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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2818.)
© 1999 American Heart Association, Inc.

Thrombosis

Comparison of Plasminogen Activator Inhibitor-1 Concentration in Insulin-Resistant Versus Insulin-Sensitive Healthy Women

Fahim Abbasi; Tracey McLaughlin; Cindy Lamendola; Izabella Lipinska; Geoffrey Tofler; Gerald M. Reaven

From the Departments of Medicine, Stanford University School of Medicine, Calif (F.A., T.M., C.L., G.M.R.); Beth Israel Deaconess Hospital, Boston, Mass (I.L., G.T.); and Royal North Shore Hospital, Sydney, Australia (G.T.).

Correspondence to G.M. Reaven, MD, Shaman Pharmaceuticals, Inc, 213 East Grand Avenue, South San Francisco, CA 94080-4812. E-mail greaven{at}shaman.com

	Abstract

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Abstract—The primary goal of this investigation was to see whether plasminogen activator inhibitor-1 (PAI-1) concentrations varied as a function of differences in insulin-mediated glucose disposal in 2 groups of healthy women matched for every other variable that might play a role in regulation of PAI-1. For this purpose, we recruited 32 healthy women, divided on the basis of their steady-state plasma glucose (SSPG) concentrations during the insulin suppression test into an insulin-resistant (SSPG=216±12 mg/dL, n=16) and an insulin-sensitive (94±6 mg/dL, n=16) group. PAI-1 antigen concentrations were significantly higher (26±4 versus 14±3 ng/mL, P<0.02) in the insulin-resistant group. In addition, fasting plasma insulin (18±3 versus 11±2 µU/mL, P<0.02) and triglyceride (160±19 versus 93±10 mg/dL, P<0.001) concentrations were higher in the insulin-resistant individuals, whereas HDL concentrations were lower (44±3 versus 58±3 mg/dL, P<0.005). However, the 2 groups were essentially identical in terms of age, menopausal status, hormone replacement therapy, body mass index (BMI), ratio of waist-to-hip girth, and blood pressure. When the experimental population was considered as 1 group, there were statistically significant correlations between PAI-1 antigen and the following variables: adjusting for differences in age and BMI, SSPG (r=0.56, P<0.001); triglyceride (r=0.39, P<0.05); and HDL cholesterol (r=-0.65, P<0.001) concentrations. Finally, multiple regression analysis revealed the major determinants of PAI-1 to be insulin resistance, or insulin concentration, and HDL cholesterol. These results: 1) demonstrate that PAI-1 concentrations are higher in healthy, insulin-resistant women as compared with insulin-sensitive individuals, independent of differences in BMI or ratio of waist-to-hip girth; and 2) provide another mechanism by which insulin-resistant individuals are at increased thrombotic cardiovascular risk.

Key Words: PAI-1 • insulin resistance • HDL cholesterol • hyperinsulinemia • triglycerides

	Introduction

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Reports published over the last several years have presented a substantial amount of evidence of an association between plasma insulin concentrations and plasminogen activator inhibitor-1 (PAI-1) activity.^{1 2 3 4} Perhaps the most compelling evidence in this context came from the report of the European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Study.⁴ The results of the ECAT Study of 1484 patients with angina pectoris demonstrated an independent relationship between hyperinsulinemia and PAI-1 levels in individuals with evidence of coronary atherosclerosis. Given the very close relationship in nondiabetic individuals between insulin resistance and hyperinsulinemia,^{5 6} it has been suggested that the elevated levels of PAI-1 are a reflection of insulin resistance.^{1 2 3 4} On the other hand, results of studies in which insulin resistance has been measured directly have not universally confirmed the assumed relationship between insulin resistance and PAI-1 level.^{7 8 9 10} Indeed, 3 of these studies^{7 8 9} have been unable to demonstrate an independent relationship between insulin resistance and PAI-1, with the only positive report¹⁰ based on an experimental population of 70-year-old men. It is not clear why a disparity seems to exist concerning the consistency of the relationship of PAI-1 to plasma insulin concentration as compared with insulin resistance. However, several of the reports have been based on analysis of data collected in large population-based studies,^{8 9 10} not research efforts specifically initiated to evaluate the relationship between insulin resistance and PAI-1 levels. In some instances, the population was composed of individuals who were hypertensive⁹ or obese and often glucose intolerant.⁷ Finally, all of the publications relied on the use of multivariate analysis to take into account the wide differences in values of both the demographic and metabolic variables that were evaluated for their relationship to PAI-1. Although this can be a useful approach, it is based on many assumptions as to the quantitative nature of the relationships between the variables in question and certainly can be confounded by differences in the intra- and interindividual variability of each of the variables.

