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Background Transferring results obtained in cardiovascular outcome trials (CVOTs) to the real-world setting is challenging. We herein transposed CVOT results to the population of patients with type 2 diabetes (T2D) seen in routine clinical practice and who may receive the medications tested in CVOTs. Methods We implemented the post-stratification approach based on aggregate data of CVOTs and individual data of a target population of diabetic outpatients. We used stratum-specific estimates available from CVOTs to calculate expected effect size for the target population by weighting the average of the stratum-specific treatment effects according to proportions of a given characteristic in the target population. Data are presented as hazard ratio (HR) and 95% confidence intervals. Results Compared to the target population (n = 139,708), the CVOT population (n = 95,816) was younger and had a two to threefold greater prevalence of cardiovascular disease. EMPA-REG was the CVOT with the largest variety of details on stratum-specific effects, followed by TECOS, whereas DECLARE and PIONEER-6 had more limited stratum-specific information. The post-stratification HR estimate for 3 point major adverse cardiovascular event (MACE) based on EMPA-REG was 0.88 (0.74–1.03) in the target population, compared to 0.86 (0.74–0.99) in the trial. The HR estimate based on LEADER was 0.88 (0.77–0.99) in the target population compared to 0.87 (0.78–0.97) in the trial. Consistent results were obtained for SUSTAIN-6, EXSCEL, PIONEER-6 and DECLARE. The effect of DPP-4 inhibitors observed in CVOTs remained neutral in the target population. Conclusions Based on CVOT stratum-specific effects, cardiovascular protective actions of glucose lowering medications tested in CVOTs are transferrable to a much different real-world population of patients with T2D.

Type 2 diabetes (T2D) is a risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD), which is becoming the commonest cause of chronic liver disease worldwide. We estimated MAFLD prevalence among patients with T2D using the hepatic steatosis index (HSI) and validated it against liver ultrasound. We also examined whether glucose-lowering medications (GLM) beneficially affected HSI.We collected data from 46 diabetes clinics (n = 281,381 T2D patients), extracted data to calculate HSI and validated it against ultrasound-detected hepatic steatosis. We then examined changes in HSI among patients with a follow-up visit within 1 year after initiating newer GLMs.MAFLD (defined by HSI 36, i.e., a high probability of steatosis) was present in 76.3% of the 78,895 included patients, while only 2.7% had HSI 30 (low probability of steatosis). After age- and sex-adjusting, higher HSI was associated with higher prevalence of chronic kidney disease (odds ratio 1.35; 95%CI 1.22-1.51) and macroangiopathy (odds ratio 1.18; 95%CI 1.07-1.30). Among 2,179 subjects in the validation cohort, the prevalence of MAFLD was 67.8% and was greater in those with high HSI. Performance of HSI for ultrasound-detected MAFLD was moderate (AUROC 0.70), yet steatosis prevalence was threefold higher among subjects with HSI 36 than among those with HSI 30. Notably, HSI declined significantly ~ 6 months after initiation of dapagliflozin or incretin-based therapies, but not gliclazide.About three quarters of patients with T2D have HSI values suggestive of MAFLD, a condition associated with macroangiopathy and nephropathy. Treatment with dapagliflozin or incretin therapies might improve MAFLD in T2D.

Aims Cardiovascular disease (CVD) is the greatest burden of type 2 diabetes mellitus (T2DM) in terms of morbility, mortality and costs for individuals and societies. Therefore, its prevention is a major goal in diabetes care. Optimal treatment of hyperglycemia is certainly instrumental to CVD prevention. Optimal treatment means both establishing the most appropriate glycemic target for the given individual and selecting the medication(s) with the most favourable benefit/safety ratio. CVD safety, if not a clear CVD benefit, is certainly required for all antidiabetic agents. Dipeptidyl-peptidase-4 (DPP-4) inhibitors are among the classes of antidiabetic agents most recently made available for diabetes care. A major question to be addressed is the effect of these compounds on CVD. Expectations were high for their mechanism of action, which targets also post-prandial glucose and minimize hypoglycemia risk, thereby providing a sort of global glucose control, and for some potentially beneficial extra-glycemic effects. This article reviews the existing literature on this issue. Data synthesis Data published so far document that DPP-4 inhibitors have a wide spectrum of glycemic and extra-glycemic effects potentially reducing the risk of CVD as well as favourable effects on intermediate or surrogate CVD endpoints. These data heralded a better CVD outcome. Accordingly, pooling CVD safety data from phase 3 and 4 studies conducted with DPP-4 inhibitors suggested that their use might translate into a better CVD outcome. Data from three CVD outcome RCTs with alogliptin, saxagliptin and sitagliptin documented no harm but did not show any benefit on major CVD events. A modest but significant increased risk of hospitalization for heart failure was observed with saxagliptin and with alogliptin (only in subjects with no history of heart failure before randomization) but not with sitagliptin. A study currently in progress with linagliptin will provide further insights in the issue of CVD safety and benefit. Conclusions It should be considered that most alternative oral antidiabetic agents generally do not possess a better CVD risk profile than DPP-4 inhibitors and that some of them, indeed, should be used with caution because of potentially adverse effects on heart and vasculature. Overall, the selection of antidiabetic agent(s) with the most favourable CVD profile is mandatory but still challenging in diabetes care.

