two patients in the metformin group withdrew from the study. Complete case analysis was performed.Results: Compared with metformin, rosiglitazone increased subcutaneous abdominal fat (between-treatment change from baseline, 27 cm(2) [95% CI, 7 cm(2) to 46 cm(2)]) and visceral abdominal fat (between-treatment change from baseline, 24 cm(2) [CI, 6 cm(2) to 51 cm(2)]). The area under the curve for insulin after the oral glucose tolerance test decreased similarly with both agents, but only rosiglitazone increased adiponectin levels. Metformin showed greater benefits on fasting lipid profile than rosiglitazone. Flow-mediated vasodilation statistically significantly increased with metformin (mean change, 1.5% [CI, 0.4% to 3.3%]) and not with rosiglitazone (mean change, 0.7% [CI, -1.1% to 2.7%]). The metformin versus rosiglitazone increases did not statistically differ. Rosiglitazone and metformin did not change C-reactive protein levels.Limitations: This small trial was not blinded or placebo-controlled and did not measure clinical outcomes.Conclusions: The findings emphasize the importance of individualized care in HIV-Infected patients. Although rosiglitazone may partly correct lipoatrophy, metformin improves visceral fat accumulation, fasting lipid profile, and endothelial function.

OBJECTIVE:Increased postprandial lipemia is part of diabetic dyslipidemia and is associated with accelerated atherosclerosis. We investigated the effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone on postprandial lipemia in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS:A randomized, 8-week, crossover, placebo-controlled, double-blind trial was performed in which rosiglitazone at 4 mg was administrated twice daily in 19 patients with type 2 diabetes. Standardized 6-h oral fat-loading tests were performed after each treatment period. Postprandial curves were calculated as the total area under the curve (AUC) and the incremental area under the curve (dAUC). RESULTS:Rosiglitazone did not change fasting plasma triglycerides compared with placebo (1.97 +/- 0.22 vs. 1.88 +/- 0.20 mmol/l, respectively) but decreased postprandial triglyceride levels, leading to significantly lower triglyceride dAUC (-37%, P < 0.05), without changing total triglyceride AUC. Significant postprandial triglyceride reductions in the chylomicron fraction (Svedberg flotation rate [Sf] >400) were achieved with rosiglitazone, which resulted in a significant lower triglyceride AUC (-22%) in this fraction. The postprandial triglyceride increase in VLDL1 (Sf 60-400) was also lower after rosiglitazone (-27%), but this did not result in a significant lower triglyceride AUC. In VLDL2 (Sf 20-60), there were no significant differences in triglyceride AUC and triglyceride dAUC between rosiglitazone and placebo. Rosiglitazone decreased free fatty acid (FFA) AUC (-12%) and FFA dAUC (-18%) compared with placebo. CONCLUSIONS:Rosiglitazone improves the metabolism of large triglyceride-rich lipoproteins and decreases postprandial FFA concentrations in type 2 diabetes. This may have clinical implications, as these effects may contribute to cardiovascular risk reduction.

