Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1

Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor -1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.     

Impact of adipose tissue on plasma plasminogen activator inhibitor-1 in dieting obese women.

The increased incidence of cardiovascular diseases in obese subjects could be partially attributed to impaired fibrinolysis due to elevated plasma levels of tissue plasminogen activator inhibitor 1 (PAI-1). The associations between changes in plasma PAI-1, metabolic variables, and adipose tissue during weight loss and regain were studied in 52 healthy, premenopausal, obese women participating in a weight reduction program with a hypocaloric diet. PAI-1, insulin, triglyceride, leptin, and adipsin levels were determined at entry, after the first week, after completion of the program, and after 5 months of follow-up. In the 33 obese women who completed the program, decreases in PAI-1 antigen (-54%), PAI activity (-74%), and leptin (-51%), but not of adipsin, were observed. Changes in PAI-1 were associated with changes in body mass index (BMI), body fat, leptin, and insulin. The decreased level of PAI-1 remained low after follow-up in the 14 women who maintained their reduced weight but increased in the 16 women who regained weight. This increase in PAI-1 was correlated with an increase in body fat and leptin. On multivariate analysis, BMI was the major determinant of PAI-1 level. In conclusion, during weight reduction with a hypocaloric diet, the decrease in PAI-1 is more closely related to changes in adipose tissue than to changes in metabolic variables, suggesting a significant role for adipose tissue in regulating plasma levels of PAI-1.     

Different metabolic correlations of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 in non-obese type 2 diabetic patients

We investigated the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1) and their relation with clinical and metabolic parameters in non-obese type 2 diabetic patients. The plasma levels of TAFI and PAI-1 were evaluated in 47 non-obese type 2 diabetic patients and 31 normal subjects. The intra-abdominal visceral and subcutaneous fat areas were measured by computed tomography (CT). The degree of insulin resistance was evaluated by the euglycemic-hyperinsulinemic clamp technique using artificial pancreas. The plasma levels of TAFI (169.0+/-108.8% versus 103.7+/-52.3%; p<0.001, mean+/-S.D.) and PAI-1 (82.7+/-54.5ng/ml versus 52.9+/-51.7ng/ml; p<0.05) were significantly higher in non-obese type 2 diabetic patients than in normal subjects. Univariate analysis showed that the plasma TAFI levels are significantly and inversely correlated with the glucose infusion rate (GIR) (r=-0.42, p<0.005) in all diabetic patients. Moreover, the plasma levels of TAFI were significantly correlated with fasting plasma glucose levels (r=0.47, p<0.001) and HbA(1c) (r=0.38, p<0.005) in all subjects. The plasma levels of PAI-1 were significantly and proportionally correlated with the visceral fat area (r=0.42, p<0.005) and body mass index (r=0.33, p<0.05). There was no significant correlation between plasma levels of TAFI and PAI-1 (r=0.04). These results show that the plasma levels of TAFI and PAI-1 differently correlate with insulin resistance and visceral fat accumulation, suggesting that different factors are implicated in the plasma elevation of TAFI and PAI-1 in non-obese type 2 diabetes mellitus.     

2型糖尿病血清脂联素与心血管相关标志物相关性的研究

目的检测老年糖尿病(DM)患者血清脂联素(APN)与3个心血管相关标志物水平并探讨二者之间的相关关系。方法将70例老年受试者分为3组:正常对照组、老年DM未合并大血管病变组(DM1)和老年DM合并大血管病变组(DM2),检测血清APN与心血管相关标志物-血浆C反应蛋白(c-reactive protein,CRP)、Ⅰ型血浆纤溶酶原活化抑制剂(plasminogen activator inhibitor type-1,PAI-1)和血清基质金属蛋白酶-9(matrx metalloproteinase-9,MMP-9)的水平变化。结果从正常对照组、DM1到DM2组血清APN水平依次下降,各组间差别均具有显著意义(均P<0.01)从正常对照组、DM1到DM2组,CRP、PAI-1、MMP-9的水平逐渐升高,CRP、PAI-1升高在各组间均具有显著性(均P<0.05),MMP-9在DM2组开始出现显著升高(P<0.01),DM1组较正常对照组升高没有显著意义。APN水平与CRP、PAI-1、腰围、BMI、WHR及FBG、2h PBG、HbA1C、TG呈显著负相关。多元逐步回归分析显示APN与CRP(r2=0.18)、PAI-1(r2=0.16)、WHR(r2=0.21)及HbA1C(r2=0.19)具有高度的相关性(均P<0.05)结论APN可能是老年DM动脉粥样硬化发生发展中的保护因素。     