Purpose: The optimal macronutrient composition of the diet for the management of type 2 diabetes is debated, particularly with regard to the ideal proportion of fat and carbohydrates. The aim of the study was to explore the association of different proportions of fat and carbohydrates of the diet—within the ranges recommended by different guidelines—with metabolic risk factors. Methods: We studied 1785 people with type 2 diabetes, aged 50–75, enrolled in the TOSCA.IT Study. Dietary habits were assessed using a validated food-frequency questionnaire (EPIC). Anthropometry, fasting lipids, HbA1c and C-reactive protein (CRP) were measured. Results: Increasing fat intake from

To explore associations between serum 25-hydroxyvitamin D(3) [25(OH)D] concentrations and liver histology in patients with non-alcoholic fatty liver disease (NAFLD).We studied 60 consecutive patients with biopsy-proven NAFLD, and 60 healthy controls of comparable age, sex and body mass index (BMI). NAFLD patients had a marked decrease in winter serum 25(OH)D concentrations (51.0+/-22 vs. 74.5+/-15 nmol/L, P0.001) compared with controls. Metabolic syndrome (MetS; as defined by the Adult Treatment Panel III criteria) and its individual components occurred more frequently among NAFLD patients. The marked differences in 25(OH)D concentrations observed between the groups were little affected by adjustment for age, sex, BMI, creatinine, calcium, homeostasis model assessment (HOMA)-insulin resistance, and the presence of the MetS. Interestingly, among NAFLD patients, decreased 25(OH)D concentrations were closely associated with the histological severity of hepatic steatosis, necroinflammation and fibrosis (P0.001 for all) independent of age, sex, BMI, creatinine, calcium, HOMA-insulin resistance, and presence of the MetS.Compared with controls, NAFLD patients have a marked decrease in serum 25(OH)D concentrations, which is closely associated with histopathological features of NAFLD. Further investigation into whether vitamin D(3) may play a role in the development and progression of NAFLD appears to be warranted.

Background and aims Guidelines for the primary prevention of cardiovascular disease recommend the use of risk-assessment methods to identify high risk patients who can benefit from lifestyle changes and/or drug treatment. Although all these risk-prediction methods are based on the same principle, they produce different risk estimates. The aim of this study was to compare the most recent and widely used cardiovascular risk-prediction methods and the respective guidelines when applied to Italian cohorts. Methods and results Seven different risk-assessment methods were applied to two groups of subjects, 536 healthy individuals and 426 diabetic patients. Sensitivity and specificity of Framingham-based risk-assessment methods were calculated using the Framingham full equation as the reference standard. The extent of concordance among the different risk-assessment methods was determined by kappa test. By using NCEP-ATPIII risk calculator, modified Sheffield tables, Joint European Societies charts, Joint British Societies charts, Italian CUORE Project charts, European SCORE charts and New Zealand National Heart Foundation charts in the group of 536 healthy subjects, lipid-lowering treatment would be recommended in 17.5%, 12.7%, 12.1%, 8.6%, 5.0%, 4.7%, and 1.1% subjects, respectively. By using the same risk-assessment methods in the group of 426 diabetic patients, treatment would be recommended for 100%, 82.9%, 66.9%, 77.7%, 43.0%, 74.9%, and 47.4% patients, respectively. The Joint British charts and the modified Sheffield tables showed the closest agreement with the reference standard. Conclusions Our study confirms that the use of different risk-assessment methods in clinical practice can substantially change risk estimation and consequently statin prescription rate. The Framingham-based risk-assessment methods and particularly the NCEP-ATPIII guidelines select for lipid-lowering treatment a higher number of subjects than those identified according to European and Italian recommendations.

Summary Objective To estimate the prevalence of hypovitaminosis D among type 2 diabetic adults and to assess the relationship between hypovitaminosis D and intimal medial thickening (IMT) of the common carotid artery, a marker of preclinical atherosclerosis. Design, patients and measurements We compared winter serum 25-hydroxyvitamin D3 [25(OH)D] concentrations in 390 consecutive type 2 diabetic patients and 390 nondiabetic controls who were comparable for age and sex. Common carotid IMT was measured with ultrasonography only in diabetic patients by a single trained operator blinded to subjects’ details. Results The prevalence of hypovitaminosis D (i.e. 25(OH)D ≤ 37·5 nmol/l) was higher in diabetic patients (34·0 vs 16·4%, P

SummaryThe relationship between liver steatosis, evaluated by ultrasonography, and various plasma haemostatic factors was examined in 64 apparently healthy males, aged 38 years. Plasma levels of factor VII clotting activity (F-VIIc), plasminogen activator inhibitor-1 (PAI-1) activity and antigen, tissue-type plasminogen activator (t-PA) activity significantly differed in men with liver steatosis (n = 31) as compared with those without steatosis (n = 33). No significant differences were found in t-PA antigen and F-VII antigen. The men with liver steatosis also had significantly higher body mass index (BMI), plasma triglyceride and 2 h post-load insulin concentrations. While the differences in plasma haemostatic factors were substantially unchanged after adjustment for BMI, they totally disappeared when further allowance was made for plasma triglyceride and 2 h insulin concentrations. In conclusion, these results indicate that liver steatosis correlates specifically with increased PAI-1, F-VIIc and decreased t-PA levels, and suggest that such a relation is largely mediated by concomitant alterations in plasma triglyceride and insulin concentrations.

OBJECTIVE: To investigate the relationship between blood pressure and the plasma fibrinolytic system and to verify whether this association was independent or mediated by one or more potential confounding factor.DESIGN: A random sample of 94 males aged 38 years subdivided into normotensives, hypertensives and those hypertensives with the highest blood pressure values.METHODS: Overall and regional obesity, blood lipids, fasting and 2-h post-load glucose, C-peptide and insulin levels, and main behavioural variables, including adipose tissue fatty acid composition (an objective index of dietary fat intake), were measured. The plasma fibrinolytic system was evaluated by determining activities and total plasma concentrations of both tissue-type plasminogen activator before and after venous occlusion, and its inhibitor plasminogen activator inhibitor type-1 (PAI-1).RESULTS: PAI-1 activity was significantly higher in the hypertensives than in the normotensives. PAI-1 antigen tended to parallel PAI-1 activity, and levels of tissue-type plasminogen activator antigen and activity tended to be lower in the hypertensives at baseline and after venous occlusion, but not significantly different from those in the normotensives. The hypertensives also had significantly higher body mass index and body fat content (measured by bio-impedance), increased plasma triglycerides, uric acid, fasting and 2-h glucose, C-peptide and insulin concentrations. In univariate linear regression analysis both systolic and diastolic blood pressures were found to be positively correlated with PAI-1 levels (r = 0.27, P < 0.01, for both). This correlation was maintained after adjustment for total body fat, fasting glucose, fasting insulin concentration or adipose tissue alpha-linolenic acid; however, it was no longer significant after adjustment for plasma 2-h insulin, 2-h C-peptide, 2-h glucose or triglyceride levels. Multivariate regression analysis revealed that only 2-h insulin and triglyceride concentration showed an independent association with PAI-1 levels.CONCLUSIONS: This study confirms that, in 38-year-old males, hypertension is associated with increased PAI-1 activity. It supports the possibility that the relationship between blood pressure and PAI-1 may reflect the overall effect of the insulin resistance syndrome (in particular hyperinsulinaemia and hypertriglyceridaemia) rather than a direct effect of blood pressure on the fibrinolytic system.

