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Objective: Metformin has been associated with the serious side-effect lactic acidosis. However, it remains unclear whether the use of metformin was a cause or a coincidence in lactic acidosis.Design: A literature search of the Index Medicus (1959-66) and of the databases Embase, Medline, Medline Express (1966-99) was performed using the keywords metformin, biguanides and lactic acidosis. All articles of cases with metformin-induced lactic acidosis (MILA) were cross-referenced.Subjects: Cases were included for analysis if they met the following criteria: serum pH < or =7.35, lactate concentration > or =5 mmol L(-1).Intervention: A forum of six experts in intensive care medicine independently categorized the cases in MILA unlikely (score 0), possible MILA (score 1) or probable MILA (score 2).Main Outcome Measures: Statistical analysis included the paired interobserver agreement (kappa) and multivariate regression analysis.Results: Of 80 reported cases, 33 were excluded because of insufficient quality. The forum scores of the remaining 47 cases were distributed normally with a mean score of 7 (range 2-10). The kappa-value was 0.041 (SD = 0.24, range -0.514, 0.427). Neither lactate concentration nor mortality correlated with serum metformin concentrations.Conclusions: Given the low interobserver agreement and the lack of any relationship between metformin levels and outcome parameters, the concept that there is a simple, causal relationship between metformin use and lactic acidosis in diabetic patients has to be reconsidered. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes mellitus have an elevated risk of morbidity and mortality from cardiovascular disease. This risk is partly attributable to an increased prevalence of classic coronary artery disease risk factors and partly because of hyperglycemia itself and a highly atherogenic lipid profile. The altered composition of lipoproteins and lipids in type 2 diabetic patients, termed diabetic dyslipidemia, is characterized by: (1) elevated levels of triglyceride; (2) normal levels of total and low-density lipoprotein cholesterol (LDL-C); (3) reduced levels of high-density lipoprotein cholesterol (HDL-C); (4) elevated levels of apolipoprotein B; (5) a preponderance of small, dense LDL particles; and (6) increased levels of cholesterol-rich very-low-density lipoprotein. In most cases, diabetic dyslipidemia is preceded by hyperinsulinemia resulting from insulin resistance. Because patients with type 2 diabetes and insulin resistance are at a markedly increased risk of atherosclerosis, and because strict control of glycemia has proved beneficial in reducing microangiopathy but not macroangiopathy, treatment of diabetic dyslipidemia should be aggressive. Target levels have, therefore, been set at <2.6 mmol/L (100 mg/dL) for LDL-C, <2.3 mmol/L [200 mg/dL] for triglycerides, and >1.15 mmol/L (45 mg/dL) for HDL-C. Trial data suggest that these target levels are likely to be achieved with statins, if necessary, in combination with fibrates or nicotinic acid derivatives. Furthermore, in large-scale clinical trials (eg, Scandinavian Simvastatin Survival Study [4S] and the Cholesterol and Recurrent Events [CARE] study), it has been demonstrated that lipid lowering can appreciably reduce cardiovascular events in diabetic patients. [ABSTRACT FROM AUTHOR]

Background: Both in research and in various clinical situations, prolonged euglycaemia can be desirable. In recent years, its benefit in (critically) ill patients and patients with acute myocardial infarction has been established. The objective of this study was to assess safety and efficacy of a practical, bodyweight-dependent algorithm to establish euglycaemia in both lean and obese patients with type 1 and type 2 diabetes., Methods: In 43 patients with type 1 diabetes and 17 patients with type 2 diabetes insulin were infused overnight to establish euglycaemia. Plasma glucose concentration was determined at 45 min intervals, and the insulin infusion rate was altered according to the algorithm., Results: Baseline plasma glucose concentrations were 13.1+/- 4.4 and 12.7 +/- 4.0 mmol/l in type 1 and type 2 diabetic patients, respectively. In both groups mean plasma glucose was reduced below 8.0 mmol/l within 3 h, and averaged 7.4 +/- 1.4 and 7.2 +/- 1.0 mmol/l (P = 0.11) over the next 7 h. Five (11.6%) patients with type 1 diabetes required administration of glucose because plasma glucose concentrations fell below 4.4 mmol/l. Consequently, type 1 diabetic patients were hypoglycaemic during 0.89% of the total study period. The lowest plasma glucose recorded was 3.9 mmol/l. In the type 2 diabetic patients the lowest plasma glucose was 5.5 mmol/l and no glucose administration was required for near-hypoglycaemia. The algorithm was equally effective in both lean and obese patients., Conclusions: Euglycaemia was established simply, swiftly and safely during the study period with the practical weight-based algorithm used in this study, in both lean and obese type 1 and type 2 diabetic patients, with a very low rate of mild hypoglycaemia. The algorithm is applicable in research and various several clinical settings. Its validity for a prolonged period of time and in critically ill patients needs to be further evaluated.

Objective: We aimed to assess the accuracy of the HemoCue Beta-glucose analyzer (HemoCue) and its correlation with the Yellow Springs Instrument (YSI 2300 STAT; YSI) glucose oxidase analyzer, in particular for hypoglycemic values., Design and Methods: Samples were taken from 24 volunteers during hyperinsulinemic glucose clamp studies. Glucose concentrations were determined immediately with the HemoCue in whole blood and with the YSI in plasma from the same sample. After correction for the difference between whole blood and plasma, the paired plasma glucose concentrations were analyzed with various statistical methods., Results: A total of 500 paired glucose values were obtained, 209 of which were in the hypoglycemic range. Mean+/-s.e. values were 4.85+/-0.004 mmol/l for the HemoCue (range 1.87-16.17) and 4.81+/-0.004 mmol/l for the YSI (range 1.88-15.00; P = 0.80). In the hypoglycemic region, values were 3.26+/-0.004 mmol/l for the HemoCue (range 1.87-5.17) and 3.22+/-0.003 mmol/l for the YSI (range 1.88-4.20; P = 0.59). Regression analyses were HemoCue = 1.019(YSI) -0.0577 mmol/l, with r = 0.9787 for all values; for hypoglycemic values the HemoCue = 1.1169(YSI) -0.3393 mmol/l, with r = 0.8798. Using Altman's residual plot, the difference was 0.03+/-0.0009 mmol/l, with 18 (3.6%) paired values outside the 95% limits of agreement (-0.82 to 0.89 mmol/l). In the hypoglycemic range, the difference was 0.04+/-0.001 mmol/l, with six (2.9%) values outside the 95% limits of agreement (-0.71 to 0.79 mmol/l). In error grid analysis, one value was in zone D (0.2%) and five values (1%) were in zone B; 98.8% were within zone A., Conclusions: Determination of glucose with the HemoCue system had very good correlation with the YSI system in a broad range of glycemia and also for hypoglycemic values. We believe that these methods can be used interchangeably for research and clinical purposes in adults.