Thrombin activatable fibrinolysis inhibitor antigen levels are inversely correlated with plasminogen activator inhibitor-1 antigen levels in hyperthyroid patients

Both increased and decreased fibrinolytic activity have been reported in patients with hyperthyroidism. Elevated levels of plasma plasminogen activator inhibitor-1 (PAI-1) antigen have been found in hyperthyroid patients. Thrombin activatable fibrinolysis inhibitor (TAFI) is a novel plasma protein, which inhibits fibrinolysis through removal of C-terminal lysines from partially degraded fibrin. Previously, we showed that plasma TAFI antigen levels were increased in patients with overt and subclinical hypothyroidism. The aim of this study is to investigate plasma levels of TAFI and PAI-1 antigens in hyperthyroid patients. PAI-1 and TAFI antigen levels were measured in the plasma of 29 patients with hyperthyroidism (14 overt hyperthyroid and 15 subclinical hyperthyroid), and 26 healthy individuals. Although there were increased levels of PAI-1 antigen in hyperthyroid patients, plasma TAFI antigen levels were significantly lower compared to controls (80.79 ng/ml vs. 32.42 ng/ml, p = 0.000 for PAI-1; 10.42 microg/ml vs. 12.24 microg/ml, p = 0.009 for TAFI). Elevated PAI-1 antigen levels were positively correlated with free thyroid hormones, although TAFI antigen levels were in negative correlation with free thyroxine. Furthermore, an inverse correlation between PAI-1 and TAFI antigen levels was found. Our study demonstrated that TAFI antigen levels were decreased in patients with hyperthyroidism. Inverse correlation with PAI-1 suggests that the decrease in TAFI antigen levels may be due to activation of TAFI pathway. Further studies evaluating the underlying mechanisms of low TAFI antigen levels in hyperthyroidism should be undertaken.     

Plasma plasminogen activator inhibitor-I is associated with plasma leptin irrespective of body mass index, body fat mass, and plasma insulin and metabolic parameters in premenopausal women.

Leptin, the satiety hormone expressed almost exclusively in adipose tissue, is a marker of body fat accumulation in humans. Recent studies have shown that plasminogen activator inhibitor-1 (PAI-1), a prothrombotic factor associated with atherosclerosis complications, is also produced in adipose tissue. The objective of the present study was to determine whether PAI-1 antigen plasma concentrations are associated with leptin plasma levels or the body fat mass (FM) independently of the variables known to influence PAI-1 production. Sixty-one nondiabetic women aged 18 to 45 years with a wide range of values for the body mass index ([BMI] 18.1 to 37.7 kg/m2) were evaluated for (1) body FM and fasting plasma levels of (2) PAI-1 antigen, (3) PAI-1 activity, (4) leptin, (5) insulin, (6) blood glucose, and (7) lipids (cholesterol, high-density lipoprotein [HDL]-cholesterol, and triglycerides [TG]). Body FM and fat-free mass (FFM) were estimated during fasting conditions by the bioimpedance analysis (BIA) method using a tetrapolar device. Body fat distribution was evaluated by the waist circumference and the waist to hip ratio (WHR). FM was directly associated with both PAI-1 antigen (r = .585, P < .001) and PAI-1 activity (r = .339, P < .001). Seemingly, leptin was positively related to both PAI-1 antigen (r = .630, P < .001) and PAI-1 activity (r = .497, P < .001). Moreover, both PAI-I antigen and PAI-1 activity were directly correlated with FFM (r = .285, P < .05, and r = .336, P < .01, respectively), BMI (r = .594, P < .001, and r = .458, P < .001, respectively), and WHR (r = .510, P < .001, and r = .391, P < .005, respectively). Insulin was directly related to PAI-1 antigen (r = .540, P < .001), PAI-1 activity (r = .259, P < .05), leptin (r = .447, P < .001), and FM (r = .435, P < .001). The association between PAI-1 antigen (dependent variable) and leptin or FM was tested by a stepwise regression model simultaneously including leptin, FM, BMI, WHR, age, FFM, and fasting insulin, blood glucose, TG, cholesterol, and HDL-cholesterol as independent variables. PAI-1 antigen maintained a significant positive independent relationship only with leptin (t = 2.923, P < .01), insulin (t = 3.489, P < .001), and fasting blood glucose (t = 2.092, P < .05), and a negative independent relationship with HDL-cholesterol (t = -2.634, P < .05). In conclusion, the strong relationship between PAI-1 antigen and leptin irrespective of other variables known to influence these factors seems to indicate that leptin per se may potentially increase PAI-1 plasma concentrations in obese subjects.     

Enhancement of fibrinolysis in poorly controlled, hospitalized type 2 diabetic patients by short-term metabolic control: association with a decrease in plasminogen activator inhibitor 1.

