© 1997 American Heart Association, Inc.
Articles |
Gender Differences in the Relationships Between Plasma Plasminogen Activator Inhibitor-1 Activity and Factors Linked to the Insulin Resistance Syndrome in Essential Hypertension
From the Institutes of Clinical Medicine (I.T.), Community Medicine (K.H.B.), and Medical Biology (O.C.I.), University of Tromsø; the Department of Internal Medicine, Tromsø University Hospital (A.N., T.J.); and the Department of Clinical Chemistry, Aker Hospital, Oslo (K.I.B.), Norway.
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Abstract |
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Abstract Impaired fibrinolysis due to elevated levels of plasma plasminogen activator inhibitor type 1 (PAI-1) is a risk factor for thromboembolic disease. Hypertension, obesity, derangements in lipid and glucose homeostasis, and elevated levels of PAI-1 are features of the insulin resistance syndrome. The interrelationships between PAI-1 and the metabolic disturbances seen in this condition are unsettled. We investigated the associations between PAI-1 activity and components of the insulin resistance syndrome in 53 men and 31 women with untreated hypertension. In men, PAI-1 activity correlated significantly with plasma glucose (r=.41, P=.002), insulin sensitivity (r=-.35, P=.01), and insulin-induced suppression of nonesterified fatty acid (NEFA) (r=-.43, P=.007). Plasma glucose and NEFA suppression were independently associated with PAI-1 activity in a multivariate analysis. In women, PAI-1 activity correlated with body mass index (r=.62, P=.0005), waist-to-hip ratio (r=.75, P=.0001), plasma glucose (r=.50, P=.007), insulin (r=.49, P=.009), proinsulin (r=.57, P=.002), C-peptide (r=.60, P=.0009), insulin sensitivity (r=-.74, P=.0001), NEFA suppression (r=-.64, P=.003), and triglycerides (r=.58, P=.001). In multivariate analyses, insulin sensitivity and NEFA suppression were independently associated with PAI-1 if waist-to-hip ratio was not included in the model. After introduction of waist-to-hip ratio into the model, waist-to-hip ratio was the only independent predictor of PAI-1 activity. We conclude that in women, waist-to-hip ratio, body mass index, and insulin-induced NEFA suppression are determinants for PAI-1 activity. In men, insulin-induced NEFA suppression and plasma glucose are independently associated with PAI-1 activity.
Key Words: hypertension • plasminogen activator inhibitor-1 • insulin action • waist-to-hip ratio
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Introduction |
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Hypertension, hyperlipidemia, hyperinsulinemia, and central obesity are concomitant disorders in many individuals. This cluster of metabolic disturbances has been labeled the insulin resistance syndrome,1 since insulin resistance and hyperinsulinemia have been postulated to be the underlying features.2 3 The failure of insulin to adequately suppress lipolysis may also play an important role in the development of the metabolic derangements seen in this condition.4
PAI-1 is an inhibitor of fibrinolysis5 that may predict future risk of thrombosis and myocardial infarction.6 7 8 9 The role of PAI-1 in the insulin resistance syndrome is therefore of interest. Elevated PAI-1 levels have been associated with several metabolic cardiovascular risk factors such as obesity,10 11 insulin resistance,12 13 and increased levels of glucose,14 insulin,10 15 proinsulin,16 17 and blood lipids.18 The exact nature of these interrelationships is not established,11 19 20 21 and the importance of each factor may differ with gender.14 22
In the present study we investigated the relationships between plasma PAI-1 activity and several metabolic risk factors of coronary artery disease in 53 men and 31 women with stable, untreated, essential hypertension. The study was done to evaluate whether any of these factors are independently associated with fibrinolytic activity and thus may be of specific importance for the development of hypercoagulability. Men and women were investigated separately to identify possible gender differences in the interrelations between fibrinolytic and metabolic variables. According to our findings, increased waist-to-hip ratio, body mass index, and inadequate insulin-induced suppression of NEFA were the most important determinants of increased PAI-1 activity in women, whereas decreased NEFA suppression and elevated plasma glucose were independently associated with decreased fibrinolytic activity in men.