Familial combined hyperlipidemia (FCHL) patients have an impaired catabolism of postprandial triglyceride (TG)-rich lipoproteins (TRLs). We investigated whether atorvastatin corrects the delayed clearance of large TRLs in FCHL by evaluating the acute clearance of Intralipid (10%) and TRLs after oral fat-loading tests. Sixteen matched controls were included. Atorvastatin reduced fasting plasma TG (from 3.6 +/- 0.4 to 2.5 +/- 0.3 mM; mean +/- SEM) without major effects on fasting apolipoprotein B48 (apoB48) and apoB100 in large TRLs. Atorvastatin significantly reduced fasting intermediate density lipoprotein (Svedberg flotation, 12-20)-apoB100 concentrations. After Intralipid, TG in plasma and TRL showed similar kinetics in FCHL before and after atorvastatin treatment, although compared with controls, the clearance of large TRLs was only significantly slower in untreated FCHL, suggesting an improvement by atorvastatin. Investigated with oral fat-loading tests, the clearance of very low density lipoprotein (Sf20-60)-apoB100 improved by 24%, without major changes in the other fractions. The most striking effects of atorvastatin on postprandial lipemia in FCHL were on hepatic TRL, without major improvements on intestinal TRLs. Fasting plasma TG should be reduced more aggressively in FCHL to overcome the lipolytic disturbance causing delayed clearance of postprandial TRLs.

Cardiomyopathy is a major cause of death in overt acromegaly. Recent progress in research has increasingly revealed the molecular mechanisms concerning growth hormone and insulin-like growth factor in the development of heart failure. In this article, we propose mechanisms according to which heart failure occurs, and we aim to extrapolate this knowledge to more general processes involved in heart failure.

The role of endogenous estrogens and androgens and their potential interaction in atherosclerosis is not well understood. Therefore, we investigated the effects of natural menopause and endogenous sex steroids on triglycerides (TG), a major risk factor for cardiovascular disease in women. Fasting lipid and lipoprotein concentrations, postheparin lipase activities, kinetic indicators of triglyceride lipolysis, and various hormone levels, including dehydroepiandrostenedione-sulfate (DHEA-S), (bioavailable) testosterone, and androstenedione, were determined in 18 premenopausal and 18 postmenopausal women, matched for age and body composition. Fasting plasma TG were 0.69 +/- 0.29 mmol/L in postmenopausal women and 0.73 +/- 0.33 mmol/L in premenopausal women (difference not significant [NS]). Approximately 30% of all plasma TG were present in the very-low-density lipoproteins (VLDLs) in both groups. No differences were found between groups in plasma lipolytic potential of TG-rich lipoproteins. Univariate analysis revealed that VLDL-TG concentrations were strongly related to insulin (r = 0.84, P =.0001) and androstenedione (r = 0.65, P =.004) in postmenopausal women. Multivariate analysis of potential determinants of VLDL-TG showed that insulin, androstenedione, and bioavailable testosterone were independent variables, explaining 87% of the variability (r = 0.93, P =.0001) in postmenopausal women. In contrast, in premenopausal women, the only identified predictor of fasting VLDL-TG in univariate and multivariate analysis was insulin (r = 0.72, P =.001). Our results show that the association of androgens with TG varied depending on androgen concentrations, the relative androgenic potential, and most importantly on hormonal milieu. Endogenous androgens were only related to plasma VLDL-TG in the estrogen-deficient state.

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.

Objective: An increased hepatic flow of free fatty acids (FFAs) is associated with impaired peripheral FFA trapping by malfunctioning of the complement component 3 (C3)/acylation-stimulating protein system and overproduction of VLDL in familial combined hyperlipidemia (FCHL). Postprandial ketone bodies reflect FFA oxidation in the liver, but the postprandial changes in male and female patients separately have not been determined yet. Gender differences in postprandial ketone bodies and C3 changes were investigated in normolipidemic patients and patients with untreated FCHL., Methods and Results: Thirty-two normolipidemic patients (16 female and 16 male) and 19 patients with untreated normolipidemia (9 female and 10 male) underwent an oral fat-loading test. Total and incremental areas under the curves (AUC and dAUC, respectively) after the oral fat load were calculated. Triglyceride AUC was similar between genders in each group. Normolipidemic female subjects showed a higher levels of dAUC-hydroxybutyric acid than male subjects (1.37+/-0.49 and 0.98+/-0.43 mmol x h/L). In FCHL, a similar trend was observed in female (1.92+/-0.38) compared with male (1.55+/-0.87) subjects. In contrast to normolipidemia, FCHL did not show a postprandial increase in C3, although C3 was higher in FCHL., Conclusions: Women have higher postprandial ketone bodies than men, probably reflecting enhanced postprandial hepatic FFA oxidation. In FCHL, both genders have higher postprandial ketone bodies and therefore higher hepatic FFA delivery. The higher fasting and postprandial C3 levels in FCHL may reflect resistance of the C3/acylation-stimulating protein system to promote peripheral fatty acid trapping.

Unlabelled: GROWTH HORMONE AND ATHEROSCLEROSIS: Adult-onset growth hormone (GH) deficiency is associated with an increase in cardiovascular morbidity and mortality., Mechanisms: Other than classical risk factors, such as dyslipidemia, a direct interaction between the activity of the GH/IGF-1 axis and the endothelium also plays a part. It is possible that the modulating effect of IGF-1 on nitric oxide (NO) synthesis is also important, together with the anabolic effect on the myocardiocytes. Substitution of recombinant GH induces rapid reduction in the atherosclerotic plaques, suggesting a direct effect of the GH/IGF axis on the atherosclerotic process. In addition to the acquired GH deficiency, as in non-substituted patients following hypophysectomy, attention has recently been focused on the relative GH deficiency as is seen in obesity and in the course of ageing. PERSPECTIVES FOR CARDIOVASCULAR ENDOCRINOLOGY: Therapeutic intervention in the GH/IGF axis might influence the atherosclerotic process. Study of the GH/IGF axis activity and of its correlation with atherosclerosis opens new perspectives in the understanding of the role of this axis in cardiovascular diseases.

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.

Objective: The cholesteryl ester transfer protein (CETP) plays a key role in the remodeling of triglyceride (TG)-rich and HDL particles. Sequence variations in the CETP gene may interfere with the effect of lipid-lowering treatment in type 2 diabetes., Research Design and Methods: We performed a 30-week randomized double-blind placebo-controlled trial with atorvastatin 10 mg (A10) and 80 mg (A80) in 217 unrelated patients with diabetes., Results: CETP TaqIB and A-629C polymorphisms were tightly concordant (P < 0.001). At baseline, B1B1 carriers had lower plasma HDL cholesterol (0.99 +/- 0.2 vs. 1.11 +/- 0.2 mmol/l, P < 0.05), higher CETP mass (2.62 +/- 0.8 vs. 2.05 +/- 0.4 mg/l, P < 0.001), and slightly increased, though not significant, plasma TGs (2.7 +/- 1.05 vs. 2.47 +/- 0.86, P = 0.34) compared with B2B2 carriers. Atorvastatin treatment significantly reduced CETP mass dose-dependently by 18% (A10) and 29% (A80; both vs. placebo P < 0.001, A10-A80 P < 0.001). CETP mass and activity were strongly correlated (r = 0.854, P < 0.0001). CETP TaqIB polymorphism appeared to modify the effect of atorvastatin on HDL cholesterol elevation (B1B1 7.2%, B1B2 6.1%, B2B2 0.5%; P < 0.05), TG reduction (B1B1 39.7%, B1B2 38.4%, B2B2 18.4%; P = 0.08), and CETP mass reduction (B1B1 32.1%, B1B2 29.6%, B2B2 21.9%; P = 0.27, NS). Similar results were obtained for the A-629C polymorphism., Conclusions: In conclusion, the B1B1/CC carriers of the CETP polymorphisms have a more atherogenic lipid profile, including low HDL, and they respond better to statin therapy. These results favor the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify patients who will benefit most from statin therapy.