Impaired fibrinolysis in type 2 diabetes may be caused by an increased plasma concentration of plasminogen activator inhibitor 1 (PAI-1), although the effects of short-term hypoglycemic therapy on fibrinolytic activity are poorly understood. This study investigated the effects of metabolic improvement on fibrinolysis activity and plasma concentrations of PAI-1 in poorly controlled, hospitalized type 2 diabetic patients. Forty-eight poorly controlled type 2 diabetic patients were studied; 26 were subsequently treated with sulfonylurea (SU) and 22 with insulin. The plasma concentrations of plasmin-alpha2-antiplasmin (PAP), a measure of fibrinolytic activity, plasma PAI-1, and fasting triglycerides and glucoses were measured at the beginning and the end of hospitalization. The body mass index and fasting triglyceride decreased significantly after treatment (p < 0.0001). The plasma concentration of PAP increased significantly (p < 0.01), and the plasma PAI-1 decreased by 50% after treatment. There was an inverse correlation between the changes in the plasma concentrations of PAP and PAI-1 (r= - 0.36, p = 0.023). Treatment with SU or insulin showed an increase in plasma PAP with a concomitant decrease in the plasma PAI-1 with equivalent glycemic control. In poorly controlled type 2 diabetic patients, the plasma PAP concentration can be significantly increased and the plasma PAI-1 antigen significantly reduced, even with short-term metabolic improvements including weight reduction, a better lipid profile, and tighter glycemic control with either SU or insulin therapy, and that enhanced fibrinolysis may be mediated partly through a decrease in the plasma PAI-1 after metabolic control.     

Comparison of the effects of pioglitazone and voglibose on circulating total and high-molecular-weight adiponectin, and on two fibrinolysis inhibitors, in patients with Type 2 diabetes.

BACKGROUND: To investigate short-term effects of pioglitazone and voglibose on serum concentrations of both total and high-molecular-weight (HMW) adiponectin measured with a novel sandwich enzyme-linked immunosorbent assay (ELISA) ,and on plasma fibrinolysis indicators, in Type 2 diabetic patients with inadequate glycaemic control on sulphonylureas. METHODS: Thirty-four diabetic patients were randomized to receive pioglitazone or voglibose treatment for 12 weeks, after which serum HMW adiponectin was measured. Plasma plasminogen activator inhibitor (PAI) 1 and thrombin-activatable fibrinolysis inhibitor (TAFI), a recently identified inhibitor of fibrinolysis, were measured as fibrinolysis inhibitors. RESULTS: At baseline, serum HMW adiponectin correlated negatively with plasma TAFI in all patients with Type 2 diabetes (r = -0.367, P = 0.0423). Both groups showed similar improvements in glycaemic control. Serum total and HMW adiponectin increased in patients treated with pioglitazone, but did not change in patients treated with voglibose. The HMW : total adiponectin ratio increased significantly after treatment with pioglitazone (P = 0.0004). The change in HbA(1c) correlated negatively with changes in serum HMW adiponectin in patients treated with pioglitazone (r = -0.694, P = 0.0034). Plasma PAI-1 and TAFI did not change with pioglitazone treatment. CONCLUSION: Increased serum HMW adiponectin may contribute to the improvement in glycaemic control after pioglitazone treatment. Plasma PAI-1 and TAFI were unchanged by either drug.     

血清可溶性肿瘤坏死因子受体与胰岛素抵抗的关系

目的　了解血清可溶性肿瘤坏死因子受体 (STNFR) 1,2与胰岛素抵抗 (IR)的关系。方法　测定 43名男性和 41名绝经期前女性的STNFR1,2。以稳态模型 (HomaModel)公式评估IR。结果　肥胖男、女组STNFR1与非肥胖男、女组相近 ,而其STNFR2高于非肥胖男、女组 ,差异有显著性 (P <0 .0 5 )。所有男性STNFR1和STNFR2水平高于女性 (P <0 .0 1)。所有对象相关分析示STNFR2与臀腰比 (WHR)、空腹血糖、体重指数 (BMI)、HomaIR、空腹胰岛素正相关。STNFR1与上述指标无相关性。在男性中 ,STNFR2与瘦素正相关 (r =0 .34 ,P <0 .0 5 ) ,调整BMI、WHR影响后 ,STNFR2仍与瘦素正相关 (r=0 .30 ,P <0 .0 5 )。逐步回归分析示WHR和STNFR2对HomaIR的影响达 41.3%。结论　STNFR2与IR相关 ,在人类TNF系统对IR的影响可能主要通过TNFR2起作用。     

Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEEP) study

An impaired fibrinolytic function due to elevated plasma levels of plasminogen activator inhibitor (PAI)-1 activity or tissue plasminogen activator (tPA) antigen is correlated with the development of myocardial infarction (MI) in patients with manifest coronary heart disease. Recently, methods for determining the specific tPA/inhibitor complexes constituting tPA antigen in plasma have become available. In the Stockholm Heart Epidemiology Program (SHEEP) study, 86 of 1212 MI patients, subjected to blood sampling in a metabolically stable period, suffered reinfarction before the end of 1996. These individuals have been compared with an approximately equal number of matched MI patients without recurrence and a group of matched healthy control subjects regarding the plasma concentrations of some hemostatic factors. The hemostatic compounds studied (fibrinogen, von Willebrand factor, tPA antigen, PAI-1, and the tPA/PAI-1 complex) were typically higher in the groups (men and women) with recurrence of MI compared with those without. The plasma concentrations were also typically higher in the pooled groups of patients compared with the groups of healthy control subjects. The largest between-group differences were found for the plasma tPA/PAI-1 complex. The crude odds ratio for reinfarction associated with higher concentration (>/=75th percentile among the control subjects) of tPA/PAI-1 was 1.8 (95% CI 1.1 to 3.1); the corresponding crude odds ratio for von Willebrand factor was 2.3 (1. 3 to 4.0). The tPA/PAI-1 complex correlated strongly with PAI-1 and tPA antigen in all groups and with serum triglycerides and body mass index in all groups except for women with reinfarction. An increased plasma level of tPA/PAI-1 complex is a novel risk marker for recurrent MI in men and women. Most likely, increased plasma levels of tPA/PAI-1 complex reflect impaired fibrinolysis, because the correlation with PAI-1 is strong. Further support is obtained indicating that the plasma concentration of von Willebrand factor is also an important risk marker for recurrent MI.     

Influence of free testosterone on antigen levels of plasminogen activator inhibitor-1 in premenopausal women with central obesity.

Women with upper body obesity are at increased risk for cardiovascular disease (CVD). Several studies have demonstrated a reduced fibrinolytic activity in these patients, mainly due to an enhanced activity of plasminogen activator inhibitor-1 (PAI-1). Since an increase of androgenic activity is a feature of central obesity in women, the present study was aimed at evaluating the possibility of a relationship between androgens and PAI-1 (antigen and activity) in 20 premenopausal women, 10 with upper body obesity and 10 controls. In obese women, PAI-1 antigen showed a positive Pearson correlation with free testosterone (FT), insulin, c-peptide, triglycerides (TG), and waist to hip ratio (WHR) (P less than .01), whereas PAI-1 activity correlated positively only with insulin and WHR (P less than .01). In control women, PAI-1 antigen and activity were positively related only to TG (P less than .01). When we applied the multiple regression model with stepwise backward method to our data, both PAI-1 antigen and activity did not maintain any significant association. However, when the data from both the groups were pooled (n = 20), and PAI-1 antigen was considered as the dependent variable, body weight (Sig T = 0.0001), TG (Sig T = 0.0053), FT (Sig T = 0.013), and luteinizing hormone (LH) (Sig T = 0.0474) met the stepwise criteria, suggesting an independent effect of each of these parameters on PAI-1 antigen. On the other hand, when PAI-1 activity was tested as the dependent variable, only body weight maintained a significant relationship with this parameter (Sig T = 0.0006).(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired fibrinolytic compensation for hypercoagulability in obese patients with type 2 diabetes: association with increased plasminogen activator inhibitor-1

In patients with type 2 diabetes, fibrinolysis is considered impaired by increased plasma concentrations of plasminogen activator inhibitor (PAI)-1. However, several investigators found both coagulation and fibrinolysis to be activated in these patients. We further characterized the balance between coagulation and fibrinolysis in lean and obese patients with type 2 diabetes. We studied 112 type 2 diabetic patients (66 lean, 46 obese) and 69 age-matched healthy subjects (46 lean, 23 obese). We measured plasma concentrations of fibrinogen and prothrombin F1+2 (F1+2) as indicating coagulation activity and plasmin-antiplasmin complex (PAP) and D dimer as indicating fibrinolytic activity. Plasma PAI-1 concentrations also were determined. Plasma concentrations of F1+2, PAP, D dimer, and PAI-1 were higher in diabetic patients than in control subjects. Plasma fibrinogen and F1+2 were similar between lean and obese diabetic patients, but plasma PAP and D dimer were significantly lower in obese than lean diabetic patients (P <.0001, P =.0194, respectively). By multivariate analysis, plasma PAI-1 and body mass index (BMI) were independent factors in diabetic patients predicting PAP, while BMI and glycosylated hemoglobin (HbA(1c)) independently predicted D dimer. Plasma PAI-1 concentrations were significantly higher in obese than lean diabetic patients (P <.0001). In conclusions, both coagulation and fibrinolytic systems are enhanced in lean and obese type 2 diabetic patients compared with healthy subjects. Although the degree of activation of coagulation was similar between lean and obese diabetic patients, the fibrinolytic activity was lower in obese than lean patients. Fibrinolytic compensation for hypercoagulation is incomplete in obese patients with type 2 diabetes, partly because of elevated PAI-1 in the blood.     

Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease: subclinical hyperthyroidism increases plasma factor X activity

BACKGROUND AND OBJECTIVES: Various abnormalities of coagulation and fibrinolysis occur in patients with thyroid diseases, and may range from subclinical laboratory abnormalities to clinically significant disorders of coagulation and, rarely, major haemorrhage or thromboembolism. The influence of subclinical hypothyroidism (SHypo) on haemostasis is controversial, both hypercoagulable and hypocoagulable states have been reported. A hypercoagulable state might be a risk factor for thromboembolic disease in SHypo. On the other hand, subclinical hyperthyroidism (SCHyper) is associated with enhanced cardiovascular risk. In the English literature, there are no studies on changes in coagulation and fibriolytic status in subjects with SCHyper. Therefore, the aim of the present study was to investigate the markers of endogenous coagulation and fibrinolysis, and to evaluate the relationships between serum lipid profile and thyroid hormones and these haemostatic parameters in subclinical thyroid patients. DESIGN AND METHODS: Various haemostatic parameters were investigated in 30 patients with SHypo and 20 patients with SCHyper and compared to 20 euthyroid controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors V, VII, VIII, IX and X activities, vWF, antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor-1 (PAI-1), as well as common lipid variables, were measured. The relationships between serum thyroid hormones and these haemostatic parameters were examined. RESULTS: Compared with the control subjects, only FX activity was significantly increased in patients with SCHyper (P < 0.01). Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly higher in patients with SHypo compared with the control group (P < 0.001 and P < 0.01, respectively). TC levels were significantly higher in patients with SCHyper than in controls (P < 0.05). No differences could be found in coagulation/fibrinolysis parameters between subclinical hypothyroid patients and control subjects. In patients with SCHyper, serum TSH level was positively correlated with FX activity (r: 0.58, P < 0.01) and inversely correlated with PAI-1 (r: -0.55. P < 0.05). Serum TG levels were inversely correlated with plasma activities of factors V, VII, VIII, IX, X and vWF (r: -0.83, P < 0.001; r: -0.68, P < 0.05; r: -0.61, P < 0.05; r: -0.77, P < 0.01; r: -0.63, P < 0.05; r: -0.60, P < 0.05, respectively). Serum TC levels were positively correlated with plasma fibrinogen levels (r: 0.72, P < 0.05). Serum HDL-C levels were positively correlated with protein S activity (r: 0.68, P < 0.05) and negatively correlated with F VII activity (r: -0.69, P < 0.05). Also, in patients with SHypo, serum TG levels were positively correlated with serum TSH levels (r: 0.42, P < 0.05), plasma activities of factors V, VII and X (r: 0.42, P < 0.05; r: 0.54, P < 0.01; r: 0.57, P < 0.01, respectively) and negatively correlated with plasma fibrinogen levels (r: -0.41, P < 0.05). Serum TC levels were positively correlated with factors V and X (r: 0.42, P < 0.05; r: 0.58, P < 0.01, respectively) and negatively correlated with t-PA Ag levels (r: -0.44, P < 0.05). Serum HDL-C levels were inversely correlated with F VII activity (r: -0.48, P < 0.05). INTERPRETATION AND CONCLUSIONS: Some differences were found in the haemostatic parameters and lipid profile between the subclinical thyroid patients and healthy controls. Increased factor X activity in patients with subclinical hyperthyroidism represent a potential hypercoagulable state, which might augment the already existing risk for atheroscleroic complications. Also, subclinical hypothyroid patients exhibit a more atherogenic lipid profile compared with healthy individuals. Therefore, subclinical hypothyroidism is also associated with an increased risk of cardiovascular disease. However, thyroid hormones may play a role at different levels of the complex haemostatic system in subclinical thyroid disease.     

