The Mediterranean diet in Italy: An update.
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Aged↗
Biomedical subjects
F P Mancini
Publications and source records attributed to F P Mancini.
Fasting plasma free fatty acid concentrations and Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma2 gene in healthy individuals.
BACKGROUND: The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR) gamma gene has been associated in some, but not all, studies with lower body mass index (BMI) and improved insulin sensitivity; how an altered transcriptional activity of PPARgamma2 could influence insulin sensitivity is currently unclear. The free fatty acids (FFAs) released from adipose tissue triglycerides via lipolysis are key mediators of impaired insulin sensitivity; however, no study has described the relationship of the Pro12Ala mutation with circulating levels of FFAs under physiological conditions. OBJECTIVE: To investigate in a population-based sample of Caucasians the relation of the Pro12Ala polymorphism with plasma concentrations of FFAs and other markers of lipid and glucose metabolism described as components of the insulin resistance syndrome. SUBJECTS: Four hundred and thirty-eight nondiabetic employees of the Italian Telephone Company, aged 35-65 years, randomly selected from a total population of 3900 participants in a company-sponsored health screening. MEASUREMENTS: The Pro12Ala polymorphism of the PPARgamma was studied together with plasma FFAs, insulin, glucose, triglycerides, high density lipoprotein (HDL) cholesterol, blood pressure and anthropometry. The Homeostatic Model Assessment (HOMA) index was calculated as a measure of insulin resistance. RESULTS: Carriers and noncarriers of the Pro12Ala polymorphism showed very similar circulating levels of FFA (0.46 +/- 0.2 vs. 0.47 +/- 0.2, NS); plasma glucose, triglycerides, HDL cholesterol and blood pressure were also similar in the two groups with or without the polymorphism. To allow for the possible confounding effect of obesity, a separate analysis was conducted in overweight (BMI > or = 25 kg/m(2)) and normal-weight people (BMI < 25 kg/m(2)). Circulating plasma FFA concentrations, as well as triglycerides, blood pressure and HOMA, were significantly higher in overweight than normal-weight, as expected, but no significant differences were detected between carriers and noncarriers of the Pro12Ala polymorphism within each BMI group (0.49 +/- 0.2 vs. 0.48 +/- 0.2, NS, and 0.44 +/- 0.2 vs. 0.47 +/- 0.2, NS, in overweight and normal-weight, respectively). The Pro12Ala polymorphism was also analysed across increasing quartiles of FFA concentrations and no relationship was observed between the frequency of the polymorphism and FFA values (overall chi2 = 0.48, NS). CONCLUSION: This study does not show any relationship between the Pro12Ala polymorphism of the PPARgamma gene and fasting FFAs in the general population. The possibility of a different handling of FFAs under different conditions (i.e. postprandial) cannot be excluded and remains to be explored.
Adult↗
Fenofibrate prevents and reduces body weight gain and adiposity in diet-induced obese rats.
Fibrates are hypolipidemic drugs that activate the peroxisome proliferator-activated receptors. Since fibrates may also increase energy expenditure, we investigated whether fenofibrate (FF) had this effect in diet-induced obese rats. A 2-month administration of a high-fat palatable diet to adult rats increased body weight by 25% and white adipose mass by 163% compared with a standard diet. These effects were prevented by FF, both when administered for the 2 months of high-fat feeding and when given for only the second month. Consequently, FF-treated rats had a final body weight and white adipose tissue mass similar to untreated animals on the standard diet. FF also increased resting metabolic rate, hepatic peroxisomal and mitochondrial palmitoyl-dependent oxygen uptake and mRNA levels of acyl-CoA oxidase and lipoprotein lipase. Finally, FF lowered mRNA levels of uncoupling protein-2 and did not affect mitochondrial respiration in skeletal muscle. Therefore, FF seems to act as a weight-stabilizer mainly through its effect on liver metabolism.
Adipose Tissue↗
Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and severe obesity: a case-control study.