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Methods |
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Subjects
In 1986 and 1987, 81.3% of the population between 20 and 61 years old living in the municipality of Tromsø, Norway, participated in a health survey.23 On the basis of that survey, 103 hypertensive subjects who were known from a previous trial24 were asked to participate in the present study. Fifty-eight subjects were on no medication, had systolic blood pressure <190 mm Hg and diastolic pressure between 90 and 110 mm Hg on three separate occasions, and appeared otherwise healthy on clinical examination. They participated in the present study, together with 26 hypertensive subjects recruited from the primary health care services according to identical criteria. The ages ranged from 26 to 66 years (men, 26 to 66 years; women, 27 to 63 years). Four of the volunteers had been treated with antihypertensive drugs (atenolol, amlodipine, or felodipine), which were discontinued at least 8 weeks before the study. None of the participants had ischemic heart disease or type II diabetes mellitus. Twenty (65%) of the 31 female volunteers were postmenopausal. The study was approved by the Regional Board of Research Ethics, and each subject gave written informed consent before participation.
Clinical and Laboratory Measurements
A weight-maintenance diet was followed for 3 days before
experiments, and the participants were asked to abstain from alcohol
during this period. All studies were performed at 8 AM
after an overnight fast. Blood was drawn from a cannulated dorsal hand
vein without stasis, and the blood was arterialized by keeping the hand
in a heating device at 65°C.25
For measurement of PAI-1 activity, citrated plasma was collected and immediately cooled on ice. Determination of plasma PAI-1 activity was done with a commercial two-stage indirect enzymatic kit (Spectrolyse Biopool AB).26 The interassay CV was 13.9%. Samples for measurement of tPA activity were collected in Biopool Stabilyte blood collection tubes and determined according to Wiman et al27 as previously described.28 The interassay CV was 9.9%. Plasma fibrinogen was measured with an ACL 3000 coagulation system manufactured by Instrumentation Laboratory SpA. The reagents were IL Test PT-Fibrinogen, catalog No. 97567-10. Coagulation factor VII (percent activity) was measured with the same instrument. Factor VII–deficient plasma (Instrumentation Laboratory, catalog No. 84662-50), calibration plasma, and additional reagents were delivered from the same manufacturer.
All participants underwent an oral glucose tolerance test with 1 g dextrose monohydrate per kilogram body weight or a maximum of 75 g dextrose. On a separate day, a standard hyperglycemic clamp was performed to measure insulin sensitivity29 30 to both glucose disposal and suppression of lipolysis under physiological conditions. An infusion of 20% dextrose was administered into an antecubital vein to keep plasma glucose stable at 10 mmol/L for 3 hours by variable infusion rates. Blood samples for insulin and C-peptide were drawn at -30, 0, 2.5, 5, 7.5, 10, 15, 20, 40, 60, 80, 100, 120, 140, 160, and 180 minutes. Insulin sensitivity to glucose disposal was assessed as the insulin sensitivity index, calculated by dividing mean glucose infusion rate during the last hour of the clamp (1 mol·kg-1·min-1) by the average plasma insulin concentration (pmol/L) during the same period of time. On a third occasion, 31 randomly selected subjects also underwent a euglycemic, hyperinsulinemic clamp, which is considered to be the gold standard for measurements of insulin sensitivity.29 Pearson's correlation coefficient for the insulin sensitivity index calculated by the two clamp techniques was 0.69 (P=.0001). This finding confirms previous results showing that the hyperglycemic clamp can be used to measure insulin sensitivity.30
Plasma glucose concentrations were analyzed bedside by a YSI glucose analyzer (2300 STAT PLUS). All other blood samples were stored at -70°C. Plasma insulin and C-peptide were measured by radioimmunoassay methods as previously published.31 32 The assays for measurements of plasma insulin and C-peptide do not cross-react, and they both have a cross-reactivity with proinsulin of <15%. Proinsulin was measured with an immunofluorometric method as previously described,33 using monoclonal antibodies, one directed against insulin and another against C-peptide (PEP-001 and HUI-001 from Novo Nordisk). Cross-reactivities with insulin, C-peptide, and 65,66-split proinsulin were <1% and with 32,33-split proinsulin 66%. The lower limit of detection was 1 pmol/L and CV was <10% at all concentration levels.