Six-month efficacy of benfluorex (Mediator) (150-450 mg/day) was assessed in a double-blind multicenter study vs. placebo or metformin hydrochloride (850-2550 mg/day). After a 2-month run-in period of strict dieting, 722 type 2 diabetic patients were randomized (1:2:2) to receive placebo (n=144), benfluorex (n=294) or metformin (n=284). After a 5-week dose-finding phase, the efficacy of benfluorex was compared with that of placebo (test for difference, main analysis) and metformin (non-inferiority test, secondary analysis) during a 6-month fixed-dose treatment. At entry after strict dieting, there was no difference between groups for HbA(1C) (placebo, 7.4%+/-1.5%; benfluorex, 7.7%+/-1.6%; metformin, 7.8%+/-1.6%) and fasting plasma glucose (FPG; placebo, 9.7+/-2.3 mmol/l; benfluorex, 10.0+/-2.0 mmol/l; metformin, 10.2+/-2.5 mmol/l). At the end of the dose-finding phase, mean doses were 2.71 tablets/day for placebo group, 2.65 tablets/day for benfluorex (397.5 mg/day) and 2.50 tablets/day for metformin (2125 mg/day). At the end of treatment, HbA(1C) level decreased by 0.60% ( p<0.001) in benfluorex patients while it increased by 0.50% ( p<0.001) with placebo (intent-to-treat analysis). The mean endpoint difference was -0.86% (SE, 0.17%; p<0.001). Mean endpoint difference in HbA(1C) between benfluorex and metformin was 0.28% (SE, 0.12%) [90% CI, 0.07 to 0.48] (non-inferiority test, p=0.037). Treatment with benfluorex was well tolerated; 39% of these patients reported one or more emergent adverse events (compared to 38% on placebo and 43% on metformin) and only two patients suffered a treatment-related, serious adverse event. This study demonstrates that benfluorex: (1) significantly reduces HbA1C and fasting plasma glucose when compared to placebo; (2) has a good safety profile; and (3) has relatively lower potency compared to metformin, although the non-inferiority test (equivalence limit for HbA(1C) of 0.5%) was significant.

Increased cardiovascular mortality due to premature atherosclerosis is a clinical feature in the adult-onset GH deficiency (AGHD) syndrome. Inflammation is a key feature in atherogenesis and may be triggered by postprandial lipoprotein remnants. We hypothesized that increased postprandial lipoprotein remnant levels in AGHD may be associated with an inflammatory response. In this case-control study, 10 AGHD patients [6 males and 4 females; age, 48 +/- 9 yr; body mass index (BMI), 26.9 +/- 2.6 kg/m(2)] and 10 healthy control subjects (matched for age, BMI, gender, baseline lipid levels, and apolipoprotein E genotype) were included. They all ingested an oral fat load. Fasting and postprandial levels of plasma remnant-like particle-cholesterol (RLP-C; 0.31 +/- 0.13 mmol/liter and 4.14 +/- 1.37 mmol/liter.h in GHD; 0.18 +/- 0.06 mmol/liter and 2.56 +/- 1.02 mmol/liter.h in controls, respectively) were significantly increased in AGHD patients compared with control subjects. The median inflammatory cytokines, IL-6 and TNF-alpha, were higher in the fasting [3.9 (range, 3.1-11.9) pg/ml and 6.8 (range, 2.5-27.6) pg/ml, respectively] and postprandial [151.7 (range, 87.0-294.3) pg/ml.24 h and 289.9 (range, 87.5-617.6) pg/ml.24 h, respectively] states in AGHD than in controls [fasting, 0.9 (range, 0.2-5.2) pg/ml and 2.8 (range, 2.5-5.7) pg/ml; and postprandial, 54.5 (range, 11.50-126.5) pg/ml.24 h and 118.3 (range, 81.2-243.1) pg/ml.24 h, respectively]. In addition, postprandial profile of RLP-C and IL-6 in AGHD and in the total group were significantly associated (r(2) = 0.44, P < 0.05; and r(2) = 0.38, P < 0.01, respectively). In conclusion, the increased postprandial RLP-C level in GHD is associated with an inflammatory response that may result in increased susceptibility for premature atherosclerosis.

Background: Women are relatively protected against coronary artery disease (CAD). Whether female gender has a similar protective influence on the development of peripheral artery disease (PAD) has not been extensively investigated and was the main subject of our study., Methods: We analysed 2707 consecutive patients (2008 men and 699 women) who underwent a first diagnostic coronary angiography for suspicion of CAD and 2367 consecutive patients (1426 men and 941 women) who underwent a first ankle arm index measurement because of suspicion of PAD., Results: We found that a positive diagnosis for CAD and PAD was more common in men compared with women (80.7% vs 57.9%, p<0.0001 and 68.0% vs 60.7%, p<0.0001). Once CAD or PAD was established, severity of disease was similar for men and women, which pleads against a referral bias. Women had a reduced risk of CAD after adjustment for risk factors (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.22-0.46, p<0.0001), but not of PAD (OR 0.82, 95% CI 0.66-1.03, p=NS). In patients with CAD and in those with PAD, women were older, more often had diabetes and hypertension, while men were more likely to be current smokers. Hypertension, smoking and diabetes were associated with CAD in both men and women. Current smoking was associated with PAD in men and women. Hypertension and diabetes were associated with PAD in women but not in men., Conclusion: After adjustment for risk factors, the female protection for CAD seems to less present for PAD.

Very low density lipoprotein overproduction is the major metabolic characteristic in familial combined hyperlipidemia (FCHL). Peripheral handling of free fatty acids (FFAs) in vitro may be impaired in FCHL by decreased action of acylation-stimulating protein (ASP), which is identical to the immunologically inactive complement component 3a (C3adesArg). Because decreased FFA uptake by impaired complement component 3 (C3) response (as the precursor for ASP) may result in enhanced FFA flux to the liver in FCHL, we have evaluated postprandial C3 changes in vivo in FCHL patients. Accordingly, 10 untreated FCHL patients and 10 matched control subjects underwent an oral fat loading test. Fasting plasma C3 and ASP levels were higher in FCHL patients (1.33+/-0.09 g/L and 70.53+/-4.37 mmol/L, respectively) than in control subjects (0.91+/-0.03 g/L and 43.21+/-8.96 mmol/L, respectively; P=0.01 and P<0.05). In control subjects, C3 concentrations increased significantly after 4 hours (to 1.03+/-0.04 g/L). In FCHL, plasma C3 was unchanged after 4 hours. The earliest postprandial C3 rise in FCHL patients occurred after 8 hours (1.64+/-0.12 g/L). The maximal apolipoprotein B-48 concentration was reached after 6 hours in FCHL patients and control subjects. Postprandial FFA and hydroxybutyric acid (as a marker of hepatic FFA oxidation) were significantly higher in FCHL patients than in control subjects, and the early postprandial C3 rise was negatively correlated with the postprandial FFA and hydroxybutyric acid concentrations. The present data suggest an impaired postprandial plasma C3 response in FCHL patients, most likely as a result of a delayed response by C3, as the precursor for the biologically active ASP, acting on FFA metabolism. Therefore, an impaired postprandial C3 response may be associated with impaired peripheral postprandial FFA uptake and, consequently, lead to increased hepatic FFA flux and very low density lipoprotein overproduction.