Given evidence of the association between impaired fibrinolytic activity and thrombotic cardiovascular risk,^{11 12} an attempt to clarify the relationship between insulin resistance and elevations of PAI-1 seemed to be a worthwhile goal. The current study was initiated for this purpose and was based on a protocol aimed at avoiding some of the confounding variables present in previous studies. Specifically, we limited enrollment to healthy individuals and used selection criteria that minimized or avoided differences in age, gender, obesity, etc.

	Methods

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Thirty-two healthy nondiabetic women were selected for this study. They were recruited from a larger group that responded to a newspaper advertisement indicating our interest in studying the relationship between insulin resistance and risk factors for coronary heart disease. To enter the study, women had to be in good general health, with a body mass index (BMI) between 20 to 33 kg/m², a normal medical history and physical examination, normal values on a routine hematological survey and chemical screening battery, and a nondiabetic glucose tolerance test by National Diabetes Data Group criteria.¹³ The population was subdivided into 2 groups—insulin-sensitive and insulin-resistant—on the basis of the results of their insulin suppression test as described below.

Patients were admitted to the General Clinical Research Center of Stanford Medical Center after informed consent had been obtained. Insulin-mediated glucose disposal was estimated by a modification¹⁴ of the insulin suppression test,¹⁵ as validated by our laboratory.¹⁶ After an overnight fast, an IV catheter was placed in each of the patients’ arms. Blood was sampled from 1 arm for measurement of plasma glucose and insulin concentrations, and the contralateral arm was used for administration of test substances. Somatostatin was administered (250 µg/h in a solution containing 2.5% [wt/vol] human serum albumin) to suppress endogenous insulin secretion. Simultaneously, insulin and glucose were infused at rates of 25 µU/(m² · min) and 240 mg/(m² · min), respectively. Blood was sampled every 30 minutes until 150 minutes into the study and then every 10 minutes until 180 minutes had elapsed. The 4 values obtained from 150 to 180 minutes were averaged and considered to represent the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations achieved during the infusion. Because SSPI concentrations are comparable in all individuals, SSPG concentrations provide a direct estimate of insulin-mediated glucose disposal in each individual: the lower the SSPG, the more insulin-sensitive the individual. Volunteers were separated into 2 groups using an SSPG concentration of 150 mg/dL as the cut point. This somewhat arbitrary value was chosen based on unpublished data showing that 1/3 of ~300 healthy volunteers will have an SSPG concentration >150 mg/dL. With this criterion, we created 2 equal groups of 16.

Aliquots of the blood specimens obtained on the morning of the insulin suppression test were also obtained to measure concentrations of triglycerides (TG), LDL cholesterol, and HDL cholesterol concentrations, as described previously.¹⁷ Finally, an aliquot was also taken to measure PAI-1 antigen concentration.¹⁸ All blood samples were collected in citrate tubes, centrifuged at 4°C immediately, and plasma stored in aliquots at -70° until used for the various analyses. Plasma for PAI-1 measurements were shipped by overnight express under dry ice to G.T.’s laboratory in Boston for measurement.

Results are expressed as mean±SEM. Means of 2 groups were compared with Student’s nonpaired t test and Kruskal-Wallis 1-Way ANOVA. Pearson’s product-moment correlations and partial correlation coefficients were calculated to determine relations between variables of interest. Finally, multiple regression analysis was performed using different models (see Results) with dependent variable being PAI-1 antigen concentration. Statistical analyses were conducted using Systat 7.0 package for Windows.