To investigate the "metabolic" syndrome in different European populations, samples of 38-year-old healthy men were randomly selected from six centers: Gothenburg (Sweden), Warsaw (Poland), Deinze (Belgium), Verona (Italy), Lumiar (Portugal), and Ede (The Netherlands). In total, 515 men were studied. Anthropometric measurements and blood pressure levels were taken by one or two operators in each center after a common operator's training course. Each blood parameter was analyzed in one laboratory. There were significant intercenter differences in mean values for anthropometric parameters, blood pressure, serum lipids (except for low-density lipoprotein [LDL] cholesterol), and fasting insulin. In particular, fasting serum insulin showed the highest values in Sweden and The Netherlands and the lowest values in Italy and Portugal. In pooled men, fasting insulin was strongly related (P < .001) to body mass index (BMI), waist to hip (WHR) and waist to thigh (WTR) circumference ratios, serum lipids (except for LDL cholesterol), and blood pressure. On the contrary, there were relevant differences in the correlation of insulin with serum lipids and blood pressure when the data were evaluated for each center. However, generally both in each center and in all centers together all these correlations disappeared after adjustment for BMI, with the exception of the correlation with serum triglycerides. In pooled men, multiple regression analysis showed an independent association of fasting insulin, BMI, and WHR with serum triglyceride (P < .001). On the contrary, total, LDL, and high-density lipoprotein (HDL) cholesterol and blood pressure values showed independent associations with BMI and/or WHR but not with fasting insulin in multivariate models.2+ off

Increased plasma levels of plasminogen activator inhibitor-1 (PAI-1), responsible for reduced fibrinolytic activity, have been shown to be an important risk factor for cardiovascular disease. PAI-1 plasma levels are influenced by several factors which have not yet been fully clarified, including dietary fat intake. The relationships of PAI-1 with other cardiovascular risk factors are still not well known. In a random sample of 38-year-old healthy men (n = 94), the association of PAI-1 plasma levels (measured as activity and antigen) with anthropometric parameters, serum lipids, fasting and 2 h insulin and glucose concentration after oral glucose-load was analysed. Furthermore, the fatty acid composition of subcutaneous adipose tissue, as an objective and reliable index of dietary fat intake, was measured. The univariate analysis showed that plasma levels of PAI-1 were significantly associated with body mass index (BMI) (r = 0.37, P < 0.001), waist/hip ratio (WHR) (r = 0.26, P < 0.01), serum triglycerides (r = 0.47, P < 0.0001), HDL/total cholesterol ratio (r = -0.35, P < 0.001), fasting and 2-h insulin (r = 0.27, P < 0.01 and r = 0.34, P < 0.001) and glucose concentrations (r = 0.25, P < 0.05 and r = 0.28, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Background. A potentially modifiable and underestimated risk factor for cardiovascular disease (CVD) in subjects with kidney dysfunction is 25-hydroxyvitamin D deficiency, although the relationship between inadequate vitamin D status and manifest CVD in type 2 diabetic subjects with mild kidney impairment has not been extensively examined. Methods. We evaluated the relationship between serum 25-hydroxyvitamin D concentrations, baseline kidney function (estimated using the modification of diet in renal disease equation) and manifest CVD (myocardial infarction, angina, ischaemic stroke, coronary revascularization or carotid endarterectomy) among 462 consecutive patients with type 2 diabetes. Results. In the whole population, the mean age was 62 � 7 years, 64% were men, 76.3% had hypertension and the mean estimated glomerular filtration rate (GFR) was 94 � 33 ml/min/1.73 m 2 . Kidney function was strongly and inversely associated with CVD. In multivariate logistic regression analysis, there was an inverse association between serum 25-hydroxyvitamin D concentrations and prevalent CVD [odds ratio 0.95 (95% CI 0.92–0.98; P ¼ 0.001)] in the whole population independent of baseline kidney function and other known risk factors. Additionally, the association between serum 25-hydroxyvitamin concentrations and CVD [odds ratio 0.97 (95% CI 0.94–0.99; P ¼ 0.045)] remained statistically significant in participants in the lowest estimated GFR tertile after adjustment for potential confounders. Conclusions. Decreased 25-hydroxyvitamin D concentrations are independently associated with prevalent CVD in type 2 diabetic patients with mild kidney dysfunction.

In this study in 437 women born in 1948 selected from five European towns we show that several anthropometric measurements are consistently and significantly associated with a metabolic risk profile in premenopausal women of 38 years of age. Among the circumferences, breast and waist circumference were, after adjustment for body mass index positively correlated with diastolic blood pressure, serum total cholesterol, HDL-cholesterol (negative associations), serum triglycerides, and serum insulin. The optimal level for measuring waist circumference was determined as being midway between the lower rib margin and the superior anterior iliac crest. Circumference ratios generally did show less consistent and similar or lower correlations with diastolic blood pressure, serum cholesterol and serum insulin. Waist/thigh circumference ratio showed the strongest partial associations with HDL-cholesterol and serum triglycerides among all anthropometric variables studied. The authors conclude that, independently of the degree of fatness, indicators of truncal fat distribution (in the region of the breast as well as the abdomen) are related to an unfavourable risk profile in European premenopausal women. The study gives a rationale for selecting the most informative anthropometric measurements to be added to height and weight in epidemiological studies.

Abdominal fat distribution is associated with increased incidence of cardiovascular disease and stroke [ 1,2]. Metabolic risk factors are likely to be involved in this association since abdominal fat accumulation is related to alterations of serum lipids, blood pressure, insulin action and glucose tolerance [2]. Waist to hip and waist to thigh circumference ratios are widely used indicators of abdominal fat distribution in epidemiological and clinical studies [1,3,4]. Since men have both higher metabolic risk factors and larger abdominal fat accumulation than body fatand age-matched premenopausal women, in this study we aimed at evaluating the main metabolic risk factors in women with the same circumference ratios as men.