One of the best studied aspects of the insulin resistance syndrome in familial combined hyperlipidemia (FCHL) is impaired insulin-mediated suppression of FFA by diminished inhibition of hormone-sensitive lipase (HSL). In vitro experiments have shown that stimulation of HSL activity by catecholamines is decreased in FCHL. The aim of this study was to investigate HSL inhibition by insulin and stimulation by endogenous catecholamines in vivo in FCHL patients. Twelve FCHL subjects using lipid-lowering medication and 12 controls underwent a mental stress test after random ingestion of either 50 g glucose or placebo. After ingestion of glucose, insulin concentrations increased from 76.8 +/- 21.5 pM to a maximum of 520.2 +/- 118.4 pM (P < 0.01) in FCHL and from 38.0 +/- 5.0 to 221.7 +/- 25.1 pM (P < 0.01) in controls. The percent decreases in plasma FFA during the first hour after glucose ingestion were similar in FCHL and controls (67 +/- 5% vs. 72 +/- 3%, respectively), suggesting a comparable inhibition of HSL in both. During the placebo test, FFA increased similarly in FCHL (56 +/- 9%) and controls (57 +/- 19%). In contrast, FFA concentrations did not change during mental stress after ingestion of glucose (from 0.17 +/- 0.02 to 0.15 +/- 0.02 mmol/liter in FCHL and from 0.11 +/- 0.02 to 0.12 +/- 0.02 mmol/liter in controls). In conclusion, the present study provides in vivo evidence for intact insulin-mediated suppression of FFA in FCHL, although this inhibition of HSL was achieved by higher insulin levels, suggesting insulin resistance at the level of HSL. Secondly, the induction of HSL activity by endogenous catecholamines in vivo is not decreased in FCHL, in contrast to earlier in vitro findings. Finally, catecholamine-induced HSL activation can be inhibited by insulin in a similar manner in both FCHL and controls.

Objective: This study was performed to evaluate whether an additional dose of NPH insulin at lunchtime might overcome the deleterious effects of waning basal insulinemia on pre-dinner and evening glucose values during insulin lispro intensive therapy with once daily basal insulin at night., Research Design and Methods: The study was a 10-month multicenter, randomized, crossover trial. After a 2-month run-in period, subjects injected NPH insulin once (1 x NPH) or twice (2 x NPH) daily for 4 months in a randomized order. Adult patients were included if they had HbA(1c) levels <8.5%. Efficacy measures were HbA(1c) levels, 8-point glucose profiles, and the frequency of hypoglycemia. The statistical analysis included a within-patient comparison for crossover trials., Results: In all, 104 patients completed the trial. The mean HbA(1c) level before randomization was 7.1 +/- 0.85%. The HbA(1c) levels did not change significantly within patients (t test, mean difference = 0.06%; 95% confidence interval [CI] -0.073 to 0.20). The pre-dinner blood glucose values were significantly lower during the 2 x NPH daily protocol, with a mean difference of 0.76 mmol/l (t test, P = 0.004; CI 0.25 to 1.3). In the evening, the frequency of hypoglycemia increased significantly during the 2 x NPH daily protocol with a median difference of 0.56 mild episodes/30 days (P = 0.001) and 6.9 severe episodes/patient year (P = 0.007), respectively., Conclusions: Equal HbA(1c) levels and increasing frequencies of hypoglycemia in the evening overshadow the slight improvement of the evening glucose profiles during a regimen with 2 x NPH daily insulin. Therefore, generalized use of a second injection of NPH insulin at lunchtime cannot be recommended to all adult patients with type 1 diabetes using intensive insulin lispro therapy.

Objective: Is the concept of primary and secondary cardiovascular prevention an old-fashioned concept that needs to be re-defined?, Design: Discussion paper., Results: Cardiovascular prevention means reduction of absolute risk for cardiovascular disease (CVD), irrespective of clinical stage., Conclusion: For the calculation of an individual probability to develop CVD all factors that contribute to the risk must be taken into account, including previous CVD events.

It has been recognized over the past years that women form a distinct subpopulation within patients with coronary heart disease. This phenomenon should be acknowledged in the management and in the assessment of coronary heart disease. Over the past years remarkable progress has been made concerning our knowledge of cardiovascular risk factors related to gender. For instance, diabetes, high density lipoproteins and triglycerides levels have been found to have a greater impact on coronary heart disease risk in women compared to men. On the other hand, evidence showing that lipoprotein (a) is a cardiovascular risk factor seems to be stronger in men than in women. For optimal treatment and prevention of coronary heart disease it is necessary to acknowledge that it is not self-evident that women and men show similar responses to risk factors or to treatment. This review article addresses the role of cardiovascular risk factors focusing on the differential impact they might have on men and women.

Free fatty acids (FFAs) are involved in the transportation of energy; in the postprandial phase to the peripheral tissues and in the postabsorptive phase from the adipose tissue to the liver. In the postprandial phase, FFAs are mainly derived from hydrolysis of triglyceride-rich particles like chylomicrons and very low-density lipoproteins (VLDL). The flux of FFAs is directed to peripheral cells such as adipocytes and muscle cells. In the postabsorptive period, FFAs are transported to the liver after being released from intracellular storage in the adipocytes. Complement component 3 (C3) plays an important role in the uptake of free fatty acids by the peripheral cells and their esterification to triglycerides. Since C3 is also involved in the pathogenesis of the insulin resistance syndrome, and since a deviant FFA metabolism with an increased FFA flux to the liver may induce insulin resistance, it is hypothesized that C3 may form the missing link between FFA metabolism and insulin resistance. In addition, recent studies have increasingly indicated that atherosclerosis is in fact an inflammation-based process involving complement-dependent responses, in which FFAs seem to play a role in the complement-dependent pathway. It has recently become apparent that FFAs have a regulatory function in the transcription of DNA, in relation to lipoprotein metabolism. This is where PPAR-gamma and PPAR-alpha agonists ('glitazones' and fibrates respectively) are active (PPAR is an abbreviation for peroxisome proliferation activating receptor). Glitazons may play an important role in the treatment of insulin resistance and related disorders. Acquiring more knowledge about the relationship between complement and FFA metabolism may increase our understanding of these processes and provide openings for the development of new antiatherogenic strategies.

Objective: The sulfonylurea (SU) glyburide may cause severe and prolonged episodes of hypoglycemia. We aimed at investigating the impact of glyburide on glucose counterregulatory hormones during stepwise hypoglycemic clamp studies., Research Design and Methods: We performed stepwise hypoglycemic clamp studies in 16 healthy volunteers (7 women and 9 men aged 44 +/- 10 years). We investigated counterregulatory hormonal and symptom responses at arterialized venous plasma glucose levels (PG) of 3.8, 3.2, and 2.6 mmol/l, comparing 10 mg glyburide orally and placebo in a double-blind, randomized crossover fashion., Results: The increase in plasma glucagon with time from PG = 3.8 onward was smaller for glyburide than for placebo (P = 0.014). Plasma glucagon area under the curve (AUC)(60-180) was lower after glyburide than after placebo (1,774 +/- 715 vs. 2,161 +/- 856 pmol. l(-1). min, P = 0.014). From PG = 3.8 onward, plasma growth hormone (GH) levels with placebo were nearly two times (1.9 [95% CI 1.2-2.9]) as high as with glyburide (P = 0.011). AUC(60-180) for GH was lower after glyburide than after placebo (geometric mean [range] 665 [356-1,275] and 1,058 [392-1,818] mU. l(-1). min, respectively; P = 0.04). No significant differences were observed for plasma cortisol, epinephrine and norepinephrine, or incremental symptom scores., Conclusions: The SU glyburide induces multiple defects in glucose counterregulatory hormonal responses, notably decreases in both glucagon and GH release.