OBJECTIVE: To explore the association of the Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 with severe obesity and the features of the metabolic syndrome in a population-based sample of Caucasians. PARTICIPANTS AND METHODS: The study is based on a case-control design: 95 non-diabetic severely obese (body mass index, BMI > 35 kg/m2) cases and 280 normal weight (BMI < 25 kg/m2), age- and sex-matched controls selected from the same population were studied. Height, weight, waist circumference, as well as blood pressure were measured according to a standard protocol. BMI at age 25 y was calculated on the basis of current height and reported weight at age 25 y Biochemical measurements included fasting glucose, triglycerides, high-density lipoprotein cholesterol and insulin. DNA analysis was conducted by PCR and gel electrophoresis. RESULTS: Age and gender distribution were similar in obese and normal weight participants. The percentage of people with the Pro12Ala mutation was not significantly different in obese or normal weight participants (20% and 15%, respectively; P = 0.32). Conversely, in obese participants with obesity starting in early adulthood (ie with BMI at age 25 above 26.9kg/m2 which represents the median of the whole obese group), the Pro12Ala mutation was observed significantly more frequently than in the normal weight controls (29% vs 15%; chi square = 4.5, P < 0.05; odds ratio 2.4; 95% CI 1.03-5.36). No association of the Pro12Ala variant with any of the component of the metabolic syndrome measured in the study was observed in either obese, juvenile obese or normal weight participants. CONCLUSIONS: Results of this study indicate that the Pro12Ala mutation does not play a major role as a determinant of severe obesity and/or features of the metabolic syndrome in the general population. However, this mutation may be of greater importance as a contributor to early onset obesity.
Adult↗
Homocysteine, coagulation, platelet function, and thrombosis.
Over the last 30 years, a growing body of evidence has documented the role of hyperhomocysteinemia (HHcy) as an independent vascular risk factor. However, the mechanisms through which elevated circulating levels of homocysteine (Hcy) cause vascular injury and promote thrombosis remain elusive. Most findings have been achieved in in vitro studies employing exceedingly high concentrations of Hcy, whereas only a few studies have been carried out in vivo in humans. In homocystinuric patients, homozygotes for mutations of the gene coding for the cystathionine beta-synthase enzyme, abnormalities of coagulation variables reflecting a hypercoagulable state, have been reported. In vitro studies provide a biochemical background for such a state. In homocystinuric patients, an in vivo platelet activation has also been reported. The latter abnormality is not corrected by the bolus infusion of concentrations of hirudin, which determines a long-lasting impairment of the conversion of fibrinogen to fibrin by thrombin; in contrast, it appears at least in part lowered by the administration of the antioxidant drug probucol. During the autooxidation of Hcy in plasma, reactive oxygen species are generated. The latter initiate lipid peroxidation in cell membranes (potentially responsible for endothelial dysfunction) and in circulating lipoproteins. Oxidized low-density lipoproteins (LDL) may trigger platelet activation as well as some of the hemostatic abnormalities reported in such patients. Thus the oxidative stress induced by Hcy may be a key process in the pathogenesis of thrombosis in HHcy. Accumulation of adenosylhomocysteine in cells (a consequence of high circulating levels of homocysteine) inhibits methyltransferase enzymes, in turn preventing repair of aged or damaged cells. This mechanism has been recently documented in patients with renal failure and HHcy and provides an additional direction to be followed to understand the tendency to thrombosis in moderate HHcy.
Adolescent↗
Plasma homocysteine and its determinants in diabetic retinopathy.
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Biomarkers↗
Plasma homocysteine and microvascular complications in type 1 diabetes.