Serum cholesterol and triglycerides were measured on a Hitachi 737
automatic analyzer with kits from Boehringer Mannheim. HDL cholesterol
was determined after isolation of HDLs according to the method
described by Burstein et al.34 VLDL cholesterol was
calculated as 0.46 multiplied by the triglyceride level, and LDL
cholesterol was calculated as total cholesterol minus the sum of VLDL
and HDL cholesterol, according to the formula of Friedewald et
al.35 Serum free fatty acids were analyzed by an acyl-CoA
oxydase–based colorimetric kit (Wako Nefa C Kit). The percentage
suppression of lipolysis during the hyperglycemic clamp was calculated
by the formula
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The waist-to-hip ratio was calculated as the body circumference at the level midway between the inferior border of the rib cage and superior border of the iliac crest divided by the maximal circumference of the buttocks.37
Statistical Analysis
The data were analyzed using the SAS software package
(SAS).38 All data were checked with regard to frequency
distribution and transformed to normal distribution by logarithmic
transformation when appropriate. A two-sample t test was
used for between-group comparisons. Correlations were tested by
computing Pearson correlation coefficients. Relationships between PAI-1
activity and metabolic risk factors were examined separately in men and
women by using a two-step procedure. First, we included in a forward,
stepwise regression analysis those metabolic risk factors that showed
significant univariate associations with PAI-1 activity. The variable
with the highest partial correlation coefficient entered the model at
each step and was removed in order of significance (if
P>.15). Next, in a multiple linear regression model, we
included age and those variables that were selected by the stepwise
analyses. Waist-to-hip ratio and body mass index were included in
separate models to see whether body fat distribution or body weight
modified PAI-1 activity. Interaction terms were included to test
whether the associations of waist-to-hip ratio or body mass ratio with
PAI-1 activity differed in men and women. A two-sided value of
P<.05 was considered statistically significant. Data are
given as mean±SD.
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Results |
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Characteristics of the participating men and women are presented in Table 1
. Compared with men, women had significantly
lower waist-to-hip ratio, lower levels of fasting plasma glucose,
triglyceride, VLDL cholesterol, and a higher percentage suppression of
NEFA during the hyperglycemic clamp. PAI-1 activity in the total study
group was 11.8±8.7 U/mL (mean±SD); the range varied from 0.5 to 36.5
U/mL. PAI-1 activity was similar in men and women. Fifty-three percent
of the men and 57% of the women were glucose intolerant according to
the World Health Organization criteria.39 Twenty-five
percent of the men and 29% of the women had hypertension with a low
metabolic risk profile, ie, they had levels of fasting plasma glucose
<5.5 mmol/L, postload glucose <7.8 mmol/L, fasting insulin
<60 pmol/L, insulin sensitivity index >0.09, fasting triglycerides
<1.9 mmol/L, and LDL cholesterol <5.0 mmol/L. Mean glucose
and insulin levels during 120 to 180 minutes of the hyperglycemic clamp
were 10.1±0.3 mmol/L and 258±162 pmol/L for men, 10.1±0.2
mmol/L and 256±158 pmol/L for women, and 10.1±0.2 mmol/L and
258±160 pmol/L for the total study group.
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Associations Between PAI-1 Activity and tPA Activity and Metabolic
Risk Factors
In men, PAI-1 and tPA activity correlated weakly with age
(r=-.20, P=.15 and r=.38,
P=.006, respectively). The corresponding coefficients for
women were r=-.08 (P=.66) and r=.29
(P=.13), respectively. Table 2 shows
age-adjusted correlation coefficients of PAI-1 and tPA with various
metabolic risk factors in men and women. In men, only fasting glucose
(r=.41), insulin sensitivity index (r=-.35), and
percentage NEFA suppression (r=-.43), were significantly
associated with PAI-1 activity. In women, PAI-1 activity was
significantly associated with body mass index (r=.62),
waist-to-hip ratio (r=.75), insulin sensitivity index
(r=-.74), percentage NEFA suppression (r=-.64),
plasma glucose (r=.50), insulin (r=.49),
proinsulin (r=.57), C-peptide (r=.60),
triglycerides (r=.58), and VLDL cholesterol
(r=.58). Relations between PAI-1 activity and percentage
NEFA suppression during hyperglycemic clamp are shown in the
Figure.
