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(Stroke. 1997;28:1147-1152.)
© 1997 American Heart Association, Inc.

Articles

Relationship Between Insulin and Carotid Atherosclerosis in the General Population

The Bruneck Study

E. Bonora, MD, PhD; J. Willeit, MD; S. Kiechl, MD; F. Oberhollenzer, MD; G. Egger, MD; R. Bonadonna, MD; M. Muggeo, MD

From the Department of Endocrinology and Metabolic Diseases, University of Verona (Italy) Medical School (E.B., R.B., M.M.), the Department of Internal Medicine, Hospital of Bruneck (Italy) (F.O., G.E.), and the Department of Neurology, University of Innsbruck (Austria) Medical School (J.W., S.K.).

Correspondence to Professor Enzo Bonora, Endocrinologia e Malattie del Metabolismo, Ospedale Civile Maggiore, Piazzale Stefani, 1, I-37126 Verona, Italy.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Although several studies have investigated the association between insulin and coronary heart disease, the relationship between this hormone and carotid atherosclerosis is not well established.

Methods As a part of a population-based survey on atherosclerosis and its risk factors, serum insulin was measured at fasting (n=888) and at 2 hours after an oral glucose load (n=811; known diabetic subjects were excluded). The study population comprised an age- and sex-stratified random sample of men and women aged 40 to 79 years. Atherosclerosis in the common and internal carotid arteries was assessed twice (in 1990 and 1995) by duplex sonography. Progression during the 5-year follow-up was defined by an increase in the atherosclerosis score of more than the doubled measurement error (>27%) or by the occurrence of new plaques. Subjects were stratified in quintiles according to baseline serum insulin at fasting or 2 hours after glucose loading.

Results Logistic regression analysis revealed a significant association of carotid atherosclerosis with both low and high insulin (U-shaped relation). This finding was found before and after adjustment for several covariates (sex, age, body mass index, glucose tolerance, triglycerides, apolipoproteins A1 and B, fibrinogen, blood pressure status, behavioral variables, and socioeconomic status). This relation applied equally to fasting and postglucose insulin and was more pronounced in the prospective analysis than in the cross-sectional analysis.

Conclusions We conclude that both "hypoinsulinemia" and hyperinsulinemia are independent risk indicators of carotid atherosclerosis.

Key Words: carotid artery disease • insulin • risk factors

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
As reported in the last decade by several investigators, including ourselves, hyperinsulinemia is associated with an unfavorable risk profile for atherosclerosis^{1 2 3 4 5 6} and predicts the development of metabolic and hemodynamic abnormalities associated with high cardiovascular risk.⁷ In addition, there are several reports supporting the idea that hyperinsulinemia is a risk factor for CHD independent of classic risk factors such as dyslipidemia, glucose intolerance, hypertension, and others.^{8 9 10 11 12 13 14}

So far no prospective study and only a few cross-sectional studies have explored the relationship between serum insulin and CA. All previous cross-sectional reports used the IMT as a surrogate of early atherosclerosis in the carotid arteries.^{15 16 17} These studies yielded contradictory results and only partially adjusted for confounding factors.^{15 16 17} Consequently, there is still a rather high degree of uncertainty concerning the role of insulin as an independent risk factor for CA.

In the present cross-sectional and prospective population-based study, we examined the relationships existing between serum insulin and CA in a large random sample of men and women aged 40 to 79 years.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects
The Bruneck Study is a cross-sectional and prospective population-based survey on atherosclerosis and its risk factors that was carried out in Bruneck, a small town of about 13 500 persons in northeastern Italy. As previously reported,¹⁸ the baseline evaluation was carried out between July and November 1990 on subjects aged 40 to 79 years. Of the 4793 subjects of the appropriate age range, 125 men and 125 women for each age decade (40-49, 50-59, 60-69, and 70-79) were randomly selected and invited to participate in the study. Of the 1000 subjects, 936 volunteered after the purposes and modalities of the study had been carefully presented. After excluding 2 subjects who were insulin treated, 17 subjects with incomplete data collection, and 29 subjects with insufficient serum, 888 subjects (450 men and 438 women) underwent a measurement of serum insulin at fasting; 811 of them also underwent measurement after oral glucose loading (known diabetic patients did not undergo this test).