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/m2) 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/m2). 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 (R2=0.49 for males and R2=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.

The regulation of hormone-sensitive lipase activity in vivo has not been studied in detail before. We have performed noninvasive in vivo tests to measure hormone-sensitive lipase activity under high plasma levels of endogenous insulin and catecholamines. For this purpose, two mental stress tests were carried out at random in 13 healthy volunteers. The subjects ingested 200 ml of a placebo solution or 20% glucose, followed by 1 h of rest, 20 min of mental stress, and 40 min of rest. Twenty minutes after the ingestion of glucose, insulin levels increased from 6.8 +/- 1.6 to a maximum of 30.5 +/- 4.8 mU/liter (P < 0.01), whereas the increase in insulin was significantly less after placebo (from 5.7 +/- 0.9 to 9.5 +/- 1.5 mU/liter; P < 0.01). The increase in heart rate, as an estimate of the amount of stress, was similar in both tests (12% increase). During stress, plasma norepinephrine and epinephrine concentrations increased by 24% and 44%, respectively, after glucose and by 4% and 21%, respectively, after placebo (n = 6). Fasting plasma FFA were similar in both tests (placebo, 0.35 +/- 0.07 mM; glucose, 0.46 +/- 0.08 mM). Forty minutes after ingestion of placebo, plasma FFA concentrations decreased to 0.27 +/- 0.07 mM, compared with a stronger suppression to 0.11 +/- 0.02 mM after ingestion of glucose (P < 0.01). By 10 min after mental stress, plasma FFA concentrations increased by 53% after placebo (P < 0.01), in contrast to unchanged FFA concentrations after ingestion of glucose. Taken together, these results suggest that the suppression of hormone-sensitive lipase by endogenous insulin in healthy, insulin-sensitive subjects is stronger than the stimulation by endogenous catecholamines.

Plasma concentrations of the third complement component (C3) predict the risk of myocardial infarction. Because chylomicrons stimulate C3 production by adipocytes in vitro, we investigated plasma C3 changes in vivo after an oral fat load. Thirty-seven subjects (20 normolipidemic patients with coronary artery disease [CAD] and 17 healthy control subjects) underwent an oral fat load (50 g/m(2)). C3 was measured at baseline and at 2-hour intervals after fat intake for 10 hours. The effects of lipid lowering by simvastatin were evaluated in 16 patients. Fasting plasma C3 was 1.06+/-0.26 and 0.90+/-0.12 g/L in CAD patients and control subjects, respectively. Fasting C3 was correlated with several parameters associated with insulin resistance. The best determinant of fasting C3 was waist circumference (adjusted R(2)=0.48, beta=0.71, P<0.001); the addition of postprandial triglyceridemia to the model improved it (adjusted R(2)=0.63). Plasma C3 levels at 2, 4, and 6 hours after fat ingestion were significantly higher than fasting levels in patients and control subjects. C3 increased maximally to 1.39+/-0.33 g/L in patients and to 1.11+/-0.18 g/L in control subjects (P<0.01 for patients versus control subjects). Total postprandial triglyceridemia was the best determinant of maximal C3 increase (adjusted R(2)=0.47, beta=0.70; P<0.001). Treatment with simvastatin decreased fasting and postprandial C3 by 6% and 39%, respectively (P<0.05 for both versus no treatment). Postprandial plasma C3 concentrations increase in CAD patients and control subjects. Fasting C3 is associated with waist circumference, but postprandial C3 increment is associated with postprandial lipemia. Fasting and postprandial C3 concentrations decrease after treatment with simvastatin.

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.

Background: Premature atherosclerosis is a clinical feature in untreated acromegaly. Increased postprandial lipoprotein remnant levels are associated with premature atherosclerosis. In most studies, remnants have been measured indirectly using retinyl esters (RE) as a chylomicron core label. Remnants can also be directly quantified by immunoseparation using monoclonal antibodies to apolipoprotein (apo) AI and apo B100 to remove nonremnant lipoproteins. Cholesterol is quantified in the remaining apo E-rich remnant fraction (RLP-C)., Objective: The aim of the present study was to investigate the role of postprandial lipaemia in patients with acromegaly to further define abnormalities leading to increased susceptibility for atherosclerosis., Patients: In a case-control study, the plasma postprandial lipoprotein remnant fraction (RLP-C and RE) were analysed in six patients with active acromegaly [two females, four males; aged 53 +/- 9 years; body mass index (BMI), 29 +/- 4 kg/m2] and in six normolipidaemic control subjects (matched for age, gender, BMI and apo E genotype). They underwent an oral vitamin A fat loading test., Results: Baseline plasma triglycerides (TG) were not significantly different in patients (1.75 +/- 0.71 mM) and controls (1.15 +/- 0.46 mM). Lipoprotein lipase activity was significantly lower in patients than in controls (108 +/- 21 vs. 141 +/- 19 U/l, respectively; P < 0.05). Baseline plasma apo E levels were higher in patients (60.8 +/- 7.9 mg/l) than in controls (48.3 +/- 5.9 mg/l; P < 0.05). No differences were found in the area under the postprandial TG curve (AUC-TG), the incremental AUC-TG (DeltaAUC-TG) and AUC-RE in the Sf < 1000 remnant fraction. However, fasting plasma RLP-C concentrations, isolated by immunoseparation, were increased in patients with active acromegaly (0.41 +/- 0.13 mM) compared to control subjects (0.20 +/- 0.07 mM; P < 0.05). Incremental postprandial RLP-C response (corrected for fasting values) was also significantly elevated in patients (2.14 +/- 1.19 mM/h/l) compared to controls (0.86 +/- 0.34 mM/h/l; P < 0.05). In both groups, the maximal RLP-C concentration was reached between 2 and 4 h., Conclusions: In conclusion, the atherogenic postprandial remnants, represented by RLP-C, were significantly elevated at baseline and in the postprandial period, whereas the larger-sized remnants, represented by retinyl esters (Sf < 1000), were not different from controls. The disturbances in the postprandial RLP-C response increased the susceptibility for premature atherosclerosis as observed in patients with acromegaly.