Relationship of body fat topography to insulin sensitivity and metabolic profiles in premenopausal women

The relationship of body fat distribution to metabolic profiles was determined in 80 healthy premenopausal white women of a wide range of obesity levels [percentage of ideal body weight (% IBW) 92-251]. Distribution of fat between the upper and lower body was assessed from the waist/hips girth ratio (WHR), which varied from 0.64 to 1.02. In 23 women, in vivo insulin sensitivity was also determined from the steady-state plasma glucose (SSPG) level at comparable insulin levels of approximately 100 microU/mL attained by the intravenous infusion of somatostatin, glucose, and insulin. Increasing WHR was accompanied by progressively increasing fasting plasma insulin levels (r = 0.47, P less than 0.001), insulin and glucose areas after glucose challenge (r = 0.53, P less than 0.001; r = 0.50, P less than 0.001, respectively) and fasting plasma triglyceride concentrations (r = 0.48, P less than 0.001). Obesity level was similarly correlated with these metabolic indices. Partial and multiple regression analysis and analysis of variance with a linear contrast model revealed that the effects of body fat topography were independent of, and additive to, those of obesity level. Within obese subjects alone (%IBW: 130), %IBW had no predictive value, but WHR remained a significant predictor of plasma glucose, insulin, and triglyceride concentrations. The WHR also correlated with the plasma cholesterol level, but this association was largely dependent on its relationship to %IBW. Both WHR and %IBW correlated with the insulin resistance index, SSPG (r = 0.60, P less than 0.01; r = 0.61, P less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Diminished fibrinolysis and thrombosis: clinical implications for accelerated atherosclerosis

Obesity is associated with an increased risk of atherosclerotic coronary artery disease. Cytokines and oxygen-centered free radicals implicated in insulin resistance stimulate adipocyte and endothelial production of plasminogen activator inhibitor type-1 (PAI-1), the primary physiologic inhibitor of fibrinolysis, in vitro. In obese hyperinsulinemic animal models simulating insulin resistance, plasma PAI-1 activity is increased. As the cardiovascular risk profile in specific populations may differ, endogenous fibrinolysis in lean and obese subjects was characterized and the mechanisms underlying differences were identified. Obese subjects (body mass index > 26) exhibited increased blood levels of PAI-1 antigen compared with corresponding values in lean controls. Blood t-PA antigen differed as well, yet basal endogenous fibrinolytic activity was decreased because of the high PAI-1 activity. The increased PAI-1 level was associated with increased levels of immunoreactive insulin (IRI). In diabetic subjects, coronary atherectomy specimens exhibited strong positive PAI-1 immunostaining, suggesting that in the diabetic vascular wall, intramural fibrinolytic activity is diminished. Using the oral glucose tolerance test, patients with significant stenosis confirmed by coronary angiography exhibited increased sigmaIRI, sigmaBS, sigmaIRI/sigmaBS, and IRI at 120 min compared to subjects without significant stenosis. IRI at 120 min was closely correlated with the severity of coronary artery disease. These results indicate that adipocyte overproduction of PAI-1 by insulin induces decreased endogenous fibrinolytic activity and contributes to the accelerated coronary macroangiopathy in hyperinsulinemic obese subjects with insulin resistance.     

Blood growth hormone-binding protein levels in premenopausal and postmenopausal women: roles of body weight and estrogen levels

A substantial proportion of GH circulates bound to high affinity GH-binding protein (GHBP), which corresponds to the extracellular domain of the GH receptor. Current evidence indicates that nutritional status has an important role in regulating plasma GHBP levels in humans. In the present study the relationship among plasma GHBP levels, body composition [by bioelectrical impedance analysis (BIA) and dual energy x-ray absorptiometry (DEXA)] and serum estradiol (E(2)) was evaluated in premenopausal (n = 92) and postmenopausal (n = 118) healthy women with different body weight [three groups according to body mass index (BMI): normal, 18.5-24.99; overweight, 25-29.99; obese, 30-39.99 kg/m(2)]. Plasma GHBP levels were measured by high pressure liquid chromatography gel filtration. GH and insulin-like growth factor I levels were determined by immunoradiometric assay and RIA, respectively. GHBP levels were significantly higher in premenopausal women with BMI above 25 kg/m(2) (overweight, 3.789 +/- 0.306 nmol/L; obese, 4.372 +/- 0.431 nmol/L) than those observed in postmenopausal women (overweight, 1.425 +/- 0.09 nmol/L; obese, 1.506 +/- 0.177 nmol/L). No significant differences were found between normal weight premenopausal (1.741 +/- 0.104 nmol/L) and postmenopausal (1.524 +/- 0.202 nmol/L) women. In premenopausal women GHBP levels correlated positively with BMI (r = 0.675; P < 0.001), fat mass (FM; r = 0.782; P < 0.001; by BIA; r = 0.776; P < 0.001; by DEXA), truncal fat (TF; r = 0.682; P < 0.001), waist to hip circumference ratio (WHR; r = 0.551; P < 0.001), and E(2) (r = 0.298; P < 0.05), whereas no significant correlation was found in postmenopausal women between GHBP levels and BMI, FM, TF, WHR, or E(2). In normal weight pre- and postmenopausal women GHBP levels did not change between the ages of 20 and 69 yr. No statistically significant correlation was found between GHBP and age for all groups studied. Moreover, in two distinct subgroups of pre- and postmenopausal women, aged 40-49 yr, the direct relationship between GHBP levels and all indexes of adiposity were only observed in premenopausal women [BMI: r = 0.836; P < 0.001; FM: r = 0.745 (BIA) and r = 0.832 (DEXA); P < 0.001; TF: r = 0.782; P < 0.001; WHR: r = 0.551; P < 0.05], but not in postmenopausal women. In conclusion, the present data indicate a strong direct correlation between GHBP and body fat in premenopausal, but not in postmenopausal women, whereas they failed to detect a relationship between GHBP and age. Therefore, these results suggest that endogenous estrogen status may be an important determinant of the changes in GHBP levels in women with different body weights.     