From July through November 1995, a reevaluation of the cohort was carried out. Of the 888 subjects who had serum insulin measurement in 1990, 54 were deceased, 1 had moved away and could not be traced, and 29 refused to participate in the follow-up study. As a consequence, 804 subjects were reexamined 5 years later.

Clinical Data
The following demographic and clinical data were collected by the use of a standardized questionnaire as previously described¹⁸ : sex, age, cigarette smoking, alcohol consumption, physical activity, and socioeconomic status. Comorbidity was recorded, and health condition was regarded as "poor" if a given individual was suffering from malignancy, severe autoimmune disorders (eg, systemic lupus erythematosus or rheumatoid arthritis), heart failure (New York Heart Index=4), cardiovascular disease (positive history of myocardial infarction, stroke, or symptomatic peripheral artery disease), active tuberculosis, liver cirrhosis, or uremia as ascertained by medical history, physical examination, and routine laboratory analysis or when the subject reported a weight loss >10 kg within the last 5 years or had a Barthel Index score 80.

Subjects were regarded as diabetic if they were receiving insulin and/or oral hypoglycemic agents, fasting plasma glucose exceeded 7.8 mmol/L, or plasma glucose at 2 hours after oral glucose loading exceeded 11.1 mmol/L.¹⁹ Impaired glucose tolerance was diagnosed when plasma glucose at 2 hours after glucose load exceeded 7.8 mmol/L.¹⁹

Physical Examination Data
Weight (to the nearest 0.5 kg) and height (to the nearest 0.5 cm) were measured while the subjects were fasting and wearing only underwear. BMI was calculated as weight (kilograms) divided by height (meters) squared. Subjects with BMI exceeding 25 kg/m² were categorized as obese. This criterion does not exactly conform to conventional ones²⁰ and was arbitrarily used for descriptive purposes.

Blood pressure was measured with a standard mercury sphygmomanometer on the left arm after the subjects had been seated for at least 10 minutes. Mean values were determined from two independent measurements taken at 10-minute intervals. Hypertension was defined by a systolic blood pressure 160 mm Hg or diastolic blood pressure 95 mm Hg or when an antihypertensive treatment was in progress.²¹

Laboratory Data
In the morning, after subjects had fasted overnight, 10 mL of venous blood was collected for the measurement of the levels of glycosylated hemoglobin (HbA_1c), plasma concentrations of glucose, serum concentrations of total and HDL cholesterol, triglycerides, apolipoproteins A1 and B, fibrinogen, antithrombin III, and insulin. Thereafter, a 75-g oral glucose load was administered to all subjects, except for those with well-established diabetes mellitus; venous blood was collected at 120 minutes for the measurement of plasma glucose and serum insulin. Glycosylated hemoglobin, plasma glucose, serum lipids and apolipoproteins, fibrinogen, and antithrombin III were measured as previously described.¹⁸ Serum insulin was measured in sera stored at -30°C within 6 months after collection according to the method of Hales and Randle.²² Intra-assay and interassay coefficients of variation were 3.2% and 6.9%, respectively.

Assessment of CA
At baseline and 5 years later, CA was determined by high-resolution B-mode ultrasound (ATL UM8, Advanced Technology Laboratories) as previously described.¹⁸ All measurements were carried out by a single specialist physician (J.W.), who was blinded to any clinical information about the subjects. Images were recorded on videotape. Briefly, the scanning protocol included imaging of the common and internal carotid arteries in multiple longitudinal and transverse planes. The near and far walls at each of four well-defined imaging sites of both carotid arteries were explored: proximal common carotid artery, 15 to 30 mm proximal to the carotid bulb; distal common carotid artery, <15 mm to the carotid bulb; proximal internal carotid artery, carotid bulb and the initial 10 mm of the vessel; and distal carotid artery, >10 mm above the flow divider. Overall, 16 regions of interest were scanned, and plaques, if any, were measured in millimeters; the measurements were summed to derive an atherosclerosis score. Subjects were considered to be positive for CA at baseline when a focal plaque of any size was detected in either the common or the internal carotid arteries and negative when all segments were free of atherosclerotic lesions. The coefficient of agreement²³ for this categorization of the CA score (cross-sectional analysis) was 0.92. Five-year progression of atherosclerosis was coded present when the increase in the atherosclerosis score during the follow-up period (1990 through 1995) exceeded the doubled measurement error (>27%) or when new plaques occurred in subjects with an atherosclerosis score equal to 0 in 1990.