Abnormal postprandial lipoproteins are associated with an increased risk for cardiovascular disease. Postprandial remnant lipoproteins were usually analyzed indirectly using retinyl esters (RE) as a chylomicron core label during an oral fat loading test. Apo B-100 containing VLDL remnants in addition to apo B-48 containing chylomicron remnants can also be directly quantified using the RLP-Cholesterol Immunoseparation Assay. This recently available method uses monoclonal antibodies to apo A-I and apo B-100 to remove non-remnant lipoproteins and quantifies cholesterol in the remaining apo E-rich remnant fraction. In the present study we compared the analysis of retinyl ester with the immuno-based RLP-Cholesterol (RLP-C) analysis in measuring postprandial remnant lipoproteins in healthy normolipidemic subjects. Sixteen healthy normolipidemic subjects were selected for this study. Postprandial plasma retinyl esters peaked at 5.0+/-1.2 h, whereas plasma RLP-C showed a peak significantly earlier (P<0.001) at 3.5+/-0.6 h. In comparison, postprandial plasma TG and FFA peaked at 3.3+/-1.1 h (P<0.005 compared to retinyl esters). In conclusion, levels of RLP-C changed, during the postprandial phase, in parallel with plasma TG and FFA concentrations and peaked significantly earlier than retinyl esters. Postprandial measurements of RLP-C can be considered as a fast alternative method for the more laborious retinyl-ester analysis in clinical studies.

Background: Postprandial lipemia is associated with endothelial dysfunction. Remnant-like particles (RLP) have been suggested to contribute to these adverse vascular effects. We investigated the effect of cerivastatin and gemfibrozil upon oral fat load induced changes in endothelial function and postprandial lipid profile in vivo., Methods: In a randomized cross-over trial, 15 healthy volunteers received cerivastatin (0.4 mg once daily), gemfibrozil (900 mg once daily) or placebo for 3 weeks. Lipid profiles and flow mediated dilation (FMD) were assessed before and 4 h after an oral fat load. Endothelium-independent dilation was tested after nitroglycerine 0.4 mg sublingual spray., Results: After the placebo period, the oral fat load induced an increase in triglycerides (TG) and RLP-cholesterol (RLP-C) (0.9 +/- 0.7 and 0.08 +/- 0.04 mmol/l, respectively) and a significant decrease in FMD (9.1 +/- 3.4 to 4.3 +/- 3.3%, P < 0.05). After gemfibrozil, TG increase was attenuated (0.5 +/- 0.5 mmol/l), whereas RLP-C increase (0.05 +/- 0.09 mmol/l) and FMD decrease (9.0 +/- 3.8 to 5.2 +/- 2.6%, P < 0.05) were not different from placebo therapy. Cerivastatin did not affect TG increase (0.7 +/- 0.8 mmol/l). RLP-C increase (0.02 +/- 0.07 mmol/l) and FMD (7.9 +/- 2.6 to 8.4 +/- 2.8%) change were attenuated significantly compared to placebo. Endothelium-independent vasodilatation remained unaltered throughout the protocol., Conclusion: Cerivastatin, but not gemfibrozil significantly reduces RLP-C increase after an oral fat load in combination with a reversal of fat-load induced endothelial dysfunction. The present data imply that lowering of RLP-C, rather than lowering of total TG levels, may contributes to the prevention of endothelial dysfunction after an oral fat load during statin use.

Dyslipidemia emerges as an important modifiable risk factor for cardiovascular disease in diabetes mellitus, especially as part of the metabolic syndrome in type 2 diabetes. In type 1 diabetes mellitus, tight glucose regulation usually will correct dyslipidemia. Both total cholesterol and triglyceride levels predict cardiovascular disease in diabetes, and HDL-cholesterol may prove to be an even better predictor. In type 2 diabetes, increased triglyceride and reduced HDL-cholesterol levels are the key characteristics of dyslipidemia. Increased hepatic VLDL production and impaired catabolism of triglyceride-rich particles contribute to hypertriglyceridemia. Subsequent formation of small dense LDL particles leads to increased atherogenicity. Small dense LDL particles have a longer circulation time, are susceptible to glycoxidation, and are taken up by macrophages and the vessel wall. Post-hoc analysis of diabetic subgroups in primary and secondary prevention trials suggest that individuals with diabetes may enjoy substantial cardiovascular risk reduction from lipid-lowering therapy. Trials prospectively addressing the benefit of lipid lowering therapy in diabetes are under way. Target levels for lipid lowering therapy in diabetes at present stem from pathophysiological plausibility rather than from clinical proof. Intensive lipid-lowering with a statin in adequate dosage or a combination of a statin and a fibrate may be used to lower LDL-cholesterol levels to values < 2.6 mmol/l and triglyceride levels to < 1.7 mmol/l, a value at which few small dense LDL particles remain in circulation. Effective medication to raise HDL-cholesterol levels adequately are not yet available for clinical use. Treatment of diabetic dyslipidemia should be as simple as possible, given the polypharmacy that is often necessary for the patient with diabetes. Therefore, single treatment with a statin in adequate dosage is the first choice.

A preponderance of small dense LDL particles is strongly associated with the occurrence of atherosclerotic disease. Although several studies have documented an increased prevalence of small dense LDL particles in diabetes mellitus no data are available to show the effect of lipid-lowering treatment upon the improvement of LDL particle size. In the present study we examined the effect of lipid-lowering treatment, following an intensive lipid-lowering strategy for 30 weeks pursuing ADA recommended target lipid levels, on LDL particle size in 50 type 2 diabetic patients with moderate hyperlipidemia. At week 0, 24 patients (48%) were characterized by small dense LDL phenotype pattern B. After the treatment period a shift towards normal LDL particle size was observed in 17 patients but seven patients (29%) showed the more atherogenic LDL subclass pattern B. After treatment, plasma HDL-cholesterol was significantly lower (P<0.05) in these patients compared to those who had LDL subclass pattern A. Multivariate regression analysis revealed VLDL-cholesterol or triglycerides and HDL(3)-cholesterol as independent determinants for LDL particle size. Change in HDL(2)-cholesterol was an independent determinant for change in LDL particle size. In conclusion, a strategy of intensive lipid-lowering, with the intention to reduce triglyceride levels below 1.7 mmol/l, may be insufficient to ensure improvement in LDL size in all patients.

Patients with diabetes mellitus are at high risk of cardiovascular diseases. Dyslipidemia is an important risk factor for cardiovascular complications in diabetes. Increased triglyceride and reduced HDL-cholesterol plasma concentrations are common features of dyslipidemia in type 2 diabetes. The LDL particles are small and dense and have an increased atherogenity. Abnormalities in lipoprotein composition are observed in diabetes mellitus, especially in type 2. Post-hoc subgroup analyses of studies on the effect of lipid-lowering therapy on cardiovascular events suggest that treatment of dyslipidemia in diabetes may prevent cardiovascular complications. There are increasing indications that dyslipidemia in diabetes mellitus deserves aggressive treatment and that lipid target levels should be very low.