We studied fat distribution and metabolic risk factors in 434 38-year old women selected from population registrars in 5 cities in different parts of Europe. In the present study we focussed on the geographical variation in serum concentrations of free testosterone and its relation to measures of obesity, fat distribution and indicators of cardiovascular risk (serum lipids, insulin, and blood pressure). There were significant differences in free testosterone levels (F = 5.4, p less than 0.001) with lowest levels in Polish women (mean +/- SEM: 1.56 +/- 0.08 pg/ml) and highest in women from Italy (2.07 +/- 0.12 pg/ml). In the pooled data, free testosterone levels were correlated with several anthropometric variables (strongest with subscapular/triceps ratio r = 0.27, with subscapular skinfold and waist/thigh circumference ratio r = 0.25 p-values less than 0.001). In addition, free testosterone was positively correlated with serum total cholesterol (r = 0.11), HDL/total cholesterol fraction (r = 0.12), serum insulin (r = 0.20) and diastolic blood pressure (r = 0.15). These associations remained significant after adjustment for body mass index and waist/thigh ratio (not for diastolic blood pressure) but were no longer significant after further adjustment for insulin levels. There were considerable differences in strength of the associations mentioned between the 5 centers. We conclude that degree of obesity, fat distribution and serum levels of free testosterone all, to a limited degree, contribute to the metabolic profile of randomly selected 38-year old women but that adjustment for such variables increases the differences in metabolic profiles between women from different centers of Europe.

Accumulating research suggests that low 25-hydroxyvitamin D3 [25(OH)D] concentrations may be inversely associated with type 2 diabetes (1,2,3), metabolic syndrome (4,5), insulin resistance (6), and cardiovascular disease (CVD) (7). Much remains to be learned, however, about the relationships between vitamin D status, metabolic syndrome, and CVD. Furthermore, the published data in humans arguing that hypovitaminosis D is a CVD risk factor remain conflicting (8,9). Because this topic has received scant attention and the available information on associations between vitamin D status and CVD among type 2 diabetic adults was lacking, we examined the relationships between serum 25(OH)D concentrations and prevalent CVD in type 2 diabetic adults. We studied 459 consecutive type 2 diabetic outpatients attending our clinic after exclusion of those with recent acute illness or advanced chronic liver or renal disease and those who were taking medications known to alter vitamin D metabolism. The control group consisted of 459 (64% men, age 61 ± 6 years) age- and sex-matched nondiabetic volunteers. Biochemical blood measurements were determined by standard laboratory procedures. Serum 25(OH)D concentrations were measured during winter months using an automated chemiluminescence immunoassay (DiaSorin Liaison). Metabolic syndrome was defined according to the Adult Treatment Panel III criteria (10). Presence of coronary (myocardial infarction, angina, or …

Elevated plasminogen activator inhibitor-1 (PAI-1) plasma levels, responsible for reduced fibrinolysis, are associated with animal and human obesity and with increased cardiovascular disease. The expression of PAI-1 has been found recently in animal and human adipose tissue. Factors and mechanisms regulating such an expression remain to be elucidated. In omental and/or subcutaneous biopsies from obese non-diabetic patients, incubated in Medium 199, we have confirmed that human adipose tissue expresses PAI-1 protein and mRNA; furthermore we have demonstrated that such an expression is clearly evident also in collagenase isolated human adipocytes and that it is stimulated by incubation itself and enhanced by exogenous human tumor necrosis factor-alpha (h-TNF-alpha). Since human adipose tissue produces TNF-alpha, to further characterize the relationship of PAI-1 to TNF-alpha, human fat biopsies were also incubated with Pentoxifylline (PTX) or Genistein, both known to inhibit endogenous TNF-alpha through different mechanisms. PTX caused a dose-dependent decrease of basal PAI-1 protein release, reaching 80% maximal inhibitory effect at 10(-3)M, the same inhibitory effect caused by Genistein at 100 microg/ml. This was associated to a marked inhibition of PAI-1 mRNA and of endogenous TNF-alpha production. Furthermore, when human fat biopsies were incubated in the presence of polyclonal rabbit neutralizing anti-human TNF-alpha antibody (at a concentration able to inhibit 100 UI/ml human TNF-alpha activity), a modest but significant decrease of the incubation induced expression of PAI-1 mRNA was observed (19.8+/-19.0% decrease, P = 0.04, n = 7). In conclusion, the results of this study demonstrate that PAI-I expression is present in human isolated adipocytes and that it is enhanced in human adipose tissue in vitro by exogenous TNF-alpha. Furthermore our data support the possibility of a main role of endogenous TNF-alpha on human adipose tissue PAI-1 expression. This cytokine, produced by human adipose tissue and causing insulin resistance, may be a link in the clinical relationship between insulin-resistance syndrome and increased PAI-1 plasma levels.