Plasma insulin, cholecystokinin, galanin, neuropeptide Y and leptin levels in obese women with and without type 2 diabetes mellitus

Obesity is an important factor predisposing to type 2 diabetes mellitus, especially for postmenopausal women. Experimental studies provided evidences that leptin, cholecystokinin (CCK), galanin (GAL), neuropeptide Y (NPY) and insulin are involved in feeding behaviour. The aim of the study was to evaluate their possible relationships in obese and diabetic women. Three groups of postmenopausal women (FSH > 30 mIU/ml) were evaluated: 8 diabetic (mean age 56.6 +/- 6.9 y, BMI 29.8 +/- 5.3 kg/m2), 10 obese non-diabetic (mean age 49.6 +/- 5.4 y, BMI 36.0 +/- 3.7 kg/m2) and 12 non-diabetic controls (mean age 52.7 +/- 3.5 y, BMI 27.3 1.9 kg/m2). For each patient BMI and WHR were measured and calculated. Blood samples were collected at 8:00 a.m. after an overnight fast. Plasma concentrations of FSH, leptin, CCK, GAL, NPY and insulin were determined using commercial RIA kits. Mean plasma NPY concentration was significantly higher in diabetic women than in controls (190.1 pg/ml +/- 85.4 vs 120.4 +/- 36.6). Compared to controls, mean plasma leptin level was significantly higher in obese non-diabetic women (32.9ng/ml +/- 9.2 vs 18.9 +/- 9.1). No significant differences were found between obese non-diabetic and diabetic women. In diabetic subjects positive correlations were found between: CCK and leptin (r= 0.8295; P= 0.011), CCK and insulin (r=0.7832; P=0.022), leptin and insulin (r=0.9302; P=0.001). In obese subjects a positive correlation between WHR and GAL (r= 0.6624; P= 0.037) and a negative between GAL and insulin (r= -0.6795; P= 0.031) were found. In controls positive correlations were found between WHR and CCK (r=0.6412; P=0.025), GAL and insulin (r=0.630; P=0.028) and negative between CCK and NPY (r = -0.6505; P= 0.022). Our results, ie higher mean plasma NPY levels in postmenopausal diabetic women and positive correlation of CCK with leptin and insulin, may suggest the role of these neuropeptides in metabolic disorders leading to type 2 diabetes mellitus.     

Relationship between plasma leptin levels and the tumor necrosis factor-alpha system in obese subjects.

OBJECTIVE: To evaluate the relationship between plasma leptin and the tumor necrosis factor-alpha (TNFalpha), TNF receptor p60 (TNF-R1) and TNF receptor p80 (TNF-R2) concentrations in obese subjects. DESIGN: Case-control study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital. MEASUREMENTS: Body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fasting plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA IR), plasma leptin, TNFalpha, TNF-R1 and TNF-R2 concentrations were evaluated in obese subjects (n = 42) and in age- and gender-matched, lean healthy controls (n = 16). RESULTS: In obese subjects, fasting plasma glucose and insulin, HOMA IR, plasma leptin, TNFalpha, TNF-R1 and TNF-R2 concentrations were significantly higher than in controls. Furthermore, females showed higher leptin, TNF-R1 and TNF-R2 plasma concentrations compared to males, in both control and obese subjects. In control subjects, plasma leptin concentrations showed a direct correlation with BMI (r=0.74, P<0.001), hip circumference (r=0.94, P<0.001), TNF-R1 (r=0.79, P<0.001) and TNF-R2 (r=0.64, P<0.01), and a negative correlation with WHR (r=-0.58, P<0.05). In obese subjects, we found a direct correlation between plasma leptin concentrations and BMI (r=0.67, P<0.001), hip circumference (r=0.66, P<0.001), fasting glucose (r=0.37, P<0.05), fasting insulin (r=0.31, P<0.05), HOMA IR (r=0.38, P<0.05), TNF-R1 (r=0.71, P<0.001) and TNR-R2 (r=0.66, P<0.001), while a negative correlation was found between circulating leptin and WHR (r=-0.44, P<0.01). In multivariate analysis, plasma leptin concentrations were significantly associated with BMI (P=0.015) and gender (P=0.047) in the control group, while in obese subjects, plasma leptin showed a significant association with BMI (P=0.019) and TNF-R1 (P=0.012). CONCLUSIONS: Our results are consistent with the hypothesis that the TNFalpha system could be involved in the regulation of plasma leptin concentrations in obese subjects.     