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In general, PAI-1 showed closer relationships with the different
metabolic risk factors than did tPA (Table 2
).
Since waist-to-hip ratio and body mass index appeared to be associated
with PAI-1 in women but not men, we examined the interrelationships of
waist-to-hip ratio and body mass index with other metabolic risk
factors separately in men and women (Table 3).
Waist-to-hip ratio and body mass index were significantly associated
with fasting plasma glucose and insulin in both genders. Men and women
differed in that waist-to-hip ratio correlated with the insulin
sensitivity index, percentage NEFA suppression, levels of
triglycerides, and tPA activity (r=-.61,
r=-.61, r=.46, and r=-.49,
respectively) in women but not men. Body mass index was associated with
triglycerides and HDL cholesterol in men but not women.
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Multivariate Analyses of PAI-1 Activity
In men, percentage NEFA suppression, plasma glucose, and age were
independently associated with PAI-1 activity, whereas the association
between insulin sensitivity and PAI-1 did not reach statistical
significance (Table 4). These variables accounted for
29% of the variability in PAI-1 activity. Neither waist-to-hip ratio
nor body mass index was associated with PAI-1 activity in men, and the
inclusion of these variables in the model did not notably modify the
relationship between and PAI-1 activity and the other variables (Table 4).
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In women, insulin sensitivity index and percentage NEFA suppression
were the first variables selected in the stepwise regression analysis.
When these variables were already in the model, none of the metabolic
variables that were associated with PAI-1 in the age-adjusted analyses
(Table 2) entered the model. Insulin sensitivity index and percentage
NEFA suppression accounted for 59% of the variability in PAI-1
activity in women (Table 4). The inclusion of waist-to-hip ratio added
significantly to the model (R2=0.64), and
insulin sensitivity and percentage NEFA suppression lost their
independent association with PAI-1 activity. The inclusion of body mass
index increased the strength of the association between the percentage
NEFA suppression and PAI-1 activity, whereas insulin sensitivity index
lost its independent association with PAI-1 activity
(R2=0.74).
The relationships of waist-to-hip ratio and body mass index with PAI-1 activity were significantly different in men and women. The probability values for an interaction term between waist-to-hip ratio and gender and between body mass index and gender were P=.01 and P=.10 (data not shown).
Relationships Between tPA Activity and Metabolic Risk
Factors
Forward stepwise regression analysis of tPA activity and all
variables that were significantly correlated with tPA in the univariate
analyses (Table 2) showed that in men, only age (r=.38,
P=.006) was independently associated with tPA (adjusted
R2=0.13). In women, insulin sensitivity index
(P=.03) and to a lesser degree age (P=.05)
predicted tPA activity (adjusted R2=0.38),
whereas NEFA suppression during hyperglycemic clamp did not reach
statistical significance (P=.10). Interaction analysis
showed that the association of tPA with insulin sensitivity index
differed significantly (P=.02) in men and women.
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Discussion |
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This study indicates that insulin sensitivity to glucose disposal, the degree of postprandial suppression of lipolysis, plasma glucose levels, and age are independently associated with PAI-1 activity in hypertensive persons. However, important gender differences appeared. The strength of the association between NEFA suppression and PAI-1 activity during hyperglycemic clamp were similar in men and women. But insulin sensitivity to glucose disposal was more strongly associated with PAI-1 activity in women than men, and plasma glucose levels were associated with PAI-1 activity in men but not women. In men, body mass index and abdominal visceral adipose tissue, expressed as waist-to-hip ratio, did not contribute significantly to explaining the variance of PAI-1. In contrast, abdominal obesity and increased body mass index seemed to be strong determinants of reduced fibrinolytic activity in women, mediated partly by mechanisms other than insulin sensitivity and altered NEFA suppression.
Women with abdominal obesity have increased risk of cardiovascular disease.40 41 Our results suggest that this could be due to decreased fibrinolytic capacity, a finding also supported by others.14 Elevated PAI-1 activity in women with android fat distribution could be mediated by sex hormones,40 42 since testosterone levels have been associated with levels of PAI-1 antigen,43 and postmenopausal hormone replacement has resulted in decreased PAI-1 activity.44 In subgroup analyses of the premenopausal women in our study, waist-to-hip ratio was the only variable associated with PAI-1 activity (r=.65, P=.05), whereas the postmenopausal women showed the same cluster of associations between PAI-1 activity and various metabolic risk factors as seen in the total group of women. This further indicates that in women, waist-to-hip ratio may be associated with PAI-1 activity independently of other metabolic risk factors.