OBJECTIVE:A novel method has been developed to study diurnal triglyceride (TG) profiles using repeated capillary self-measurements in an 'out-of-hospital' situation. We assessed the diurnal capillary TG (TGc) profile in males with mild obesity and evaluated the use of plasma and capillary TG as markers of insulin resistance.DESIGN:Cross-sectional study.SETTING AND SUBJECTS:Fifty-four lean (body mass index, BMI < 25 kg m-2) and 27 mildly obese (25 < BMI < 30 kg m-2), normolipidaemic males measured capillary TG concentrations on six fixed time-points over a 3-day period in an 'out-of-hospital' situation.MAIN OUTCOME MEASURES:The total area under the TGc curve (TGc-AUC) and incremental area under the TGc curve (TGc-IAUC) were used as estimation of diurnal triglyceridaemia. Fasting blood samples were obtained once. Food intake was recorded by all participants.RESULTS:Obese and lean subjects had comparable fasting capillary TG concentrations (1.37 +/- 0.40 mmol L-1 and 1.32 +/- 0.53 mmol L-1, respectively). However, during the day, obese subjects showed a greater TG increase, resulting in significantly higher TGc-AUC (27.1 +/- 8.4 and 23.0 +/- 6.3 mmol h-1 l-1, respectively; P < 0.05) and TGc-IAUC (7.9 +/- 5.8 and 4.6 +/- 6.6 mmolh-1 L-1, respectively; P < 0.05). The total group of 81 males was divided into quartiles based on fasting plasma TG, fasting capillary TG, TGc-AUC and TGc-IAUC. Amongst these variables, TGc-AUC was the only significant discriminator of subjects with high homeostasis model assessment (HOMA) (insulin resistance) compared with low HOMA (insulin sensitive). Overall, BMI was the strongest determinant of HOMA.CONCLUSIONS:Diurnal TG profiles can be used to investigate postprandial lipaemia in both lean and mildly obese subjects and may help to detect subjects with an underlying disposition for hypertriglyceridaemia related to insulin resistance, i.e. the metabolic syndrome.

Postprandial hyperlipidemia has been linked to premature coronary artery disease (CAD) in fasting normotriglyceridemic patients. We investigated the effects of increasing doses of simvastatin up to 80mg/day on fasting and postprandial lipoprotein metabolism in 18 normotriglyceridemic patients with premature CAD. Fasting lipoprotein subfractions and cholesteryl ester transfer protein (CETP) activity were determined after each 5-week dose titration (0, 20, 40 and 80mg/day). At baseline and after treatment with simvastatin 80mg/day, standardised Vitamin A oral fat loading tests (50g/m2; 10h) were carried out. Ten normolipidemic healthy control subjects matched for gender, age and BMI underwent tests without medication. Treatment with simvastatin resulted in dose-dependent reductions of fasting LDL-cholesterol, without changing cholesterol levels in the VLDL-1, VLDL-2 and IDL fractions. In addition, simvastatin decreased CETP activity dose-dependently, although HDL-cholesterol remained unchanged. Simvastatin 80mg/day decreased fasting plasma triglycerides (TG) by 26% (P < 0.05), but did not decrease significantly TG levels in any of the subfractions. The TG/cholesterol ratio increased in all subfractions. The plasma TG response to the oral fat loading test, estimated as area under the curve (TG-AUC), improved by 30% (from 21.5 ± 2.5 to 15.1 ± 1.9mmolh/L; P < 0.01). Treatment with simvastatin 80mg/day improved chylomicron remnant clearance (RE-AUC) by 36% from 30.0 ± 2.6 to 19.2 ± 3.3mgh/L (P < 0.01). After therapy, remnant clearance in patients was similar to controls (19.2 ± 3.3 and 20.3 ± 2.7mgh/L, respectively), suggesting a normalization of this potentially atherogenic process. In conclusion, high-dose simvastatin has beneficial effects in normotriglyceridemic patients with premature CAD, due to improved chylomicron remnant clearance, besides effective lowering of LDL-cholesterol. In addition, the lipoprotein subfractions became more cholesterol-poor, as reflected by the increased TG/cholesterol ratio, which potentially makes them less atherogenic.

