Published online before print February 25, 2002, doi: 10.1161/hc1102.105565
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(Circulation. 2002;105:1311.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Sex Differences in the Association Between Proinsulin and Intact Insulin With Coronary Heart Disease in Nondiabetic Older Adults
The Rancho Bernardo Study
From the Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego.
Correspondence to Dr Elizabeth Barrett-Connor, Department of Family and Preventive Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0607. E-mail ebarrettconnor{at}ucsd.edu
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Abstract |
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Background— Insulin or insulin resistance is considered a coronary heart disease (CHD) risk factor, but proinsulin may have a stronger association with CHD than insulin. The role of sex differences in this association is unclear. We examined the cross-sectional association of proinsulin and insulin with CHD in older men and women without diabetes.
Methods and Results— A cross-sectional study of community-dwelling men (n=554) and women (n=902), 50 to 97 years of age, without diabetes by history or oral glucose tolerance test, was done between 1992 and 1996; plasma levels of intact insulin, proinsulin, and C-peptide were measured by radioimmunoassay. Based on questionnaire, medical history, or ECG abnormalities, 25% of men (n=136) and 24% of women (n=214) had prevalent CHD. All insulin variables were positively correlated with CHD risk factors. Compared with those without CHD, men and women with CHD had significantly higher levels of proinsulin. Women but not men with CHD also had higher levels of C-peptide and fasting and postchallenge insulin. Only proinsulin was significantly and independently associated with prevalent CHD in both men (OR=2.41, 1.42 to 4.11) and women (OR=1.80, 1.22 to 2.64) (adjusted for age, body mass index, systolic blood pressure, and HDL cholesterol). Similar analyses for fasting and postchallenge intact insulin and for C-peptide showed that among these three variables, only postchallenge insulin was significantly associated with CHD, and only in women.
Conclusions— In older nondiabetic men and women, proinsulin was more strongly and consistently associated with CHD than was intact insulin.
Key Words: coronary disease • insulin • sex • diabetes mellitus
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Introduction |
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Previous prospective studies have shown an association between both fasting and postchallenge insulin levels and coronary heart disease (CHD) in men1–3 but not in women.1,4–6 In the earlier studies, insulin concentrations were measured by immunoassays with polyclonal antibodies, which cross-react with largely inactive insulin precursor molecules such as proinsulin and des-31,32 proinsulin.7 These proinsulin molecules can be distinguished from the more active intact insulin molecules by using highly sensitive and specific 2-site immunoassays based on monoclonal antibodies.8 After these assays became available, several groups reported that proinsulin was more strongly associated with heart disease risk than insulin.9–14 Disturbed fibrinolysis12,14 and autonomic dysfunction14 are considered to be possible mechanisms by which proinsulin may cause CHD. No studies have compared intact insulin versus proinsulin as a CHD risk factor in men versus women.
C-peptide, an indicator of insulin secretion, is cleaved from proinsulin, stored in secretory granules, and eventually released into the bloodstream in amounts equimolar to those with insulin.15 It has been generally accepted that C-peptide has little or no biological activity. In a recent report, however, C-peptide was a more powerful predictor of myocardial infarction than insulin.16
In the present cross-sectional study, we compared insulin, proinsulin, and C-peptide levels, CHD risk factors, and prevalent CHD in community-dwelling older men and women without diabetes.