In the cross-sectional statistical analysis, subjects who had undergone carotid endarterectomy (n=2) were included in the group with CA, since the vascular status after surgery was abnormal (ie, subjects had multiple plaques). Four subjects who had undergone endarterectomy between 1990 and 1995 were excluded from the prospective statistical analysis because surgery interfered with the atherosclerosis score in 1995 and consequently with the assessment of CA progression.

Statistical Analysis
Statistical evaluation of the association between risk factors and insulin quintiles was based on ANCOVA, with sex, age, BMI, physical activity level, smoking habits, daily alcohol intake, and socioeconomic status used as covariates. Skewed variables were preliminarily log_e-transformed to improve the approximation to a gaussian distribution.

To examine the relationship between insulin and CA, logistic regression models were fitted with the hypothesis test based on likelihood-ratio statistics.²⁴ The analyses were adjusted for variable sets of covariates. Model 1 included sex and age. Model 2 included sex, age, BMI, glucose tolerance, socioeconomic status, and behavioral variables. Model 3 included all these variables plus triglycerides, apolipoproteins A1 and B, fibrinogen, and blood pressure status. The goodness of fit of each model was assessed by the test of Hosmer and Lemeshow.²⁵ To identify the best scale in the logit, insulin was subdivided into quintiles and treated as a categorical variable (indicator variable).²⁴ The insulin quintile with the lowest atherosclerosis risk was defined as the reference category (odds ratio, 1) for ease of presentation and interpretation. We have tested whether sex and age modified the association between serum insulin and CA by inclusion of interaction terms in the logistic regression analysis. Neither of these calculations yielded evidence of significant effect modification. Likewise, separate analysis in men and women, and in different age groups, yielded similar results. Therefore, we present data pooled for sex and age decades. All analyses were carried out using SPSS-X and BMDP software.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The main clinical features of the study population are summarized in Table 1.

View this table: [in this window] [in a new window]   Table 1. Main Clinical Features of the Study Population (n=888)

At the baseline (1990), CA (ie, plaques of any size) was found in 377 subjects: 159 were women (prevalence, 36.2%) and 218 were men (prevalence, 48.4%). Prevalence rates of CA within the four age decades were 5.6% (age 40 to 49 years), 31.7% (50 to 59 years), 57.3% (60 to 69 years), and 79.5% (70 to 79 years). At the 1995 follow-up examination, 800 subjects without carotid endarterectomy had a duplex carotid reassessment, and 400 of them showed a progression of CA or occurrence of new atherosclerotic lesions (men 60%, women 41%).

Subjects with CA had an unfavorable profile of cardiovascular risk (higher concentrations of glucose, LDL cholesterol, and apolipoprotein B and higher blood pressure values). Mean serum insulin levels after glucose load were higher in subjects with CA (Table 2).

View this table: [in this window] [in a new window]   Table 2. Risk Factors of Atherosclerosis in Subjects With and Without CA at Baseline (1990)

Logistic regression analysis of cross-sectional data (Table 3) showed a significant association between insulin levels and prevalent CA when insulin was analyzed jointly with age and sex (model 1) and also after adjustment for glucose tolerance, BMI, physical activity level, smoking habits, daily alcohol intake, and socioeconomic status (model 2) or after further inclusion of blood pressure status, triglycerides, apolipoproteins A1 and B, and fibrinogen (model 3). As to fasting insulin, the type of relation approached a U shape, with an increased atherosclerosis risk observed in quintiles I-II and IV-V. Analogous calculations for 2-hour insulin levels revealed an elevated risk of prevalent CA confined to the top quintiles (IV-V).