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 24, No. 5PPAR-γ Agonists: Shifting Attention from the Belly to the Heart? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPPAR-γ Agonists: Shifting Attention from the Belly to the Heart? Jeroen P.H. van Wijk and Ton J. Rabelink Jeroen P.H. van WijkJeroen P.H. van Wijk From the Department of Vascular Medicine (J.P.H.v.W.), University Medical Center Utrecht, and the Department of Nephrology and Hypertension (T.J.R.), University Medical Center Leiden, The Netherlands Search for more papers by this author and Ton J. RabelinkTon J. Rabelink From the Department of Vascular Medicine (J.P.H.v.W.), University Medical Center Utrecht, and the Department of Nephrology and Hypertension (T.J.R.), University Medical Center Leiden, The Netherlands Search for more papers by this author Originally published1 May 2004https://doi.org/10.1161/01.ATV.0000127311.38703.1fArteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:798–800Second generation thiazolidinediones (TZDs), synthetic ligands for the peroxisome proliferator activated receptor-γ (PPAR-γ), have recently been introduced in clinical medicine to improve insulin resistance in type 2 diabetes. The two isoforms of PPAR-γ are preferentially expressed in adipose tissue, and the improvement of insulin resistance in skeletal muscle and liver tissue is probably secondary to enhanced lipid storage in subcutaneous adipocytes and improved adipocyte function, as reflected by the altered secretion of adipocytokines.1 These effects are mediated by receptor-dependent activation of the PPAR-γ–retinoid X receptor (RXR) complex and subsequent transcriptional activation of target genes.1 The PPAR-γ1 isoform is also expressed in endothelial cells, vascular smooth muscle cells (VSMCs), and monocytes/macrophages in the vasculature.2,3 PPAR-γ agonists have been shown to have interesting effects on these cells, which appear to be partially independent of the PPAR-γ–RXR–mediated transcriptional effects.4 For example, in endothelial cells, TZDs have been shown to enhance endothelial nitric oxide synthase (eNOS) activity by phosphorylation and to inhibit leukocyte–endothelial cell interaction.5,6 TZDs inhibit growth factor–induced proliferation and migration of VSMCs.7 Also in vivo, in a model of angiotensin II induced hypertension, TZDs could normalize endothelial function and correct structural vascular abnormalities.8 In monocytes/macrophages, TZDs upregulate the scavenger receptor CD369 and induce the cholesterol efflux pomp ATP-binding cassette, subfamily A, member 1 (ABCA1), suggesting altered lipid handling by macrophages whereby proatherogenic lipoproteins are taken up and antiatherogenic lipoproteins are generated.10 Finally, and perhaps most importantly, TZDs are very potent inhibitors of inflammation. There appears to be a generalized repression of NF-κB, CCAAT/enhancer-binding protein, and activator protein-1–mediated transcription of inflammatory genes.11,12 The exact mechanism is still unknown, but probably involves increased levels of corepressor molecules or transcriptional superregulation, for example by chromatin remodeling, as has been described for other nuclear hormone receptors.13 As a result, a broad spectrum of proinflammatory cytokines (eg, IL-6, TNF-α, G-CSF, CD40, MCP-1, MMP) as well as adhesion molecules (eg, ICAM-1, VCAM-1), inducible NOS (iNOS), and C-reactive protein are suppressed (Figure 1).6,11–16 The potent antiinflammatory actions of TZDs are also illustrated by the fact that TZDs have been used to treat primary inflammatory conditions, such as colitis.17 These modes of action suggest that TZDs may have important antiatherosclerotic actions. These effects can be indirect by improving insulin resistance–related metabolic risk factors. However, TZDs may also have important direct antiatherosclerotic effects, caused by repression of inflammatory transcription and resulting in restoration of endothelial function and reduced vascular (micro)inflammation. Download figureDownload PowerPointPutative mechanisms by which TZDs reduce atherosclerosis. TZDs can improve free fatty acid (FFA) trapping in adipocytes by altering the transcription of PPAR-γ–RXR complex–activated genes involved in FFA storage and lipolysis (e.g.aP2-adipocyte fatty acid binding protein [FABP], fatty acid transport protein 1 [FATP-1], fatty acid synthase [FAS], insulin receptor substrate-2 [IRS-2] FAS, and Acyl-coenzyme A [CoA] synthase). Together with increased