	Results

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Table 1 compares the values of the measured variables in the insulin-sensitive and insulin-resistant groups. It is apparent that the 2 groups were essentially identical in terms of age, overall (BMI) and regional (ratio of waist-to-hip girth [WHR]) obesity, and mean arterial blood pressure (MAP). In addition, the 2 groups were similar in terms of menopausal status and in the number of postmenopausal women receiving hormone replacement therapy. SSPG concentration was more than twice as high in the individuals defined as being insulin-resistant, associated with significantly higher plasma concentration of insulin, TG, and PAI-1 antigen, and lower HDL cholesterol concentrations. However, LDL-cholesterol concentrations were similar in the 2 groups. The significance of the differences between the 2 groups was obviously independent of the method of statistical analysis.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Insulin-Sensitive and Insulin-Resistant Women (Mean±SEM)

Although the population was selected to obtain 2 groups on the basis of their degree of insulin resistance, the difference between the insulin-sensitive individual with the highest SSPG and the insulin-resistant subject with the lowest SSPG was relatively small (135 versus 158 mg/dL). Based on this information, we thought it reasonable to consider SSPG as a continuous variable, permitting us to calculate Pearson’s correlation coefficients between PAI-1 concentration and the variables that were significantly different in Table 1. The results of this analysis are given in Table 2 and show that the PAI-1 concentration was significantly (P<0.05) correlated with age, BMI, SSPG concentration, fasting insulin, TG, and HDL cholesterol concentrations. When partial correlation coefficients between PAI-1 and the metabolic variables were determined, adjusted for differences in age and BMI, it can be seen in Table 2 that significant relationships continued to exist between PAI-1 concentrations and SSPG, insulin, TG, and HDL cholesterol concentrations. Parenthetically, the significant simple correlation coefficient (r=0.39, P=0.03) between BMI and PAI-1 was no longer significant when adjusted for differences in SSPG concentration (r=0.16, P=0.41).

View this table: [in this window] [in a new window]   Table 2. Simple and Partial Correlations for PAI-1 in the 32 Normotensive Women Volunteers

To further define the relationship between PAI-1 concentrations and the variables related to it, multiple regression analysis was used. Table 3 presents the relationship between PAI-1 and age, BMI, WHR, MAP, and SSPG. It can be seen that only SSPG was significantly related to PAI-1, with a standardized regression coefficient of 0.65, P<0.001. Because fasting insulin and SSPG concentrations are highly correlated, we did not enter them in the same model. However, when insulin concentrations replaced SSPG in the model, the standardized regression coefficient was quite similar (0.74, P<0.001). Furthermore, the r² values for the models with either SSPG or insulin entered were essentially identical, being 0.64 and 0.57, respectively.

View this table: [in this window] [in a new window]   Table 3. Multiple Regression Analysis of the Relationship Between PAI-1, Age, BMI, MAP, WHR, and SSPG

The addition of TG to the model shown in Table 3 had essentially no effect. However, when HDL cholesterol was entered, the results shown in Table 4 indicate that the strength of the relationship between SSPG and PAI-1 was greatly weakened. An essentially identical result was seen when fasting insulin replaced SSPG in the model shown in Table 4. Finally, when SSPG was replaced with HDL cholesterol in the model shown in Table 3, HDL cholesterol was independently related to PAI-1, with a standardized regression coefficient of -0.74, P<0.001. The r² for this model was 0.63, ie, essentially identical to the value when SSPG, rather than HDL cholesterol, was entered.

View this table: [in this window] [in a new window]   Table 4. Multiple Regression Analysis of the Relationship Between PAI-1, Age, BMI, MAP, WHR, SSPG, T6, and HDL Cholesterol