In this study the authors examined the relationships of plasma factor VII (F-VII) to adipose tissue fatty acid composition, as an objective index of the habitual dietary fat intake, as well as to a number of other atherogenic risk factors in 60 healthy male volunteers (aged 38 years). Significant positive correlations were found between plasma F-VII [measured as antigen (F-VIIAg) and coagulant activity, using bovine thromboplastin (F-VIIbt)] and body mass index (BMI), waist-thigh girth ratio (WTR), cigarette smoking and plasma triglyceride concentration. After adjustment for BMI, only plasma triglycerides remained positively correlated with F-VII (r = 0 center dot 27, P = 0 center dot 03, and r = 0 center dot 29, P < 0 center dot 01, for F-VIIbt and F-VIIAg respectively). A significant positive relation was found between F-VII and the total proportion of fatty acid as monounsaturated fatty acid (r = 0 center dot 26, P < 0 center dot 05, for F-VIIAg), whereas inverse relations were found between F-VII, the total proportion of fatty acid as polyunsaturated fatty acid (r = -0 center dot 26 and r = -0 center dot 25, P < 0 center dot 05, for F-VIIbt and F-VIIAg respectively), polyunsaturated-saturated fat ratio (r = -0 center dot 25, P < 0 center dot 05, for F-VIIbt) and, more significantly, between F-VII and adipose-tissue alpha-linolenic acid (r = -0 center dot 29, P < 0 center dot 01, for F-VIIbt and r = -0 center dot 49, P < 0 center dot 001, for F-VIIAg). All these correlations remained significant after matching for BMI. In a multiple linear regression analysis, only adipose tissue alpha-linolenic acid was a negative and independent predictor of F-VIIAg (P = 0 center dot 004) and, at borderline significance, of F-VIIbt (P = 0 center dot 061) when allowance was made for BMI, WTR, smoking and plasma triglycerides. In conclusion, this study shows significant relations between F-VII and adipose tissue fatty acid composition in healthy male individuals; it supports the possibility that adipose tissue poly-unsaturated fatty acids, derived from dietary intake, play a role in the relation between F-VII and coronary heart disease (CHD), thus suggesting that high dietary polyunsaturated fatty acid intake (especially alpha-linolenic acid) may reduce the risk for CHD by an improvement of a number of risk factors, including a lowering of plasma F-VII (both activity and antigen).

Abstract The associations between abdominal visceral fat and the plasma hemostatic system were examined in 38-year-old healthy men (n=52) with a wide range of fatness and fat distribution. Plasma hemostatic factors and metabolic parameters, including glucose tolerance, were measured, and body fatness and adipose tissue distribution were assessed by using computed tomography. The men with more visceral fat (ie, higher than the median value [n=26]) had a less favorable metabolic profile than the men with less visceral fat (n=26). They also had significantly ( P P

Some studies have reported an inverse correlation between serum cholesterol level and risk of cancer. This correlation might be due to a decrease in serum retinol, a lipid-soluble vitamin that controls cell proliferation and differentiation. We evaluated the influence of cholesterol-lowering therapy on serum retinol in 102 subjects (mean +/- SE: aged 47.1 +/- 4.1 years; body mass index, 23.8 +/- 0.6 kg/m2) with primary hypercholesterolemia treated for 2 years with different therapeutic protocols. Twenty-two subjects had been treated with diet alone, 35 with diet and fibrates, 37 with diet and hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitors (statins), and eight with diet and cholestyramine. Postabsorptive serum retinol, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride levels were determined at baseline and every 3 months. Baseline TC and LDL-C were significantly lower in the diet-treated group than in other groups. No intergroup differences were found in pretreatment levels of triglycerides and serum retinol. After 2 years of treatment, TC and LDL-C serum levels were not significantly decreased in the diet-alone group, whereas they were decreased by 20% and 24%, respectively, in the gemfibrozil group, 28% and 34% in the statins group; and 21% and 27% in the cholestyramine group. In the entire population (N = 102), serum retinol was 3.46 +/- 0.08 mumol/L before therapy and 3.76 +/- 0.07 after 2 years of therapy (P < .001). Serum retinol increased in diet- and statin-treated groups, but not in fibrate- and resin-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent prospective studies have reported an independent association between fibrinogen plasma levels and risk of cardiovascular events. Aim of this study was to investigate the relationships between fibrinogen level and conventional cardiovascular risk factors in a random sample of 38 year-old apparently healthy men (n = 94), and to verify whether the fatty acid composition of the diet might influence those relations. Anthropometric measurements, serum lipids, blood pressure, and smoking habits were evaluated. In addition, fasting and after glucose-load serum glucose and insulin concentrations were measured. The most significant difference in fibrinogen level was found among the tertiles of fasting serum insulin (F-ANOVA = 4.5; P < 0.01) with the highest plasma fibrinogen values in the third insulin tertile, whereas body mass index (BMI), waist/hip circumference ratio (WHR) and serum triglycerides were more weakly related. The current smokers had substantially higher levels of fibrinogen than subjects who never smoked (P < 0.001). A multivariate regression analysis showed that, among the above reported variables, only serum insulin and smoking were independently associated with plasma fibrinogen. Furthermore, as the possible association between fatty acid composition of the diet and fibrinogen level regards, we have examined the fatty acid composition of adipose tissue, as a good and objective index of quality of the dietary fat intake. It was found that, fibrinogen level was not associated with any adipose tissue fatty acid. In conclusion, this study performed in a random sample of healthy men indicates an independent relationship of fasting insulin and smoking to fibrinogen plasma level.

Fat biopsies were taken from 327 men aged 38 years from five different European communities in 1988-1989. Linoleic acid content varied widely (F = 110.6, p less than 0.001) and was lowest in men from Poland (8.6%) and highest in men from Belgium (16.7%). Adipose tissue content of alpha-linolenic acid was subject to less variation (F = 13.9, p less than 0.001) and was lowest in men from Italy (0.5%) and highest in men from Sweden and the Netherlands (0.9%). In analysis combining information from all centers, linoleic acid was negatively correlated to low density lipoprotein cholesterol (r = -0.15, p less than 0.01) and total cholesterol (r = -0.17, p less than 0.01). alpha-Linolenic acid was negatively correlated to serum triglycerides only (r = -0.14, p less than 0.05). These fatty acids were not related to body mass index, waist/hip ratio, or smoking habits. The authors conclude that there are major differences in the fatty acid composition of adipose tissue in different European populations but that these do not explain the significant differences in serum high density lipoprotein cholesterol and serum triglycerides among the different populations.

We studied male/female differences in serum lipids in randomly selected 38-year-old men (n = 337) and women (n = 342) from various cities in The Netherlands, Sweden, Italy, and Poland. Overall, men had higher triglycerides and total cholesterol levels and lower HDL-levels compared to women (P less than 0.001). Adjustment for smoking habits, city, and body mass index did not remove the gender difference. Further adjustments for waist circumference alone and waist/hip and waist/thigh circumference ratio removed the gender differences in serum triglycerides and total cholesterol. Only adjustment for waist/thigh ratio removed the gender difference in HDL-cholesterol but linear relationships were different in men and women. The average male/female difference in serum lipids, particularly for total and LDL-cholesterol varied considerably among centers. In analyses of the data from the separate centers we found that sex differences in serum triglycerides and HDL-cholesterol in all 4 centers disappeared when adjusted for waist circumference alone and for waist/hip and waist/thigh ratio. For total and LDL-cholesterol, however, adjustment for circumference ratios tended to increase the male/female difference in 2 of the 4 centers. It is concluded that, in European men and women, fat distribution may be responsible for male/female differences in serum triglycerides but that such conclusions are less clear for HDL-, total- and LDL-cholesterol.