secretion of a fat-specific secreted protein (adipocyte complement-related factor 30 [Acrp30]), this leads to enhanced insulin sensitivity. There also appears to be a generalized repression of NF-κB, CCAAT/enhancer-binding protein, and activator protein-1–mediated transcription of inflammatory genes, which may result in restoration of endothelial function and reduced vascular (micro)inflammation.See page 930In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Sidhu et al describe that the TZD rosiglitazone reduces common carotid intima media thickness (IMT) progression, a well established intermediate endpoint of atherosclerotic disease progression, after 48 weeks of treatment compared with placebo in nondiabetic patients with coronary artery disease.18 Previous studies have demonstrated that TZDs have beneficial effects on intermediate endpoints of atherosclerosis, such as endothelial function and IMT, in type 2 diabetes.19–21 The interesting point of the study by Sidhu et al is that these effects are not confined to diabetic patients, but can be extrapolated to patients with documented coronary artery disease without manifest diabetes. Another important point of the current study is that in these high-risk patients, rosiglitazone retarded carotid IMT progression on top of statins and antihypertensive agents. These observations could be interpreted as a strong argument in favor of direct vascular effects of TZDs on atherosclerosis.It should be noted that in patients with clinical cardiovascular disease the prevalence of the metabolic syndrome is very high, despite the absence of diabetes. We have recently reported that in such a cohort, almost half of the patients fulfilled the criteria of the metabolic syndrome (defined as 3 or more of the following: low high-density lipoprotein (HDL)-cholesterol, increased triglycerides, high blood pressure, glucose intolerance, and high waist circumference).22 Regrettably, there was no information about the prevalence of the metabolic syndrome in the Sidhu study, although a similar percentage would not be unlikely. For example, almost a quarter of the patients had impaired fasting glucose. This would indicate that the study group indeed could have had benefited from improved metabolic control by TZD treatment. However, only minor effects on metabolic parameters were observed. First, during rosiglitazone treatment, there was a small but significant reduction in homeostasis model assessment (HOMA), as a marker of insulin sensitivity, compared with placebo. HOMA is an independent predictor of cardiovascular events in both diabetic and nondiabetic patients,23,24 particularly in the case of high HOMA values.23 The study group in the Sidhu study had relatively low HOMA values, and rosiglitazone caused quantitatively only a minimal reduction in HOMA, which makes an important role on retarded IMT progression less likely. Second, rosiglitazone-treated patients showed a small transient increase in low-density lipoprotein (LDL)-cholesterol and triglycerides. This phenomenon is frequently observed during TZD treatment, as TZDs generally cause a shift toward larger, more buoyant LDL particles, which are less prone to oxidative modification and are therefore thought to be less atherogenic.25 Unfortunately, LDL density cannot be estimated in the current study, as there is no information available on apolipoprotein B. Nevertheless, in conjunction with statin treatment, there were no sustained effects overall on lipid parameters by rosiglitazone treatment, which makes a lipid-based explanation for the observed effect on atherosclerotic disease progression also less likely.The fact that TZDs modulate atherosclerosis progression, potentially independent of metabolic changes, offers additional opportunities to improve cardiovascular risk in a broader group of high-risk patients. However, one also has to consider potential side-effects. Edema formation and expansion of the extracellular volume is found in 3% to 5% of the patients for each of the TZDs, and the incidence increases in combination with insulin.26 Obviously, this increased risk may give rise to concern when considering treatment with TZDs in patients with cardiovascular disease accompanied by heart failure. So far, TZDs have not been studied in patients with New York Heart Association (NYHA) class III or IV congestive heart failure (CHF) and therefore are not recommend for use in these patients. In the study by Sidhu et al, patients with CHF (NYHA class