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The primary goal of the investigation was to see whether PAI-1 concentrations varied as a function of differences in insulin-mediated glucose disposal in 2 groups of healthy women matched for every other variable thought to play a role in regulation of PAI-1. As such, the results presented were unequivocal in that PAI-levels were higher in insulin-resistant as compared with insulin-sensitive women, despite the fact that the 2 groups were identical in terms of age, menopausal status, hormone replacement therapy, overall obesity (BMI), regional fat distribution (WHR), and blood pressure. Thus higher PAI-levels in insulin-resistant women cannot be attributed to differences in any of the above potentially confounding variables. This point of view is in contrast to the findings of Nagi et al,⁷ Mykkanen et al,⁸ and Toft and associates,⁹ all 3 groups coming to the conclusion that obesity, not insulin resistance, was a determinant of PAI-1. There are several possible reasons for the disparity in experimental results. For example, the subjects studied by Nagi et al⁷ were generally obese and included individuals with diabetes and impaired glucose tolerance, and Toft et al⁹ studied only patients with hypertension. In contrast, we excluded individuals with any known disease. In addition, the method¹⁹ used to quantify insulin resistance by Mykkanen and associates⁸ has a much weaker correlation in glucose-tolerant individuals (r=0.53, P<0.05) to the hyperinsulinemic clamp technique for measuring insulin-mediated glucose disposal than the approach¹⁶ we used (r=0.9, P<0.001). Although these differences may be important ones, we believe the most likely explanation for the disparity in results is the fundamental difference in the experimental protocol of the various studies. Specifically, at the outset of our study, we purposefully recruited 2 groups of volunteers, totally disparate on the basis of insulin-mediated glucose disposal but similar in terms of BMI and WHR. In contrast, the conclusion of the other research groups that these measures of obesity were independent determinants of PAI-1 was based on multiple regression analysis and in 2 instances^{8 9} involved a random selection of nondiabetic volunteers from previously conducted population-based studies initiated for other reasons. However, even when we applied multiple regression analysis to our entire population, we were unable to confirm an independent relationship between PAI-1 and either BMI or WHR (see Tables 3 and 4). On the other hand, the study population was chosen to evaluate the relationship between insulin resistance and PAI-1. It is certainly possible that the relationship between obesity and PAI-1 would have been greater if the study population had a greater range of obesity.

Although we were unable to discern any relationship between measures of obesity and PAI, our results in other respects are consistent with previous publications. In this respect, our findings resemble most closely those of Byberg and associates,¹⁰ who found that insulin sensitivity was a statistically significant determinant of PAI-1 activity, independent of TG, BMI, and WHR in men. In addition, similar to the findings of Nagi et al⁷ and Mykkanen et al,⁸ we found that in women, PAI-1 was significantly related to both HDL cholesterol concentration and/or insulin concentration. Parenthetically, given the close association between insulin resistance and hyperinsulinemia,^{5 6} it seems somewhat surprising that insulin concentration, but not insulin action, was independently related to PAI-1 in the studies of Mykkanen and associates.⁸ Again, this may be the confounding effect that exists when 2 closely related variables are entered into multiple regression models.

It should be emphasized that our conclusion that the relationship between insulin resistance and PAI-1 concentrations is independent of obesity does not rule out the possibility that obesity, per se, may contribute to an increase in PAI-1 concentrations. Indeed, the results in Table 1 documented a simple correlation coefficient between BMI and PAI-1 that was statistically significant (r=0.39, P=0.03). The fact that it was no longer significant when adjusted for differences in SSPG suggests that the relationship between PAI-1 and insulin resistance is closer than that between PAI-1 and obesity. However, our experimental population was limited to 32 subjects, and our inability to discern a relationship between BMI and PAI-1 may represent a type II error. Consequently, we would like to reiterate that our findings do not negate the possibility that BMI and PAI-1 are also significantly related.

In conclusion, PAI-1 concentrations were higher in insulin-resistant than in insulin-sensitive women, and this difference was seen despite the fact that the 2 groups were essentially identical in terms of BMI and WHR. Three metabolic variables seemed to be closely related to PAI-1 concentrations—insulin resistance, plasma insulin concentration, and HDL cholesterol concentration. The 3 variables that were most closely related to PAI-1 are themselves highly correlated. As such, we would be loath to speculate as to which of these was "independently" related to PAI-1. However, we are not reluctant to conclude that PAI-1 levels were higher in insulin-resistant as compared with insulin-sensitive women and that this was not because the insulin-resistant women were more obese. As such, elevated PAI-1 concentrations appear to be another reason why insulin-resistant individuals are at increased risk for coronary heart disease.

	Acknowledgments

 
Supported by Research Grants (HL-08506 and RR-00070) from the National Institutes of Health.