A study on 512 38-year-old European men selected from 6 different towns was conducted. There were significant differences between the centers in averages of anthropometric variables (except for thigh circumference), serum lipids (except for LDL-cholesterol), and blood pressure. In the pooled material, body mass index (BMI) as well as waist circumference, waist/hip ratio and waist/thigh ratio and subscapular skinfold were positively correlated to serum triglycerides, total cholesterol, LDL-cholesterol, and blood pressure and negatively with HDL-cholesterol. After adjustment for BMI, waist, waist/hip, and waist/thigh were all still significantly correlated with serum triglycerides (P less than 0.001). In addition, waist/hip and waist/thigh ratio showed significant partial correlations with total cholesterol (r = 0.16, P less than 0.001, r = 0.10, P less than 0.05 respectively), and diastolic blood pressure (r = 0.10, P less than 0.05, r = 0.09, P less than 0.05 respectively). In addition, waist/hip was, independently of BMI, correlated to LDL-cholesterol (r = 0.12, P less than 0.01), and waist/thigh ratio with HDL-cholesterol (r = -0.12, P less than 0.01). The partial association between waist/thigh with HDL cholesterol became insignificant after adjustment for smoking habits and physical activity. Adjustment for differences in anthropometric measurements did not explain the differences in serum lipids and blood pressure between the centers. The authors conclude that indicators of body fat distribution are associated with unfavorable risk profiles for cardiovascular disease in European men covering a large geographical and cultural variety and a wide range of body measurements and cardiovascular risk factors.

The authors studied 512 European men all born in 1950 from six different towns in the period October 1988 to May 1989. Anthropometric measurements were taken, including weight, height, and circumferences (waist, hip, thigh). Educational level, activity scores and information on smoking habits were obtained from a questionnaire. Higher educational level was associated with lower body mass index, waist/hip ratio, and waist/thigh ratio. The sports activity score was negatively related to waist/hip ratio (beta +/- standard error of the mean (SEM): -0.009 +/- 0.003) and waist/thigh ratio (-0.041 +/- 0.007), and this could be attributed to a negative relation with waist circumference and a positive relation to thigh circumference. Smoking habits were not related to body mass index but heavy smokers had larger waist circumferences (difference +/- SEM: 1.4 +/- 0.5 cm) as well as higher waist/hip ratios (difference +/- SEM: 0.014 +/- 0.005) and waist/thigh ratios (0.043 +/- 0.013) compared with men who never smoked. These associations between activity scores and smoking habits and fat distribution remained after adjustment for each other and for body mass index and educational level. The authors conclude that physical activity and smoking are independently related to indicators of fat distribution and may be potential confounders in the relations between fat distribution, risk factors, and disease.

Samples of 38-year-old women were randomly selected from five European centers: Ede (The Netherlands), Warsaw (Poland), Gothenburg (Sweden), Verona (northern Italy), and Afragola (Naples-southern Italy). In total, 452 healthy women were studied. Anthropometric measurements were taken by one operator in each country after common training of all operators and blood parameters of all women were determined in one laboratory. Body mass index (BMI) was different among centers, mainly due to the higher values in southern Italy. Women from southern Europe had more central fat distribution than women from north European centers. Fasting serum insulin was higher in women from Poland and The Netherlands than in the other three centers. After adjustment for BMI, fasting insulin was significantly related to subscapular skinfold, subscapular to triceps skinfold ratio, waist circumference, and waist to thigh circumference ratio, although the partial correlations varied somewhat between the centers. In the pooled data, waist circumference showed the highest correlations with fasting serum insulin when adjusted for BMI. Fasting serum insulin showed significant partial correlations, adjusted for BMI, with lipid profile and blood pressure only in women from the two Italian centers. In the pooled data, fasting serum insulin was significantly positively correlated with serum triglycerides and total cholesterol and negatively to high-density lipoprotein (HDL) cholesterol and HDL/total cholesterol, independently of BMI and waist circumference. While blood pressure was not related to insulin in the pooled women, when adjusted for BMI and waist circumference; here as well, there were some differences in relationships between the centers.(ABSTRACT TRUNCATED AT 250 WORDS)

Aim of the present study was to evaluate whether the inhibitory effect of somatostatin on pancreatic B-cell secretion is normal in nondiabetic obese subjects. For this purpose plasma C-peptide concentrations were measured in 10 nondiabetic obese subjects and 10 nonobese healthy controls during a 4-h hyperglycemic (11 mmol/l) glucose clamp. Somatostatin was infused (2.5 nmol/min) during the third hour of the study period in order to inhibit glucose-stimulated B-cell secretion. Fasting C-peptide averaged 0.46 +/- 0.04 nmol/l (mean +/- SEM) in nonobese subjects, and 0.85 +/- 0.08 nmol/l in obese patients (P less than 0.001). In the period 0-120 min the area under the plasma C-peptide curve was significantly higher in obese than in nonobese subjects (292 +/- 23 vs. 230 +/- 17 nmol/l x 120 min, P less than 0.05), however, in the last 20 min of the glucose infusion period without somatostatin (100-120 min) plasma C-peptide was not significantly different in the two groups (2.94 +/- 0.32 nmol/l in nonobese subjects and 3.21 +/- 0.19 nmol/l in obese patients, p = NS). During somatostatin infusion while maintaining hyperglycemia, plasma C-peptide decreased in both groups, and in the period 160-180 min it averaged 0.89 +/- 0.12 nmol/l in control subjects and 0.93 +/- 0.08 nmol/l in obese patients (P = NS), with a percent reduction similar in the two groups (70 +/- 2% in controls and 71 +/- 2% in obese patients). After discontinuing somatostatin infusion, plasma C-peptide increased to concentrations which were higher in obese than in nonobese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