I to IV) were also excluded.As we begin to better understand the vascular pathobiology of atherosclerosis, drugs that interfere with key processes in atherosclerosis biology, such as endothelial function and vascular (micro)inflammation, become important as they potentially allow cardiovascular risk reduction beyond treatment of a risk factor. The study by Sidhu et al provides us with clues that TZDs, drugs that were introduced primarily to treat such a risk factor (ie, insulin resistance), may have relevant clinical effects on the pathobiology of atherosclerosis.AcknowledgmentsJ.P.H.v.W. was supported by the Netherlands Organization for Scientific Research.FootnotesCorrespondence to Prof T. J. Rabelink, MD, PhD, University Medical Center Leiden, Department of Nephrology and Hypertension, Room C3-P, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail [email protected] References 1 Saltiel AR, Olefsky JM. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes. 1996; 45: 1661–1669.CrossrefMedlineGoogle Scholar2 Ricote M, Huang J, Fajas L, Li A, Welch J, Majib J, Witztum JL, Auwerx J, Palinski W, Glass CK. Expression of peroxisome proliferator-activated receptor-γ (PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci U S A. . 1998; 95: 7614–7619.CrossrefMedlineGoogle Scholar3 Law RE, Goetze S, Xi XP, Jackson S, Kawano Y, Demer L, Fishbein MC, Meehan WP, Hsueh WA. Expression and function of PPARγ in rat and human vascular smooth muscle cells. Circulation. 2000; 101: 1311–1318.CrossrefMedlineGoogle Scholar4 Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med. 2001; 7: 48–52.CrossrefMedlineGoogle Scholar5 Cho DH, Choi YJ, Jo SA, Jo I. Nitric oxide production and regulation of endothelial nitric-oxide synthase phosphorylation by prolonged treatment with troglitazone: evidence for involvement of peroxisome proliferator-activated receptor (PPAR) γ-dependent and PPARγ-independent signaling pathways. J Biol Chem. 2004; 279: 2499–2506.CrossrefMedlineGoogle Scholar6 Jackson SM, Parhami F, Xiao-Ping Xi, Berliner JA, Hsueh WA, Law RE, Demer LL. 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May 2004Vol 24, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/01.ATV.0000127311.38703.1fPMID: 15132970 Originally publishedMay 1, 2004 PDF download Advertisement

Postprandial hypertriglyceridemia associated with insulin resistance is one of the cardiovascular risk factors in obesity and type 2 diabetes. It is not known whether diabetics have a more pronounced postprandial hypertriglyceridemia than obese subjects. Daylong triglyceridemia, representing postprandial lipemia, was determined in obese subjects with and without type 2 diabetes and in lean subjects. Nineteen type 2 diabetics (F/M: 7/12, body mass index [BMI]: 30.6 +/- 5.4 kg/m(2)), 45 obese nondiabetics (F/M: 16/29, BMI: 29.5 +/- 2.6 kg/m(2)) and 78 lean subjects (F/M: 28/50, BMI: 23.7 +/- 2.2 kg/m(2)) measured capillary triglycerides (TGc) during 3 days on 6 fixed time-points each day in an out-of-hospital situation. Daylong TGc profiles were calculated as mean integrated area under the TGc-curve (TGc-AUC). Fasting plasma TG were higher in diabetics and obese nondiabetics (1.81 +/- 0.79 and 1.77 +/- 0.80 mmol/L) compared with lean subjects (1.23 +/- 0.67 mmol/L, P <.001). TGc-AUC was similarly increased in both diabetics and obese nondiabetics (35.0 +/- 12.1 and 35.2 +/- 10.6 mmol.1 h/L) compared with lean controls (25.5 +/- 12.0 mmol.1 h/L, P <.001). Self-reported energy intake was not significantly different between the groups. Fasting TGc (r =.87, P <.001) and waist circumference (r =.51, P <.001) were the parameters best associated with TGc-AUC. Using stepwise multiple regression analysis, fasting TGc, BMI, total cholesterol, and high-density lipoprotein (HDL) cholesterol were the best predictors of TGc-AUC, explaining 77% of the variation. The cut-off level for "normal" TGc-AUC, calculated as the 75th percentile of TGc-AUC in lean subjects, was 30.7 mmol.1 h/L and corresponded with a fasting TGc of 1.8 mmol/L (eg, 1.6 mmol/L in plasma), calculated using univariate regression analysis. In conclusion, daylong triglyceridemia is similarly increased in diabetics and obese nondiabetics compared with lean subjects. Fasting TG and central obesity largely determine daylong triglyceridemia, independent of the presence of type 2 diabetes. Decreasing fasting plasma TG below 1.6 mmol/L could lead to a normalization of postprandial lipemia in obese subjects with and without diabetes.