BACKGROUND: Homocysteine is involved in a complex and dynamic system of vascular injury and repair and may thus contribute to the development of diabetic microangiopathy. This still debated issue has important scientific and clinical implications, since hyperhomocysteinemia can be corrected nutritionally. AIMS: 1) To evaluate the association between fasting plasma homocysteine, type 1 diabetes and its microvascular complications; 2) to elucidate the basis of this association by investigating the major determinants of plasma homocysteine in relation to diabetic microangiopathy. METHODS: We studied sixty-six consecutive patients with type 1 diabetes mellitus of > 10 years duration and normal serum creatinine (< 115 mumol/L, 1.3 mg/dL), and free from clinically detectable cardiovascular diseases. Forty-four non-diabetic controls were also studied. Plasma concentrations of homocysteine, folate and vitamin B12 were investigated together with the C677T mutation in the gene coding for methylenetetrahydrofolate reductase (MTHFR), a key enzyme in homocysteine metabolism. Renal and retinal diabetic complications were evaluated as albumin/creatinine ratio on early-morning, urine spot collection and fundus photographs. FINDINGS: Fasting plasma homocysteine levels were very similar in patients and controls. Patients with microalbuminuria or proliferative retinopathy had significantly higher values than those without: 9.4 +/- 3.1 vs 7.4 +/- 2.8 mumol/L, p < 0.02 and 9.5 +/- 2.6 vs 7.3 +/- 3.0 mumol/L, p < 0.05. This difference was not attributable to confounders, such as age, sex and smoking, nor to dissimilar plasma folate and vitamin B12 concentrations. In contrast, homozygosity for the C677T mutation in the MTHFR gene--the commonest genetic defect linked to moderately increased plasma homocysteine--was significantly more frequent in patients with microalbuminuria and/or proliferative retinopathy (50% vs 13%, p < 0.004), odds ratio 6.7 (95% CI 1.7-27.6). CONCLUSIONS: Type 1 diabetes as such is not associated with increased plasma homocysteine levels, though patients with microalbuminuria and/or proliferative retinopathy display significantly higher values than those without. This difference is not attributable to obvious confounders, nor to differences in vitamin status, and may be partly mediated by genetic factors. Plasma homocysteine, together with other diabetes-related noxae, may thus be in a position to contribute to the development of nephropathy and the progression of retinopathy.
Adult↗
Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension.
We investigated the influence of major cardiovascular risk factors (smoking, hypercholesterolemia, diabetes mellitus) on the association between angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism and echocardiographic left ventricular mass in 225 patients with sustained hypertension, assessed by ambulatory blood pressure monitoring. When the study population was analyzed as a whole, the 3 ACE genotypes did not differ in left ventricular mass (II, 47 g/m2.7; ID, 49 g/m2.7; DD, 51 g/m2.7; p = NS). No difference was found in subjects (n = 135) in whom at least 1 major cardiovascular risk factor was present (II, 51 g/m2.7; ID, 51 g/m2.7; DD: 52 g/m2.7; p = NS). In contrast, in the absence of cardiovascular risk factors, DD subjects (n = 32) exhibited left ventricular mass index higher than non-DD (ID/II) subjects (n = 75; p <0.05). After controlling for age and sex, in the absence of cardiovascular risk factors, the risk of left ventricular hypertrophy was 3.8-fold higher in DD than in non-DD patients (odds ratio 3.8; 95% confidence interval 1.2 to 12.1, p <0.02). We conclude that in the present setting of patients with established sustained systemic hypertension, the absence of risk factors potentially affecting cardiovascular adaptation allows for the detection of a positive association between homozygosity for the D allele of the ACE gene and left ventricular hypertrophy.
Alleles↗
Pro12Ala substitution in the peroxisome proliferator-activated receptor-gamma2 is not associated with type 2 diabetes.
Peroxisome proliferator-activated receptor (PPAR)-gamma is a major regulator of adipogenesis and insulin sensitivity. The PPAR-gamma gene generates two isoforms through alternative splicing, PPAR-gamma1 and -gamma2, the latter having an additional stretch of 28 amino acids at its NH2-terminus in the ligand-independent activation domain. This extension renders PPAR-gamma2 more sensitive to insulin action. Since there is a Pro12Ala substitution in this domain, we tested whether it is related to type 2 diabetes or insulin resistance. Therefore, 131 type 2 diabetic patients and 312 normoglycemic control subjects were screened for the presence of the mutation and for major clinical and metabolic features. The frequency of the mutation did not differ significantly between diabetic patients and control subjects. BMI, insulin, and other metabolic and anthropometric variables were also not associated with the mutation. Although the study was carried out on a sufficiently large sample, the conclusions do not support a major role for the Pro12Ala substitution of the PPAR-gamma gene in the etiology of type 2 diabetes.
Adipose Tissue↗
Homocysteine, platelet function and thrombosis.
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Arterial Occlusive Diseases↗
A fast and accurate method for genotyping the angiotensin-converting enzyme I/D polymorphism.
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Genotype↗
Influence of cardiovascular risk factors on relation between angiotensin converting enzyme-gene polymorphism and blood pressure in arterial hypertension.