‘Department of Human Nutrition, Wageningen University, P.O. Box 8129, 6700 EV Wageningen, The Netherlands; %stitute of Clinical Medicine, University of Verona, Italy; 3National Institute of Food Science, Warsaw, Poland; 4Department of Medicine, tiniversity of Giiteborg, Sweden; SDepartment of Endocrinology, University of Ghent. Belgium; 6Department of Internal Medicine, University of Naples, Italy; 7National Institute of Health, Lisbon, Portugal

The in vivo suppressive effect of glucose and insulin on plasma free fatty acid concentrations was investigated in obese subjects with (n = 6) and without (n = 6) Type 2 (non-insulin-dependent) diabetes mellitus during a 4h-hyperglycemic glucose clamp (about 11.2 mmol/l). Somatostatin was infused (250 micrograms/h) during the third h of glucose clamp to inhibit glucose-stimulated insulin secretion. Plasma insulin values were similar in the two groups at fasting and all throughout the study (F = 0.04; p = NS, two way analysis of variance), while the amount of glucose metabolized during the clamp was lower in diabetic subjects. Plasma free fatty acid concentrations, which were similar in the two groups at fasting, decreased during hyperglycemia and glucose-induced hyperinsulinemia (0-120 min; 180-240 min), and rose during hyperglycemia and somatostatin-inhibited insulin secretion (120-180 min). However, plasma free fatty acid concentrations were significantly higher in diabetic subjects all along the study period both in absolute terms (F = 11.4; p less than 0.0001) and when individual data were recalculated as percent of fasting value (F = 13.3; p less than 0.0001). Our data suggest that suppressibility of fasting plasma free fatty acids is lower in obese Type 2 diabetes in comparison with obese non-diabetic subjects.

Seventy-six obese female outpatients underwent controlled 1000 kcal diets (50% carbohydrate, 25% fat, 25% protein). Prior-to-treatment data underwent "step-wise" multiple regression analysis to investigate the possibility of predicting body weight after 6 months of treatment (y), Body weight can be forecast using a linear regression function. This function, based on initial weight (x1) and adipose cell weight (x2), uses the equation y = 9.75 + 0.87x1 - 8.41x2 (F = 696.53; P less than 0.001; R2 = 0.95). Afterwards, patients were subdivided into three groups according to the difference between 6th and 12th month body weights: weight loss, weight stable, and weight increase groups. Weight gaining patients showed a significantly higher mean fat cell number, weight lossers had a higher mean adipose cell weight than the other two groups.

Starvation causes insulin resistance which is partly due to decrease of insulin action on glucose transport in target cells. Preliminary data from other authors suggest that starvation is associated with an increase of the time necessary for insulin to exert its maximum effect on glucose transport. In order to verify this finding, 3-O-methylglucose (3OMG) transport was studied in isolated rat adipocytes from starved and fed rats. The total intracellular space for 3OMG was not modified by 48h starvation. After 48h starvation, 3OMG transport into fat cells was less responsive to maximum insulin concentration than in controls: 33 +/- 2% (controls) vs 23 +/- 4% (starved) of total glucose space, p less than 0.05; the sensitivity to insulin was normal or even increased in comparison to controls: 50% of maximum effect was reached at 42 microU/ml insulin in controls and at 26 microU/ml insulin in starved animals. We could not find any effect of starvation on the time-response curves of insulin action.

Eighty-five randomly selected women, all born in 1948, were studied. All were nonobese (body mass index [BMI], 23.3 +/- 0.3 (means +/- SD]). The relationships between three indicators of fat distribution (waist-hip, waist-thigh, and subscapular-triceps ratios) and hormonal and metabolic variables were studied. Increased androgenic activity (ratio of free testosterone [T] to total testosterone [free-total T ratio]) and degree of obesity (BMI) were independently related to increased waist-hip ratio. Waist-hip and waist-thigh ratios showed higher correlations with all metabolic variables than did the triceps-subscapular skinfold thickness ratio except for diastolic blood pressure. After adjustment for BMI and free-total T ratio, the waist-hip ratio was still significantly positively related to total cholesterol and C peptide and negatively to the HDL-total cholesterol ratio. In such multiple regression, BMI was independently related to insulin, C peptide, and diastolic blood pressure. The free-total T ratio was independently related to triglycerides. BMI and waist-hip ratio gave important complementary information about risk factors for diseases such as cardiovascular disease and diabetes mellitus.

Brown adipose tissue (BAT), obtained from the axillary and perirenal regions of newborns 24–48 h after death, was digested with collagenase and the free cells were cultured. Only the cultures of cells from tissue obtained later than 24 h post mortem were successful. These cells grew slowly to reach confluence. Their typical mitochondria gradually disappeared, being replaced by untypical mitochondria. After confluence, the cells accumulated large amounts of lipid in non-coalescent multivacuolar depots. This model can be useful for the study of the metabolic and morphological features of human brown fat cells.

In order to verify whether intersite differences exist in glucose metabolism of subcutaneous human adipose tissue, basal and insulin-stimulated 14C-1-glucose incorporation into triglycerides and the activities of some enzymes of glucose disposal were tested in abdominal and gluteal adipose tissue of 31 nondiabetic obese otherwise healthy women during isocaloric diet and after 2 weeks of very-low-calorie-protein-sparing modified diet. Basal 14C-1-glucose incorporation into triglycerides was quite similar in the adipose tissue of the two sites, and it was not influenced by dietary restriction. Insulin stimulated this metabolic activity to the same extent in both sites during isocaloric diet; after hypocaloric diet this effect of insulin was slightly decreased in adipose tissue of the abdominal site and completely abolished in the gluteal site. No enzymatic activity was different between the examined subcutaneous regions during the isocaloric diet; after very-low-calorie intake, hexokinase activity decreased in both sites, once again more markedly in the gluteal one; glucose-6-P-dehydrogenase activity decreased in the adipose tissue of the gluteal region only. These data suggest that glucose metabolism of the adipose tissue of the gluteal region is particularly decreased by severe calorie restriction. Therefore, since lipolysis does not occur at a higher rate in gluteal adipose tissue during calorie restriction, this tissue seems to undergo a resting metabolic phase during hypocaloric diet.