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Methods |
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Study Cohort
From 1992 to 1996, older white adults (50 to 97 years) from a southern California residential community participated in the Rancho Bernardo Heart and Chronic Disease Study, a population-based cohort study begun in 1972. The current study population (n=1781) included
75% of the surviving Rancho Bernardo cohort. Informed consent was obtained from all subjects. The study was approved by the Institutional Review Board of the University of California, San Diego. A morning 75-g oral glucose tolerance test was performed after a minimum 8-hour overnight fast. Fasting and 2-hour postchallenge plasma glucose levels were measured with a glucose oxidase assay. Subjects with type 1 or 2 diabetes, based on history or glycemia defined by the 1999 World Health Organization criteria,17 were excluded (n=276). The present study includes all 554 men and 902 women without diabetes who had measurements of insulin, proinsulin, and C-peptide. Fasting and postchallenge insulin levels were measured in the research laboratory of S. Edwin Fineberg (Indiana University), with the use of a human insulin-specific radioimmunoassay (RIA) double-antibody Linco kit (Linco Research).18 This assay cross-reacts with both human proinsulin and des-31,32 proinsulin <0.2%; des-64,65 proinsulin cross-reacts 76%, but des-64,65 proinsulin is an extremely minor component of insulin-like materials, and the sensitivity was 2 µU/mL. Two levels of control external standards were used. Intra-assay and interassay coefficients of variations (CV) for control level 1 were 5.5% and 15%, respectively, and for control level 2, 3.7% and 5.1%, respectively. Proinsulin was measured with a RIA based on a method by Bowsher et al.19 Human insulin and C-peptide do not cross-react with proinsulin in this assay. Sensitivity was 2 pmol/L, and intra-assay and interassay CV were from 5% to 16%. C-peptide was measured with RIA assay kits (Linco Research). Sensitivity was 0.10 ng/mL. External controls used Biorad levels 1 through 3, with intra-assay CV of 3% to 5% and interassay CV of 11.1% to 18.3%. Cross-reactivity between proinsulin and C-peptide was <4%.
The presence of CHD was based on the Rose Questionnaire,20 medical history reported by a doctor, or major ECG abnormalities. A standard 12-lead resting ECG was performed before the oral glucose tolerance test after the subjects had been supine for at least 5 minutes. ECG tracings were coded at the University of Minnesota through the use of the Minnesota code.21 Myocardial infarction was diagnosed by the presence of major ECG Q-wave abnormalities (Minnesota codes 1.1 and 1.2),21 a history of physician-diagnosed heart attack, or severe chest pain lasting for >30 minutes. Medical history of CHD was validated for 85% of the 30% subset whose hospital records were requested.
Height and weight were measured with subjects wearing lightweight clothing without shoes; body mass index (BMI) was calculated as weight (kg)/height2 (m2). Waist and hip girth were measured in centimeters over single-thickness clothing with the participant standing in an erect position with feet together. Waist circumference was used as an integrated measure of obesity and fat distribution. Lipids were measured in a Lipid Research Clinic Laboratory certified by the Center for Disease Control. Total cholesterol and triglycerides were measured by enzymatic methods with an ABA-200 biochromatic analyzer (Abbott), HDL cholesterol was measured by precipitation according to Lipid Research Clinic protocol,22 and LDL cholesterol was calculated by means of the formula of Friedewald and colleagues.23 Personal history of hypertension, diabetes, current cigarette smoking, daily alcohol consumption, and regular exercise (
3 times per week) were determined by standardized questionnaire and interview.
Statistical Methods
Data were analyzed with SAS Version 8.1 (SAS Institute). Because fasting and postchallenge plasma insulin, triglycerides, and HDL cholesterol showed slightly skewed distributions, analyses were performed by means of log-transformed data. Mean values were presented for untransformed data; however, all probability values were based on logarithmic data. Bivariate associations between CHD prevalence and related risk factors were evaluated with a Student’s t test for continuous variables and a 
2 test for categorical variables. Age-adjusted partial correlation analyses were used to determine the relation between all insulin measurements and CHD risk factors. Multiple logistic regression analyses were used to assess the independent association of insulin with prevalent CHD. Age, BMI, systolic blood pressure, and HDL cholesterol were evaluated as covariates. Potential confounding and effect modification were explored by entering covariates and interaction terms into the logistic regression models and evaluating the differences between the log-likelihood ratio statistics. All insulin levels were analyzed as continuous variables for correlation and multiple logistic regression analyses. Insulin quartiles were used to determine if there was a graded or threshold association with prevalent CHD. All probability values were 2-tailed, and statistical significance was defined as P<0.05.