The socio-economic impact of obesity, one of the most prevalent medical disorders in Western society, is mainly due to its association with a higher risk of coronary heart disease. It is likely that atherosclerosis develops against a background of obesity as a result of the insulin resistance that is invariably present in overweight and obese subjects. Fasting plasma lipids may be normal in obese subjects, but they are usually affected by postprandial hyperlipidemia, which is probably due to competition between chylomicrons and VLDL for the same metabolic pathways. The basis for the impaired clearance of atherogenic chylomicron remnants is the fact that obesity causes hepatic apo B-VLDL overproduction, and thus leads to competition with chylomicrons and their remnants at the lipolytic pathway (lipoprotein lipase and hepatic lipase) and receptor level (LDL-receptor and remnant-receptor). The overproduction of VLDL is probably caused by an enhanced hepatic flux of free fatty acids in both the postprandial (from the lipolysis of triglyceride rich particles) and postabsorptive states (from adipocytes). Weight reduction by means of life-style changes, supported by medical interventions with inhibitors of intestinal fat absorption (e.g. Orlistat) or appetite suppressants (e.g. Sibutramine), is essential in order to decrease the risk of atherosclerosis. Furthermore, improvement of risk factors can be achieved by means of fibrate treatment to modulate fasting and postprandial triglyceride levels. Treatment with cholesterol synthesis inhibitors ("statins") may reduce hepatic VLDL production and increase the clearance of atherogenic remnants by upregulating LDL-receptors, thus leading to improved fasting lipid levels and enhanced clearance of chylomicron remnants. Finally, the use of thiazolidinedione derivatives to improve insulin sensitivity may be one of the options for reducing the risk of atherosclerosis in obese subjects.

Fasting plasma triglycerides (TG) show a high intra-individual variability, and therefore, repeated measurements and alternative methodology are necessary when studying TG metabolism. In search for novel approaches to study TG changes, we evaluated the feasibility of determining ambulatory capillary TG. In addition, well-known characteristics (e.g. gender differences) of TG metabolism in healthy subjects were determined. In 18 subjects with a wide range of fasting plasma TG, the results of standardised oral fat loading tests (50 g m(-2)) were compared to their diurnal capillary TG profiles, measured on 3 different days, six times each day in an out-patient clinic setting. The diurnal TG-profile was calculated as area under the capillary TG curve (TGc-AUC) and as incremental area (dTGc-AUC). Clearance of plasma TG after the acute oral fat load correlated well with the diurnal TGc-AUC (r=0.77; P<0.01). In addition, hypertriglyceridemic subjects (plasma TG >2.0 mmol l(-1)) had a higher diurnal triglyceridemia (49.83+/-15.37 h mmol l(-1)) as well as a higher response of plasma TG to the oral fat load (42.10+/-15.37 h mmol l(-1)), than the subjects with normal fasting plasma TG (29.83+/-11.75 h mmol l(-1) (P<0.05) and 20.75+/-5.89 h mmol l(-1) (P<0.01), respectively). In an observational study, 106 volunteers (54 females and 52 males) measured capillary triglycerides. Food intake was recorded and fasting blood was drawn once at the start of the study. Body composition was assessed by anthropometric parameters and body-impedance. Repeated measurements of diurnal triglyceridemia tended to be less variable than fasting capillary triglycerides (mean coefficients of variation 15.1% (range: 0.60-45.9%) and 24.9% (range: 1.44-72.7%), respectively; P=0.09) for the whole group and in males (18.6% (0.60-45.9%) and 24.0% (1.4-58.2%), respectively; P=0.07). The mean diurnal TGc-AUC and dTGc-AUC were lower in females (16.50+/-4.85 and 1.82+/-3.46 h mmol l(-1), respectively) than in males (23.44+/-6.50 and 6.93+/-4.67 h mmol l(-1); P<0.001 for each). The total daily energy intake was lower in females (8911+/-1905 kJ) than in males (11042+/-2604 kJ, P<0.001) because of a lower intake of all nutrients. In females, estrogen status determined significantly the capillary TG profiles. Stepwise multiple regression analysis for females and males, with TGc-AUC as the dependent variable, showed that the best predictors were fasting capillary TG, gender, systolic blood pressure and mean daily energy intake, explaining 72% of the variation. Incremental triglyceridemia was best described by gender, mean daily protein intake and systolic blood pressure, explaining 42% of the variation. Diurnal capillary TG profiles may be used to estimate the total daily load of potential atherogenic particles to which individuals are subjected during the day without the need for metabolic ward studies.

Premature atherosclerosis is a clinical feature in adult-onset GH deficiency. Evidence is accumulating that disturbances in triglyceride metabolism, reflected by abnormalities in circulating remnant lipoproteins, are associated with increased atherogenic potential. In a case-controlled intervention study, we investigated postprandial lipoprotein metabolism using a new remnant lipoprotein method based on immunoseparation principle [RLP-cholesterol (RLP-C)]. In addition, we analyzed retinyl ester (RE) analysis in plasma and in Sf < 1000 fraction. Endothelial function was assessed as flow-mediated dilatation (FMD). Eight patients diagnosed with acquired adult-onset GH deficiency and eight controls matched for gender, age, body mass index, and apolipoprotein (apo) E genotype were enrolled in the study. Oral vitamin A fat loading tests were performed at baseline in both groups and after 6 months of treatment with recombinant human GH (rh-GH) in the adult-onset GH-deficient patients. Adult-onset GH-deficient patients had significantly higher fasting RLP-C, postprandial RLP-C concentrations (plasma RLP-C, 0.29 +/- 0.14 mmol/L; and incremental area under the curve-RLP-C, 2.13 +/- 1.60 mmol*h/L, respectively) than controls (0.19 +/- 0.06 mmol/L and 1.05 +/- 0.72 mmol*h/L (P: < 0.05), respectively). They also had significantly higher postprandial RE in plasma and Sf < 1000 fraction. Treatment with rh-GH significantly reduced postprandial RLP-C concentrations (incremental area under the curve-RPL-C 0.73 +/- 0.34 mmol*h/L; P: < 0.05) but had no effects on the fasting RLP-C concentrations (0.317 +/- 0.09 mmol/L, P: < 0.05), or on the postprandial RE in plasma and in Sf < 1000 fraction. Endothelial function measured as FMD was improved from 5.9 +/- 3.3% to 10.2 +/- 4.0% (P: < 0.05) in patients treated with rh-GH. It is concluded that patients with adult-onset GH deficiency have increased levels of fasting and postprandial RLP-C and an impaired endothelial function as measured as FMD. Treatment with rh-GH resulted in a decrease of postprandial RLP-C concentration, thereby improving the postprandial atherogenic lipoprotein profile and improvement of endothelial function, however, the clearance of large chylomicron particles as reflected by RE remained disturbed.

The effect of untreated total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) as cardiovascular risk factors in both primary and secondary prevention has been extensively investigated. The predictive value of on-treatment lipid and apolipoprotein levels on subsequent cardiovascular events is as yet uncertain. Eight hundred forty-eight patients (675 men and 173 women) with angiographically proven coronary artery disease (CAD) who received effective statin therapy (>/=30% decrease of baseline TC) were studied. We analyzed the predictive value of on-treatment levels of TC, LDL-C, triglycerides (TG), apolipoprotein A-I (apoA-I) and apolipoprotein B (apoB) on subsequent myocardial infarction (MI) and all cause mortality. On-treatment LDL-C levels were 2.55+/-0.55 mmol/L and 2.58+/-0.62 mmol/L for men and women respectively. Age-adjusted Cox regression analysis showed that only on-treatment apoA-I was predictive for future CAD events in both men and women, whereas on-treatment HDL-C was exclusively predictive in women. On-treatment apoB levels were predictive for recurrent CAD events in the total population but not after separate analysis for men and women. On-treatment levels of TC, LDL-C, and TG did not predict subsequent events. Multivariate analysis showed that on-treatment apoA-I and apoB were the only significant predictors for future cardiovascular events. On-treatment levels of TC, LDL-C, and TG were no longer associated with increased risk of recurrent cardiovascular events in CAD patients treated to target levels, which justifies the current guidelines. However, on-treatment levels of apoB and in particular apoA-I (and HDL-C in women) were significantly predictive for MI and all-cause mortality and may therefore be more suitable for cardiovascular risk assessment in this population.