Postprandial hyperlipidemia is associated with premature coronary sclerosis in fasting normolipidemic subjects. Self-determined daytime capillary triglyceride (cTG) profiles were compared between 26 fasting normotriglyceridemic patients with premature coronary artery disease (CAD) and 26 controls matched for gender, age and BMI. Daytime triglyceridemia was calculated as total area under the cTG-curve (cTG-AUC). Total and LDL cholesterol were not different between CAD patients (5.4+/-0.8 mmol/l and 3.6+/-0.7 mmol/l, respectively) and controls (5.0+/-0.9 mmol/l and 3.3+/-0.8 mmol/l, respectively). Patients with CAD were characterized by a 44% higher cTG-AUC than matched controls (P<0.01). Using logistic regression analysis, cTG-AUC was the strongest predictor of the presence of CAD (P<0.001). Adding apo AI to the model improved the predictive power from 71 to 77%. Sixteen patients were studied after increasing doses of simvastatin up to 80 mg/day. Although the target for LDL cholesterol was reached by simvastatin 20mg/day, significant effects on cTG-AUC were found only by higher doses of simvastatin. Simvastatin 40 mg/day decreased cTG-AUC by 28% (P<0.05 versus baseline), reaching comparable values as in controls, without further improvement with simvastatin 80 mg/day (26% reduction versus baseline; P<0.05). Daytime triglyceridemia is linked to premature coronary sclerosis in fasting normotriglyceridemic patients. A higher dose of simvastatin was needed to normalize daytime triglyceridemia than was required to "normalize" LDL cholesterol.

BACKGROUND:Increased triglycerides (TG) are associated with atherosclerosis. We determined free-living non-fasting TG concentrations in healthy Dutch subjects.METHODS:Capillary TG (TGc) was self-measured by 109 males and 104 females during 3 days, on six fixed time-points each day; fasting, before and 3 h after lunch, before and 3 h after dinner and at bedtime. Daylong TGc-profiles were calculated as area under the mean TGc-curve (TGc-AUC). Reference values for "high" and "normal" daylong TGc concentrations were calculated as the 95th and 75th percentiles, respectively.RESULTS:Fasting TGc were higher in males compared with females (1.41+/-0.75 versus 1.27+/-0.59 mmol/l), resulting in higher TGc-AUC (25.4+/-10.4 versus 20.6+/-9.8 mmol h/l). The highest TGc-concentrations were found in the evening. The majority of subjects (95%) had TGc during the evening below 4.6 mmol/l in males and below 3.7 mmol/l in females. Seventy-five percent of the subjects had TGc during the evening below 2.9 mmol/l in males and below 2.2 mmol/l in females. During the day (with exclusion of post-dinner TGc), 95% of the subjects had TGc below 3.7 mmol/l in males and below 3.6 mmol/l in females. Finally, 75% of the subjects had TGc during the day below 2.5 mmol/l in males and 1.7 mmol/l in females.CONCLUSIONS:The present data may help to delineate normal ranges of non-fasting TG and could be used to detect groups at risk for atherosclerosis on the basis of a disturbed TG metabolism.