BACKGROUND: The angiotensin-converting enzyme gene insertion (I)/deletion (D) polymorphism might be involved in the development of several cardiovascular diseases, but its role in humans remains controversial. OBJECTIVE: To investigate the relation between the angiotensin converting enzyme gene polymorphism and extent of blood pressure elevation in arterial hypertension, taking into account the influence of cardiovascular risk factors. METHODS: We studied 171 patients (aged 49 +/- 9 years, 61 women) with abnormal clinic and 24 h ambulatory blood pressures, after a 3-week wash-out. RESULTS: We found no significant difference in clinic and ambulatory blood pressures among homozygotic D (DD), heterozygotic D (ID) and homozygotic I (II) angiotensin converting enzyme genotypes and between homozygotic D (DD) and pooled heterozygotic D (ID) plus homozygotic I (II) (non-DD) angiotensin converting enzyme genotypes. At least one additional cardiovascular risk factor (smoking, hypercholesterolaemia or diabetes) was present for 103 patients (33 DD and 70 non-DD). Non-DD subjects (n = 43) without additional cardiovascular risk factors exhibited lower values of 24 h, daytime systolic and pulse blood pressures than did members of all other groups (all P < 0.04). In the presence of risk factors, DD and non-DD subjects exhibited similar systolic and pulse ambulatory blood pressures, in that we found higher values in non-DD genotype subjects with risk factors than we did for non-DD subjects without additional risk factors. In multivariate analysis, the combination of non-DD genotype and absence of cardiovascular risk factors was associated with the lowest values of systolic and pulse blood pressures. CONCLUSIONS: Angiotensin converting enzyme insertion allele appears clustered with lower ambulatory systolic and pulse blood pressures in hypertensive patients when the potential interference of additional cardiovascular risk factors is eliminated. A high prevalence of cardiovascular risk factors in population studies might blunt a possible biological association of blood pressure with DD genotype by contributing to raising of blood pressures also in subjects with non-DD genotypes.
Adult↗
Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.
To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2+/-1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from normocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (n = 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P < 0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651+/-87,449 and 451,255+/-37,448 micron2 per section, respectively; mean+/-SD) than aortas from normocholesterolemic mothers (61,862+/-9,555 micron2; P < 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde- and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL). 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/ macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL. In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia. The fact that in very early lesions LDL and OxLDL are frequently found in the absence of monocyte/macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo.
Adult↗
Effect of low density lipoprotein fatty acid composition on copper-induced peroxidation: 1H-nuclear magnetic resonance analysis.
Oxidation of low density lipoprotein (LDL) has been implicated in atherogenesis. An increased content of oleic acid in LDL and the substitution of monounsaturated for polyunsaturated fatty acids in the diet reduce LDL oxidation. With 1H-NMR analysis, all LDL modifications, including the production of copper-induced aldehyde products, can be evaluated simultaneously. The aim of the present study was to investigate whether the fatty acid composition of LDL affected the NMR evaluation of aldehyde compounds. The LDL of the samples utilized were rich in oleic fatty acid (26.9%). After 48 h of exposure to copper sulfate, the mean production of malonyldialdehyde (MDA) by LDL was 31.2 nmol/mg of protein. Moreover, in the present study NMR did not reveal large amounts of peroxidative compounds since the nanomolar amounts of MDA produced after exposure to copper sulfate could not be detected. This study also demonstrated that the fatty acid composition (i.e. the oleic:linoleic acid ratio) must be taken into account in the evaluation of LDL peroxidation by NMR. In particular, a high concentration of oleic acid may limit the formation of large amounts of peroxidative compounds generated after exposure to the oxidant copper sulfate.
Adult↗
Hemostatic variables and ischemic cardiovascular disease: do we need a concerted effort for more profitable future clinical investigations?
Abnormally high levels of some hemostatic variables are often associated with the occurrence of the major ischemic complications of atherosclerosis, myocardial infarction, and stroke. Intervention studies have shown that prolonged treatment with antiplatelet drugs significantly reduces the recurrence of coronary and cerebral ischemic episodes. The association of the ischemic event with the hemostatic abnormality has often been just descriptive. Although suggestive, the link between the abnormality and the development and progression of atherosclerosis is only circumstantial. Finally, no information is available on the presence of one or more abnormal variables in subjects who did or did not experience a recurrence of thrombosis with treatment. To strengthen the clinical relevance of these hemostatic variables and to maximize the effectiveness of antithrombotic strategies, these indices should be taken into account in studies evaluating nonpharmacological and pharmacological interventions against arterial thrombosis. We believe that a task force on this subject would serve a useful purpose. The task force should develop and publicize within the cardiological community guidelines for (a) defining the size of the problem, (b) identifying the variables to measure, (c) standardizing detection and monitoring techniques, and (d) suggesting appropriate strategies of prevention and treatment.