Received August 27, 1998; accepted March 31, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Juhan-Vague I, Alessi MC, Joly P, Thirion X, Vague P, Declerck PJ, Serradimigni A, Collen D. Plasma plasminogen activator inhibitor in angina pectoris: influence of plasma insulin and acute phase response. Arteriosclerosis. 1989;9:362–367.[Abstract/Free Full Text]

2. Landin K, Tengborn L, Smith U. Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med. 1990;227:273–278.[Medline] [Order article via Infotrieve]

3. Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels: a possible link between insulin resistance and atherothrombosis. Diabetologia. 1991;34:457–462.[Medline] [Order article via Infotrieve]

4. Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the hemostatic system in the insulin resistance syndrome. Arterioscler Thromb. 1993;13:1865–1873.[Abstract/Free Full Text]

5. Hollenbeck C, Reaven GM. Variations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab. 1987;64:1169–1173.[Abstract/Free Full Text]

6. Reaven GM, Brand RJ, Chen Y-DI, Mathur AK, Goldfine I. Insulin resistance and insulin secretion are determinants of oral glucose tolerance in normal individuals. Diabetes. 1993;42:1324–1332.[Abstract]

7. Nagi DK, Tracy R, Pratley R. Relationship of hepatic and peripheral insulin resistance with plasminogen activator inhibitor-1 in Pima Indians. Metabolism. 1996;45:1243–1247.[Medline] [Order article via Infotrieve]

8. Mykkanen L, Tapani R, Marniemi J, Haffner SM, Bergman R, Laakso M. Insulin sensitivity is not an independent determinant of plasma plasminogen activator inhibitor-1 activity. Arterioscler Thromb. 1994;14:1264–1271.[Abstract/Free Full Text]

9. Toft I, Bfnaa KH, Ingebretsen, OC, Nordfy A, Birkeland KI, Jenssen T. Gender differences in the relationships between plasma plasminogen activator inhibitor-1 activity and factors linked to the insulin resistance syndrome in essential hypertension. Arterioscler Thromb Vasc Biol. 1997;17:553–559.[Abstract/Free Full Text]

10. Byberg L, Siegbahn A, Berglund L, McKeigue P, Reneland R, Lithell H. Plasminogen activator inhibitor-1 activity is independently related to both insulin sensitivity and serum triglycerides in 70-year-old men. Thromb Vasc Biol. 1998;18:258–264.[Abstract/Free Full Text]

11. Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Eng J Med. 1985;313:1557–1563.[Abstract]

12. Lijnen HR, Collen D. Impaired fibrinolysis and the risk for coronary heart disease. Circulation. 1996;94:2052–2054.[Free Full Text]

13. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28:1039–1057.[Medline] [Order article via Infotrieve]

14. Harano Y, Ohgaku S, Hidaka H, Haneda K, Kikkawa R, Shigeta Y, Abe H. Glucose insulin and somatostatin infusion for the determination of insulin sensitivity. J Clin Endocrinol Metab. 1977;45:1124–1127.[Abstract/Free Full Text]

15. Shen SW, Reaven GM, Farquhar JW. Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes. J Clin Invest. 1970;49:2151–2160.

16. Greenfield MS, Doberne L, Kraemer FB, Tobey TA, Reaven GM. Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp. Diabetes. 1981;30:387–392.[Abstract]

17. Carantoni M, Abbasi F, Chu L, Chen Y-DI, Azhar S, Reaven GM. Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM. Diabetes Care. 1997;20:1462–1465.[Abstract]

18. Gebara OCE, Mittleman MA, Sutherland P, Lipinska I, Matheney T, Xu P, Welty FK, Wilson PWF, Levy D, Muller JE, Tofler GH. Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation. 1995;91:1952–1958.[Abstract/Free Full Text]

19. Saad MF, Anderson RL, Laws A, Watanabe RM, Kades WW, Chen Y-DI, Sands RE, Pei D, Savage PJ, Bergman RN, for the Insulin Resistance Atherosclerosis Study. A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Diabetes. 43:1114–1121.

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This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Abbasi, F. Articles by Reaven, G. M. Search for Related Content PubMed PubMed Citation Articles by Abbasi, F. Articles by Reaven, G. M. Related Collections Coagulation and fibronolysis Lipid and lipoprotein metabolism