Gestational diabetes has no additional effect on plasma thrombin-activatable fibrinolysis inhibitor antigen levels beyond pregnancy

Pregnancy is a prothrombotic condition with increased levels of several circulating coagulation factors. Decreased fibrinolytic activity has been shown in gestational diabetes. Gestational diabetes has been found to be associated with higher plasma plasminogen activator inhibitor-1 (PAI-1) antigen levels than normal pregnancy. The aim of the present study is to investigate the effect of gestational diabetes on plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen levels.Plasma TAFI and PAI-1 antigen levels were measured in 26 pregnant women with gestational diabetes, 25 pregnant women with normal glucose tolerance, and age-matched 24 non-pregnant women with no history of gestational diabetes.Increased plasma TAFI antigen levels were found in pregnant women compared to non-pregnant controls. However, no statistically significant difference in TAFI antigen levels was observed between women with gestational diabetes and pregnant controls. Plasma PAI-1 antigen levels were higher in gestational diabetes than pregnant and non-pregnant controls.Our study revealed that pregnancy was associated with elevated plasma TAFI antigen levels. However, no additional effect of gestational diabetes was found on plasma TAFI antigen levels beyond pregnancy. We suggest that pregnancy is associated with enhanced coagulation and impaired fibrinolysis. Despite increased PAI-1 antigen levels associated with gestational diabetes, the effect of gestational diabetes on TAFI antigen levels is lacking.     

Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity.

Fat tissue is a significant source of endogenous tumor necrosis factor alpha (TNFalpha), the pluripotent cytokine that plays an important role as a mediator of the peripheral insulin resistance found in obesity. The majority of evidence for this role of TNFalpha is from studies in animal models of obesity. To explore further the role of TNFalpha in the pathogenesis of obesity-related insulin resistance in humans, we compared plasma levels of TNFalpha and the other main endocrine cytokine, interleukin-6 ([IL-6] both measured by enzyme-linked immunosorbent assay), in 26 obese women (body mass index [BMI] > 30 kg/m2) and 13 female controls (BMI < 26 kg/m2) without a history of recent or active infection. Glucose and insulin levels were measured at 0, 1, and 2 hours after a 75-g oral glucose load. There was no significant difference in plasma TNFalpha or IL-6 levels between obese and non-obese subjects overall (2.10 +/- 0.19 v 1.65 +/- 0.18 pg/mL and 2.06 +/- 0.29 v 1.50 +/- 0.17 pg/mL, respectively). However, TNFalpha levels were significantly elevated in obese subjects with a 2-hour glucose level more than 140 mg/dL (n = 8) compared with the other obese subjects (n = 18) and the non-obese controls (2.88 +/- 0.46 v 1.75 +/- 0.10 and 1.65 +/- 0.18 pg/mL, respectively, P < .01). Furthermore, the TNFalpha level correlated significantly with the waist to hip ratio ([WHR] r = .53, P < .01) and fasting and post-oral glucose tolerance test (OGTT) insulin levels (r = .47, P < .02), but not with the BMI, and was higher in obese women with a WHR more than 0.90 (n = 14) in comparison to those with a WHR less than 0.90 (n = 12, 2.47 +/- 0.29 v 1.66 +/- 0.18 pg/mL, respectively, P < .03). The corresponding plasma leptin level was significantly higher in obese women versus the control group (41.6 +/- 2.5 v22.3 +/- 2.9 ng/mL, P < .001) and was related to the BMI (r = .60, P < .01) but not to TNFalpha or the WHR. There were no significant differences in the corresponding IL-6 concentration between groups, and IL-6 did not correlate with TNFalpha, leptin, BMI, WHR, or insulin levels. In conclusion, circulating TNFalpha levels are higher in abdominal obesity compared with peripheral obesity, and may contribute to the insulin resistance that more commonly complicates the former pattern of fat distribution.