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Results |
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Twenty-five percent of men (n=136) and 24% of women (n=214) had prevalent CHD at this visit (1992 to 1996). Table 1 presents age-adjusted mean values for body size, blood pressure, lipids, lipoprotein, glucose, and insulin levels by CHD status. Men and women with CHD were older than those without CHD. Women with CHD had higher systolic blood pressure, pulse pressure, and triglyceride levels, lower HDL cholesterol levels, and a higher total cholesterol/HDL cholesterol ratio than women without CHD. Except for pulse pressure, which was higher for men with CHD, these differences were not observed in comparisons of men with and without CHD. Diastolic blood pressure was lower in men with CHD than in men without CHD. Men with CHD had significantly higher levels of fasting proinsulin (P<0.01) only. Women with CHD had significantly higher levels of fasting insulin (P<0.05), postchallenge insulin (P<0.01), proinsulin (P<0.001), and C-peptide (P<0.05). Exercise
3 times per week, daily alcohol consumption, and current smoking did not differ by CHD status in either men or women (data not shown). Significantly fewer women with CHD were current estrogen users compared with women without CHD (38.3% versus 48.8%, P<0.05).
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Tables 2 and 3 present the age-adjusted correlation coefficients for fasting and postchallenge insulin, proinsulin, and C-peptide with CHD risk factors in these nondiabetic men and women. In both sexes, BMI, waist circumference, waist-to-hip ratio, fasting and postchallenge glucose, and triglyceride levels were positively correlated with fasting and postchallenge insulin, proinsulin, and C-peptide, whereas HDL cholesterol was negatively correlated. LDL cholesterol was positively correlated with fasting and postchallenge insulin, proinsulin, and C-peptide in women only. Systolic blood pressure was positively correlated with fasting and postchallenge insulin in women only. Diastolic blood pressure was positively correlated with postchallenge insulin in men and with fasting and postchallenge insulin and C-peptide in women.
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Multiple logistic regression analyses for the association between fasting and postchallenge insulin, proinsulin, and C-peptide and CHD prevalence are shown in Table 4. After controlling for age, BMI, systolic blood pressure, HDL cholesterol, and current estrogen use (women), proinsulin remained positively associated with CHD prevalence in both men (P<0.01) and women (P<0.01). In women, postchallenge insulin was also positively associated with CHD prevalence (P<0.05). Fasting insulin and C-peptide levels were not associated with prevalent CHD in men or women. Results did not differ when analyses were adjusted for waist circumference instead of BMI or when adjusted for pulse pressure instead of systolic blood pressure (data not shown). There were no significant interactions observed.
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The age-adjusted prevalence of CHD by sex-specific quartiles of proinsulin showed a significant positive linear trend between increasing proinsulin quartiles and prevalent CHD for both men and women (Figure). Among men, this was the only significant trend observed for insulin variables. Association between fasting insulin and age-adjusted prevalence of CHD was observed in women only (P<0.05, data not shown).
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Discussion |
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In this study, proinsulin levels showed a graded positive association with prevalent CHD in older men and women without diabetes. For women only, significant associations were also observed between prevalent CHD and fasting or postchallenge intact insulin. This finding is inconsistent with previous prospective studies, which showed an association between insulin levels and CHD in men1–3 but not in women.1,4–6 One cross-sectional study showed an association between postchallenge insulin and previous myocardial infarction in women but not men.24 These studies were done in the era when insulin assays cross-reacted with proinsulin.7,25
Proinsulin is more strongly correlated with cardiovascular risk factors than fasting or postchallenge insulin in both diabetic9,10 and nondiabetic11–13 subjects. However, Kahn and colleagues26 reported no association between proinsulin and CHD independent of diabetes status in Japanese-American men (CHD was defined by the London School of Hygiene Cardiovascular Questionnaire or resting ECG abnormality). More recently, Haffner and colleagues14 reported that the association between proinsulin and carotid intima-media wall thickness, a marker for atherosclerosis, was stronger than insulin by correlation analyses. This study did not consider diabetes status and reported men and women combined. We are aware of no previous studies comparing insulin and proinsulin association with CHD in nondiabetic men and women from the same cohort.