Background: Elevated fasting and postprandial triglycerides (TG) are established risk factors for Coronary Heart Disease (CHD). Usually, fasting plasma TG are measured, although TG are mainly produced in a postprandial state. Our objective was to investigate diurnal TG profiles using serial capillary TG measurements, in normolipidemic healthy males., Materials and Methods: Forty-eight, non-obese, non-smoking males (range: 20-55 years, mean age: 32 +/- 12 years), measured diurnal capillary TG, at six fixed timepoints during the day on three different days and recorded their food intake. Insulin sensitivity was estimated by HOMA. Diurnal capillary TG profiles were calculated as integrated area under the mean capillary TG curve (TGc-AUC)., Results: All subjects had normal fasting plasma TG and cholesterol. The average TGc-AUC was 23.6 +/- 6.7 mmol h L-1. Significant correlations with TGc-AUC were: fasting insulin (r = 0. 40, P < 0.005), HOMA (r = 0.32, P < 0.05), relative fat mass (r = 0. 31, P < 0.05), dietary protein-(r = 0.31, P < 0.05) and saturated fat intake (r = 0.30, P < 0.05). Age was not associated to diurnal triglyceridemia. After subdividing the group into quartiles on the base of TGc-AUC, differences were found between the highest (n = 12) and lowest quartile (n = 12) for: fasting capillary TG, fasting insulin, HOMA and systolic blood pressure. Fasting plasma TG and dietary intake were not different., Conclusion: Diurnal TG profiles in healthy normolipidemic males are not age-dependent, but are associated to insulin sensitivity, fat mass and diet. Diurnal capillary TG profiles may be a valuable additional tool in estimating a risk profile for CHD since significant differences in diurnal TG are not always reflected by elevated fasting plasma TG.

Familial hypercholesterolemia (FH) and disturbances in postprandial lipoprotein metabolism are both associated with premature atherosclerosis. The effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors on plasma cholesterol levels in patients with FH is well established; however, it is not known whether postprandial lipoproteins are also influenced. In this case-controlled intervention study, we investigated the effects of high-dose simvastatin on postprandial lipoproteins. We used a new method to analyze remnant lipoproteins based on the immunoseparation principle (remnant-like particle cholesterol [RLP-C] assay) and the well-established measurement of retinyl ester (RE) analysis in plasma and in the Svedberg flotation unit (Sf)<1000 fraction. Seven heterozygous FH patients and 7 control subjects matched for sex, age, body mass index, triglycerides, and apolipoprotein E genotype were enrolled in the study. An oral vitamin A (RE) fat-loading test was performed at baseline in both groups and after 3 months of high-dose simvastatin (80 mg/d) treatment in the FH patients. Before treatment, FH patients had significantly higher fasting and postprandial concentrations of lipoprotein remnants (plasma RLP-C 42+/-19 mg/dL and area under the RLP-C curve 415+/-82 mg. L(-1). h(-1), respectively) than did control subjects (7+/-3 mg/dL and 101+/-35 mg. L( -1). h(-1), respectively; P<0.05), suggesting a delayed clearance of chylomicron remnant particles in the FH patients. Treatment with simvastatin significantly reduced fasting and postprandial remnant lipoprotein cholesterol concentrations (13+/-3 mg/dL and 136+/-53 mg. L(-1). h(-1), respectively; P<0.05 for both). Postprandial RE in the Sf<1000 fraction, not total RE in plasma, was also significantly higher in FH patients than in control subjects (24+/-10 versus 6.3+/-5.9 mg. L( -1). h(-1), P<0.05), but treatment with simvastatin did not result in improvement of the postprandial RE response, either in the Sf<1000 fraction or in plasma. It is concluded that heterozygous FH patients have increased fasting and postprandial remnant lipoprotein concentrations. Treatment with simvastatin significantly reduced the fasting and postprandial RLP-C concentrations but did not result in improved postprandial RE response.

Objective: To investigate the frequency of severe hypoglycemia (SH) and hypoglycemic coma and to identify clinical and behavioral risk indicators in a nonselected population of type 1 diabetic patients., Research Design and Methods: This study involved a retrospective clinical survey of 195 consecutive patients using a questionnaire addressing the frequency of SH (i.e., help from others required) and hypoglycemic coma during the previous year, general characteristics, behavior, hypoglycemia awareness, and the Hypoglycemia Fear Survey Data regarding diabetes, treatment, long-term complications, comorbidity, and comedication were obtained from the patients' medical records., Results: A total of 82% of subjects were receiving intensive insulin treatment, and mean +/- SD HbA(1c) was 7.8 +/- 1.2%. Mean duration of diabetes was 20 +/- 12 years. The occurrence of SH (including hypoglycemic coma) was 150 episodes/100 patient-years and affected 40.5% of the population. Hypoglycemic coma occurred in 19% of subjects (40 episodes/100 patient-years). SH without coma was independently related to nephropathy (odds ratio [OR] 4.8 [95% CI 1.5-15.1]), a threshold for hypoglycemic symptoms of <3 mmol/l (4.8 [1.8-12.0]), and a daily insulin dose 0.1 U/kg higher (1.3 [1.0-1.6]) (all ORs were adjusted for diabetes duration and use of comedication). Hypoglycemic coma was independently related to neuropathy (3.9 [1.5-10.4]), (nonselective) beta-blocking agents (14.9 [2.1-107.4]), and alcohol use (3.5 [1.3-9.1]) (all ORs were adjusted for diabetes duration)., Conclusions: SH and hypoglycemic coma are common in a nonselected population with type 1 diabetes. The presence of long-term complications, a threshold for symptoms of <3 mmo/l, alcohol use, and (nonselective) beta-blockers were associated with SH during the previous year. If prospectively confirmed, these results may have consequences for clinical practice.

Influenza virus epidemics are associated with excess mortality due to cardiovascular diseases. There are several case reports of excessive coagulation during generalised influenza virus infection. In this study, we demonstrate the ability of respiratory viruses (influenza A, influenza B, parainfluenza-1, respiratory syncytial virus, adenovirus, cytomegalovirus) to infect lung fibroblasts and human umbilical vein endothelial cells in culture. All viral pathogens induced procoagulant activity in infected endothelial cells, as determined in a one-stage clotting assay, by causing an average 55% reduction in the clotting time. When factor VII deficient plasma was used clotting time was not reduced. The induction of procoagulant activity was associated with a 4- to 5-fold increase in the expression of tissue factor, as measured by the generation of factor Xa. Both experiments indicate that the procoagulant activity of endothelial cells in response to infection with respiratory viruses is caused by upregulation of the extrinsic pathway. Although both enveloped viruses and a non-enveloped virus (adenovirus) induced procoagulant activity in endothelial cells by stimulating tissue factor expression, the role of the viral envelope in the assembly of the prothrombinase complex remains uncertain. We conclude that both enveloped and non-enveloped respiratory viruses are capable of infecting cultured human endothelial cells and causing a shift from anticoagulant to procoagulant activity associated with the induction of tissue factor expression.