The interpretation of gender differences related to the association between waist-to-hip ratio and PAI-1 activity in our study may be constrained by the fact that the variability in waist-to-hip ratio is smaller in men than in women. This could lead to an underestimation of the importance of waist-to-hip ratio for PAI-1 activity in men.
In men, who had higher fasting glucose levels than women, plasma glucose was an independent predictor for PAI-1 activity in our study. Plasma glucose has previously been found to predict PAI-1 activity in men with hypertriglyceridemia,18 and in vitro studies have shown that physiologically elevated glucose levels may stimulate endothelial PAI-1 production.45
The failure of insulin and hyperglycemia to adequately suppress plasma NEFA levels predicted elevated PAI-1 activity in both men and women. In women, the suppression of lipolysis lost its significance when waist-to-hip ratio was accounted for. An association between PAI-1 activity and suppression of NEFA levels has not been reported before. However, it has been suggested that visceral adiposity could lead to portal NEFA accumulation that may stimulate hepatic PAI-1 production.18 Inhibition of lipolysis is mainly related to plasma insulin concentrations36 but may be impaired in the insulin resistance syndrome.4 Increased postprandial lipolysis may lead to increased flux of NEFA to the liver, which is linked to increased hepatic triglyceride and VLDL synthesis46 and further deterioration of glucose tolerance through the Randle cycle.47 The effects of increased NEFA flux on fibrinolysis is not known, but the interpretation of our data suggest that a PAI-1–stimulating, NEFA-associated mechanism may exist. This would explain why various other markers of impaired insulin action such as plasma glucose, insulin, triglycerides, and insulin sensitivity to glucose disposal have been found to be independently associated with PAI-1 activity.15 18 48 49 In the present study, the participants who were glucose intolerant and who clearly must have had insufficient insulin action had significantly higher PAI-1 activity and lower NEFA suppression than the normoglycemic group (13.7±8.9 compared with 9.5±7.9 U/mL, P=.02 and 85±7 compared with 91±7%, P=.04)
We did not find indications that levels of either peripheral or portal insulin (C-peptide) or proinsulin had direct PAI-1–stimulating effects, as previously suggested.15 16 17 18 49 50 51 Metabolic risk factors for cardiovascular disease seemed to be more closely associated with high PAI-1 activity than with low tPA activity. In a regression analysis with PAI-1 and tPA activity as predictor variables, tPA activity did not predict insulin sensitivity independently of PAI-1 in either men or women (data not shown). This indicates that PAI-1 activity is a better marker of impaired fibrinolysis in the insulin resistance syndrome.
We found a negative association between age and PAI-1 activity and a positive association between age and tPA. This was unexpected, since the metabolic derangements seen in the insulin resistance syndrome increase with age. However, similar associations were recently found in a population screening of 1558 persons aged 25 to 64 years.22 The phenomenon may reflect a physiological adaptation of the fibrinolytic system to the various metabolic changes occurring with age.
In conclusion, waist-to-hip ratio and body mass index are independent predictors of PAI-1 activity in women but not men. Plasma glucose predicts PAI-1 activity in men. Failure of insulin to adequately suppress lipolysis under postprandial conditions is associated with decreased fibrinolytic capacity in both genders. We hypothesize that impaired insulin action in the insulin resistance syndrome may have a PAI-1 stimulatory effect through increased flux of NEFA and that impaired fibrinolysis seen in overweight women may be mediated via similar mechanisms.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Norwegian Diabetes Association, Nordic Research Funding, and The Research Council of Norway. We thank the staff of the General Clinical Research Centre and appreciate the technical assistance of Jorunn Eikrem, Åse Lund Bendiksen, and Hege Iversen.
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Footnotes |
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Reprint requests to Ingrid Toft, MD, Department of Medicine, University Hospital of Tromsø, N-9038 Tromsø, Norway.
Received April 10, 1996; accepted June 27, 1996.
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