View this table: [in this window] [in a new window]   Table 3. Odds Ratios of Fasting and Postglucose Insulin Derived from Logistic Regression Analysis of CA at Baseline on Cardiovascular Risk Factors

As a main limitation of the cross-sectional design, the insulin levels assessed together with the vascular status are not necessarily those occurring at the time when atherosclerosis developed. Changes in insulin concentration over time may attenuate type and strength of the association with atherosclerosis. To overcome this potential source of bias, we repeated the analysis after completion of the 5-year follow-up (prospective analysis). As shown in Table 4, the progression of CA was significantly associated with both fasting and postglucose insulin. Indeed, a clear U-shaped relationship was found before and after adjustment for possible confounders. All models were statistically significant, and the strength of relation was more pronounced than in the cross-sectional analysis. The use of orthogonal polynomials documented the fit of a quadratic model for the relation of insulin with progressive CA.

View this table: [in this window] [in a new window]   Table 4. Odds Ratios of Fasting and Postglucose Insulin at Baseline Derived From Logistic Regression Analysis of 5-Year Progression of CA (1990-1995) on Cardiovascular Risk Factors

Separate analyses in men and women or in subjects aged <60 or 60 years showed similar associations between insulin and CA. For example, when the focus was on 5-year progression of CA, odds ratios for the fasting insulin quintiles (I through V) were as follows: age <60 years: 1.8, 1.0, 1.0, 1.6, and 2.4 (P<.05 for the likelihood-ratio test); age 60 years: 2.0, 1.4, 1.1, 1.0, and 2.6 (P=.1); men: 2.5, 1.9, 1.0, 1.0, and 2.6 (P<.05); women: 1.4, 1.0, 1.0, 1.1, and 2.7 (P=.1).

The results were substantially identical when fasting glucose or 2-hour glucose or HbA_1c was included in the model instead of the category of glucose tolerance (normal, impaired, diabetes) or when the statistical analysis was restricted to subjects with normal glucose tolerance. The relationship between insulin and CA was not appreciably different in normotensive and hypertensive subjects, in smokers and nonsmokers, and in subsamples categorized according to other significant risk indicators (no effect modification).

Because comorbidity ("poor health") resulting in changes in lifestyle and/or undernutrition with weight loss might be potential confounders in the relationship between insulin and atherosclerosis, (especially in samples including a high proportion of elderly subjects), we repeated the logistic regression analyses after excluding subjects with "poor health." These analyses confirmed the results obtained in the entire data set (data not shown).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study points out that in cross-sectional and prospective analysis, there is an independent association between CA and hyperinsulinemia, both in the fasting state and after an oral glucose load. Remarkably, the association between hyperinsulinemia and CA extended to both sexes and persisted after adjustment for several potential confounders, including dyslipidemia, glucose intolerance, hypertension, and others. Of particular importance is the fact that the relationship between insulin and CA was independent of glucose intolerance, whether ascertained by oral glucose tolerance test or HbA_1c or fasting plasma glucose, since this condition is generally associated with fasting hyperinsulinemia.^{2 6} In a recent study, IMT, which was used as a surrogate measure of definite CA,¹⁶ was significantly associated with fasting insulin in men but not women. Moreover, the independent association between insulin and IMT was not tested after adjustment for BMI, diabetes or glucose intolerance (oral glucose tolerance test was not performed), fibrinogen, triglycerides, physical activity, socioeconomic status, and "poor health." In another study,¹⁵ a weak correlation between insulin and IMT was found, but again no adjustment for potential confounders was made. In the only other large survey of which we are aware, fasting insulin was not independently correlated to IMT.¹⁷

An original finding of our study is that low serum insulin ("hypoinsulinemia"), far from being protective, was independently associated with CA in both cross-sectional and prospective analyses. This result seems to be solid and reliable for several reasons. First, a sensitive tool such as B-mode sonography of the carotid arteries was carefully used to detect and quantify atherosclerosis in several regions of interest on both sides. Second, the statistical analysis used here took into account most of the established risk factors of atherosclerosis (male sex, age, obesity, glucose intolerance, LDL cholesterol, apolipoprotein B and triglycerides, HDL cholesterol and apolipoprotein A1, hypertension, cigarette smoking, physical activity, and fibrinogen) and also controlled for other possible confounding factors such as poor health, socioeconomic status, and alcohol intake, the importance of which has been recently emphasized.^{26 27 28} Third, the present study was carried out in a large sample of unselected persons of the age decades in which atherosclerosis is maximally expressed. Fourth, the relationship between hypoinsulinemia and CA was consistent in men and in women.