BACKGROUND Postprandial studies with standardized mixed meals have shown that ingestion of high-carbohydrate diets is associated with elevated plasma triacylglycerol (TG) concentrations. OBJECTIVE We evaluated the effects of different nutritional components on daytime triacylglycerolemia in 58 healthy, free-living, normolipemic men. DESIGN Capillary TG (TGc) was self-measured at 6 fixed time points over 3 d. Daytime TGc profiles were calculated as areas under the curve (AUCs) for absolute and incremental changes in TGc concentrations (TGc-AUC and DeltaTGc-AUC, respectively). Food intake was recorded in a diary. RESULTS The mean (+/-SD) fasting TGc concentration, TGc-AUC, and DeltaTGc-AUC were 1.20 +/- 0.41 mmol/L, 24.1 +/- 6.9 mmol x h/L, and 7.3 +/- 4.5 mmol x h/L, respectively. Mean total energy intake was 10881 +/- 2536 kJ/d. Total intakes of fat, carbohydrate, and protein were 95 +/- 25 (33% of energy), 304 +/- 69 (48% of energy), and 101 +/- 27 (16% of energy) g/d, respectively. Fasting TGc concentrations and TGc-AUC were not related to dietary intake. The mean DeltaTGc-AUC was significantly related to total carbohydrate (r = 0.38, P < 0.005), protein (r = 0.29, P < 0.05), and energy (r = 0.28, P < 0.05) intakes. Fat intake (as a % of energy) was negatively associated with the mean DeltaTGc-AUC (r = -0.30, P < 0.05). When the study group was subdivided into tertiles on the basis of fat intake (27.2%, 33.5%, and 39.1% of energy, respectively), carbohydrate intake was 50.9%, 48.1%, and 44.6% of energy, respectively. DeltaTGc-AUC was significantly lower at the highest tertile of fat intake (4.8 +/- 4.3 mmol x h/L) than at the lowest (8.2 +/- 4.0 mmol x h/L) and intermediate (8.9 +/- 4.3 mmol x h/L) tertiles (P < 0.05 for each). CONCLUSION DeltaTGc-AUC is associated with the carbohydrate content of the diet in free-living men.

AIMS: Increased fasting and postprandial triglyceridemia is one of the cardiovascular risk factors for patients with insulin resistance. Since triglyceride (TG) metabolism largely depends on gender, we have investigated diurnal TG changes in patients with and without overweight, focusing on gender differences. METHODS: Twenty-two males and 22 females with overweight (mean body mass index (BMI) 28.0±2.3 kg/m 2 ) measured capillary TG concentrations at six fixed time points on three different days. Diurnal TG profiles were calculated as area under the capillary TG curves (TGc-AUCs). The control group consisted of 24 males and 21 females who were not overweight (mean BMI 22.4±1.5 kg/m 2 ). Biochemical and anthropometric parameters associated with insulin resistance were measured. RESULTS: Lean males and lean females had comparable fasting insulin levels (6.9±2.6 and 8.1±4.7 mU/l, respectively), but females had a more favorable fasting lipoprotein profile when compared to males. Diurnal TG profiles were lower in lean females than in lean males (16.9±4.3 vs 20.3±5.7 mMh, respectively, P <0.05). Overweight males and females had comparable fasting insulin levels (10.3±3.4 and 12.1±4.9 mU/l, respectively), which were higher than in lean subjects. Overweight females also had a more favorable fasting lipoprotein profile compared to overweight males. Diurnal TG profiles were similar in overweight females and overweight males (31.1±15.6 and 32.9±13.2 mMh, respectively). Stepwise multiple regression analysis showed that in both males and females, waist circumference was the strongest determinant of diurnal TG profiles when fasting TG concentrations were excluded from the model ( R 2 =0.49 for males and R 2 =0.33 for females). These results suggest that overweight resulted in a ‘male diurnal TG profile’ in females due to abdominal fat accumulation. CONCLUSION: Insulin resistance in overweight subjects partly mitigates the gender differences of fasting and postprandial TG metabolism. The significant positive association between diurnal triglyceridemia and waist circumference supports the view that especially abdominal fat associated with insulin resistance enhances postprandial lipemia.