Arteriosclerosis↗
Decreased low-density lipoprotein oxidation after repeated selective apheresis in homozygous familial hypercholesterolemia.
Familial hypercholesterolemia was the first genetic disorder recognized to cause myocardial infarction. Patients with homozygous familial hypercholesterolemia have rapidly progressive coronary atherosclerosis with angina pectoris, myocardial infarction, or sudden death at a young age. Selective apheresis on dextran sulfate cellulose columns reduces mortality and may induce regression of coronary lesions. These patients have both increased levels and prolonged circulation residence time of low-density lipoprotein (LDL), which is not removed by cellular receptor. LDL oxidation may play a pivotal role in atherogenesis. LDL undergoes oxidation before being taken up by macrophages and then transformed into arterial wall foam cells. The aim of this study was to investigate LDL oxidation in eight homozygous patients with familial hypercholesterolemia during repeated LDL apheresis. LDL lipid peroxidation, estimated by conjugated-diene absorbance at 234 nm, lipid peroxides, and malondialdehyde showed an increased resistance against oxidation after repeated LDL apheresis. This phenomenon was also observed in the oxidative indexes of protein moiety of LDL (apolipoprotein-B100 fragmentation, trinitrobenzenesulfonic acid reactivity, and electrophoresis agarose mobility). Similarly, cholesteryl esterification was decreased after LDL apheresis. Thus selective LDL apheresis not only decreases the pool of LDL, but it also induces changes that render LDL less susceptible to oxidation. This phenomenon might contribute to reduce coronary atherosclerosis and thus mortality of these particular patients.
Apolipoprotein B-100↗
A simple and rapid purification procedure minimizes spontaneous oxidative modifications of low density lipoprotein and lipoprotein (a).
Usual purification procedures of LDL and Lp(a) require numerous, extensive and prolonged sample handlings: this greatly increases the possibility of spontaneous oxidation. We have developed a method which, making use of two short-run ultracentrifugations in vertical rotors alternated by two rapid column-chromatography steps (SRUC), significantly shortens the preparation time to 3.5 h (LDL) and does not demand additional instrumentation or particular accuracy. Purification of Lp(a) requires a further wheat germ agglutinin chromatographic step, which can be accomplished within 30 min. More importantly, the method significantly reduces spontaneous oxidation as compared with classical isolation procedures. LDL isolated by the standard sequential method exhibits more extensive apolipoprotein B100 degradation, lipid peroxidation, and endogenous antioxidant (vitamin E) loss than the same lipoproteins obtained by means of the SRUC. This procedure may have be particularly valuable in experiments evaluating the effects of oxygen radical-induced modifications, especially in vitro.
Adolescent↗
Drugs affecting plasma fibrinogen levels. Implications for new antithrombotic strategies.
Current evidence indicates that plasma fibrinogen is synthesized by the liver; that genetic and environmental factors regulate plasma fibrinogen levels; that interleukin-6 (IL-6) affects the synthesis of plasma fibrinogen by mechanisms involving protein kinase C, and that during the acute-phase response, monocytes generate a variety of monokines including IL-6. Certain drugs and nutrients have been reported to lower plasma fibrinogen levels. The mechanism(s) involved in this effect is poorly understood. However, since most of these substances quantitatively and/or qualitatively affect monocytes, the possibility that these drugs affect plasma fibrinogen levels via these cells should be considered. In addition to fibrinogen, IL-6 also regulates the synthesis of other acute-phase proteins. Especially when combined, major risk factors for atherosclerosis cause vascular injury that triggers inflammatory events. This raises the issue of whether high plasma fibrinogen levels are just the epiphenomenon of as yet unknown events in thrombosis and atherosclerosis. Thus, the issue to be addressed is whether high plasma fibrinogen concentrations should be lowered or should they serve to suggest strong interventions on established risk factors. As for other risk factors, fibrinogen measurements in population-based studies, in parallel with measurements of established risk factors will help define appropriate directions to be followed to gain insight into the issue and define new antithrombotic strategies.
Animals↗