Thus, the conclusion to be drawn from our data is that both hyperinsulinemia and hypoinsulinemia are independent risk predictors of atherosclerosis. Of course, "independent" means "not dependent" on the established risk factors and the other potential confounders for which our statistical analysis could adjust. We cannot exclude that other still unknown factors might mediate the relationship between low and high insulin with atherosclerosis.

At first glance, the association of low insulin with CA seems rather unexpected. Indeed, it gains some indirect support from previous studies concerning CHD. For example, Jarrett et al²⁹ in the Bedford Study found that insulin was a negative predictor of CHD in subjects with impaired glucose tolerance. Accordingly, Ferrara et al,³⁰ in a study of 538 men aged 50 to 80 years without diabetes or heart disease, recently reported higher mortality from CHD over 5 years in subjects with low insulin levels after oral glucose loading. In addition, in the extended follow-up of men of the Busselton Study, Welborn et al¹³ observed a U-shaped relationship between CHD mortality and postglucose insulin similar to the one we found. Finally, Fontbonne et al¹² in the Paris Prospective Study, Orchard and coworkers³¹ in the Multiple Risk Factor Intervention Trial, and Hargreaves et al³² also observed that subjects in the first quintile of fasting insulin had a tendency to a higher mortality rate for CHD than subjects of the middle quintiles.

Statistical associations in observational studies do not necessarily imply cause-effect relationships. Nevertheless, a pathophysiological (or mechanistic) interpretation of our data might cautiously be attempted. According to this hypothesis, the atherogenic factor might be a state of insufficient cell insulinization, which in the case of hypoinsulinemia, despite the expected higher insulin sensitivity,^{33 34} would be due to low ambient insulin; in the case of hyperinsulinemia, despite the higher ambient insulin, it would be the consequence of insulin resistance. Indeed, fasting and, in nondiabetic subjects, also 2-hour insulin are well correlated to direct measures of insulin sensitivity, so that hyperinsulinemia is a hallmark of insulin resistance.³⁵ In this regard, other investigators and ourselves^{17 36 37 38} have recently observed that insulin resistance rather than hyperinsulinemia is independently associated with CA.

An insufficient insulinization, whether caused by hypoinsulinemia or insulin resistance, may adversely affect the function of several cell types that are known to play a significant role in atherogenesis (monocytes/macrophages, fibroblasts, vascular smooth muscle cells, endothelial cells, platelets). This hypothesis is supported by several recent experimental studies. Indeed, it was documented that physiological concentrations of insulin have a dose-dependent inhibitory action on platelet aggregation both in vitro and in vivo³⁹ and that this action of the hormone is impaired in insulin-resistant conditions such as obesity and type 2 diabetes.⁴⁰ Moreover, physiological concentrations of insulin decrease intracellular uptake of calcium^{41 42} ; therefore, in conditions of insulin resistance, there is a higher intracellular calcium concentration,⁴³ with an inverse relationship between insulin sensitivity and cell calcium concentration.⁴⁴ The increase of the latter is known to have pleiotropic effects on monocytes, macrophages, fibroblasts, and vascular smooth muscle cells, which might be tuned into an atherogenetic mode, thereby initiating or promoting the progression of the atherosclerotic process.^{45 46} Finally, insulin stimulates the release of nitric oxide by the endothelium,^{47 48} and this molecule is thought to counteract several atherogenic effects mediated by hormones, cytokines, and other substances.⁴⁹

In conclusion, the results of the present study provide first evidence that both hypoinsulinemia and hyperinsulinemia are conditions of increased CA risk. Because hyperinsulinemia is a hallmark of insulin resistance, it may be cautiously hypothesized that insufficient insulinization of one or more cell types involved in atherogenesis, due to insulin resistance or low ambient insulin, significantly contributes to the development of CA. Credit or disproof for this hypothesis will have to wait for the results of prospective population-based studies including a direct assessment of insulin sensitivity.

	Selected Abbreviations and Acronyms

 

BMI = body mass index CA = carotid atherosclerosis CHD = coronary heart disease IMT = intimal-medial thickness

	Acknowledgments

 
This research was supported by grants from the Italian National Research Council and the Italian Ministry of University and Scientific and Technological Research.

Received January 23, 1997; revision received March 28, 1997; accepted March 28, 1997.

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