Several potential mechanisms could explain the association of hyperinsulinemia with atherosclerotic vascular disease, including a direct effect of insulin on the arterial wall,27 or an effect mediated by the clustering of hyperinsulinemia with other risk factors, such as impaired glucose tolerance, elevated triglycerides, decreased HDL cholesterol, elevated blood pressure, and obesity.28 In the present study, adjusting for these risk factors did not explain the proinsulin-CHD association.
The activity of proinsulin on glucose metabolism, in vitro or in vivo, is 10% of all insulin-like molecules29; nevertheless, high concentrations appear to have a biological effect. Altered hemostasis is one hypothesis for the mechanism whereby proinsulin influences atherosclerosis. Proinsulin is associated with increased plasminogen activator inhibitor-1 (PAI-1) activity, the main regulator of fibrinolysis.30 In experimental studies, proinsulin induced an increase in PAI-1 secretion from endothelial cells30 and hepatocytes31 in culture. Insulin therapy has been found to suppress both PAI-1 activity and proinsulin secretion in type 2 diabetic patients.32 Alternatively, Haffner and colleagues14 suggested autonomic dysfunction as a possible mechanism for an association between increased proinsulin and increased carotid atherosclerosis.
In the present study, there were significant correlations between CHD risk factors and fasting C-peptide in both men and women but no association with prevalent CHD. In one study, basal C-peptide was reported to be the most powerful determinant for myocardial infarction in men surviving a first myocardial infarction.16 In another study, C-peptide was correlated with angiographic coronary artery atherosclerosis in young men.13 Insulin is partially extracted on first pass through the liver, but C-peptide is unaffected. C-peptide could be expected to have a more powerful independent effect on atherosclerosis compared with relatively lower levels of insulin after hepatic extraction,16 but the present null results make a direct influence of C-peptide on the atherosclerotic process seem unlikely.
The present study has several potential limitations. First, these findings are limited in their generalizability because the participants were older white adults. Also, the cross-sectional study design disallows inference on temporal sequence and causality; however, one prospective study has found that high proinsulin levels precede CHD.11 Third, the methods used for classifying CHD status could have resulted in sex-specific misclassification, because women may be selectively misdiagnosed33; this would be expected to reduce associations in women, not men, the reverse of the association observed here. The Rose Questionnaire for angina pectoris is less accurate for a diagnosis of CHD in women than in men.34 In the present study, however, few men (8%) and women (10%) with CHD had angina pectoris only, and results were unchanged when the angina cases were excluded from the analysis. Diagnosis of CHD based on ECG could have been missed, because Q waves can resolve over time. None of these design characteristics seem likely to explain why proinsulin has a stronger and more consistent association with CHD than intact insulin or C-peptide. Control for confounding factors was handled in the analysis, although we cannot fully exclude residual confounding or potential confounders not accounted for.
In the present study, proinsulin and fasting and postchallenge insulin were positively and significantly associated with prevalent CHD in women, whereas only proinsulin was significantly associated with prevalent CHD in men. To our knowledge, this is the first report to evaluate the potential different effect of proinsulin on men and women. The observation that proinsulin was more strongly associated with prevalent CHD than fasting insulin in both sexes is compatible with previous studies that did not report effect modification by sex.9–14,28 The mechanism for the differential effect is unknown. Selective mortality of hyperinsulinemic men but not women cannot be excluded, but Ferrara and colleagues35 found that intact insulin did not predict future CHD in the older men in this cohort (proinsulin was not measured in this earlier study). Prospective examinations of proinsulin and CHD in older men and women are needed to confirm the sex differences observed here and to elucidate the mechanism for the association between proinsulin levels and heart disease.
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Acknowledgments |
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This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, grant DK31801, and National Institute on Aging, grant AG07181.
Received October 10, 2001; revision received December 27, 2001; accepted January 9, 2002.
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