We compared estimates of in vivo insulin action derived from insulin tolerance tests (ITT) and euglycemic and hyperglycemic glucose clamp studies in 17 normal subjects and 19 patients with various diseases characterized by insulin resistance. Fifteen subjects underwent an ITT and a euglycemic clamp study, 17 subjects underwent an ITT and a hyperglycemic clamp study, and 4 subjects underwent all 3 tests. The ITT consisted of a bolus iv injection of regular insulin (0.1 U/kg BW). The plasma glucose disappearance rate during the 3- to 15-min period following the insulin injection was taken as a measure of insulin action. In both euglycemic and hyperglycemic clamp studies, which were carried out with standard techniques, the ratio between the amount of glucose infused to maintain glycemia at the desired level and the mean plasma insulin concentration from 60-120 min (M) (euglycemic clamp studies) or 20-120 min (I) (hyperglycemic clamp studies) was used as a measure of insulin action. A close correlation was found between plasma glucose disappearance rate and the M/I ratio during either the euglycemic (r = 0.811; P less than 0.001) or the hyperglycemic (r = 0.826; P less than 0.001) clamp studies. These results suggest that the 15-min ITT is suitable as a simple and rapid estimation of in vivo insulin action when glucose clamp studies are not feasible, as in large series of subjects or serial studies.

Specimens of human adipose tissue were maintained in vitro for one week and cell size as well as metabolic rates determined before and after the culture period. Large fat cells from obese donors decreased towards 'normal' cell size while this was not the case for cells from non-obese donors. This decrease was probably due to the increased lipolysis found while glucose incorporation was unchanged. Analogous to the findings with obese subjects placed on a weight-reducing regimen, the present data show that when large fat cells are removed from their anabolic, hyperinsulinic environment, 'normalization' in cell size occurs.

Several authors have not been able to find any antilipolytic effect of insulin in adipose tissue "in vitro". We investigated the possible role of cell size and/or age of donors on this phenomenon. The lipolytic rates (glycerol release per cell) were lower in the small cells of the 4-6 weeks old rats than in the larger cells of the 25-30 weeks old animals; however, the difference disappeared when the data were expressed per unit of cell surface area. Insulin (0.5-50 ng/ml) failed to inhibit both maximally and submaximally noradrenaline stimulated lipolysis in the adipocytes of the young rats, but its antilipolytic action was fully restored by using glucose-free medium. Therefore, at our experimental conditions, a glucose dependent factor, possibly involving the preferential hydrolysis of newly synthetized triglycerides, seems to blunt or to mask the insulin induced inhibition of glycerol release. Relatively higher rates of glucose metabolism and a lower lipolysis in small fat cells might explain the difference in the action of insulin on glycerol release in the adipose tissue of young rats as compared to the older ones.

Sedimentable cells from human adipose tissue of different origins were cultured under conditions when cell multiplication was prevented but lipid filling optimized (suspension culture). In this way an estimation was obtained of the number of in vivo determined adipose precursor cells (preadipocytes) which were not filled with lipid. Under these conditions no cells from adult, non-obese subjects developed to adipocytes. Cells developing to adipocytes constituted less than 0.02% and 1% of adipocytes in tissues from obese adults and from children, respectively. It was concluded that in vivo determined adipocyte precursor cells (preadipocytes, lipid-free fat cells) are not present in a significant number in human adipose tissue either from adults or from children as tested with the method employed, allowing detection of a large number of such cells in adipose tissue from small rats.

Adipocytes in intact brown adipose tissue show multivacuolar lipid deposit and mitochondria of 'typical' morphology. Cultured brown adipocytes retain the multivacuolar lipid deposit, while 'typical' mitochondria degenerate and 'atypical' organelles appear instead of the former. Since evidence exists that catecholamines deeply influence brown adipose tissue morphology and function in vivo, we undertook the present ultrastructural investigation to assess whether exposure of cultured brown fat cell to noradrenaline could prevent (or induce regression of) the in vitro morphological modifications of brown adipocytes. Brown adipocytes cultured for 8 h in the presence of noradrenaline (5 X 10(-5) M) had a larger mitochondrial area (i.e. a larger percentage of cytoplasm occupied by non-degenerating mitochondria) in comparison with control cells, as assessed by morphometry; this was due to larger number of mitochondria in noradrenaline-treated cells. Moreover, a number of cells with mitochondria strictly resembling those of the intact tissue were visible in noradrenaline-treated cultured after 8 hr, while 'typical' mitochondria were no longer observed in parallel control cultures. After 5 days of culture without hormone addition, exposure to noradrenaline (5 X 10(-5) M) did not induce quantitative modifications of 'atypical' mitochondria or changes of their ultrastructure up to 12 hr. However, reduction in size of the lipid deposit and activation of both rough endoplasmic reticulum and Golgi apparatus were evident in noradrenaline-treated adipocytes in comparison with non-treated cells.

In the spring of 1986, the authors studied the relation between body mass index and anthropometric indicators of fat distribution to cardiovascular risk factors (serum lipids and blood pressure) in approximately 450 women aged 38 years randomly selected from population registers in five European centers. Waist circumference was, in univariate analysis, more strongly related to triglycerides (positive association) and high density lipoprotein (HDL) cholesterol (negative association) than to body mass index or any other anthropometric measurement. Among the centers, we observed considerable variation in the strength of the associations between anthropometric measurements and risk factors. After adjustment for body mass index, most associations between skinfolds and circumferences and risk factors were reduced to statistically nonsignificant levels, but in some centers there were independent contributions of circumferences or circumference ratios to serum lipids, but not to blood pressures. Adjustment for differences in body mass index and fat distribution between the centers did not reduce the differences in cardiovascular risk factors between the different centers but instead revealed that serum cholesterol levels were lowest in the centers of southern Europe (Italy) and that HDL cholesterol levels were higher. Blood pressure was highest in the Swedish women. We conclude that in some female populations, but not in others, indicators of fat distribution are related to serum lipids but not to blood pressure, independent of body mass index.