Fasting insulin levels independently associated with coronary heart disease in non-diabetic Turkish men and women

International Journal of Cardiology 86 (2002) 61–69 www.elsevier.com / locate / ijcard

Fasting insulin levels independently associated with coronary heart disease in non-diabetic Turkish men and women q ¨ ¨ ¨ Altan Onat a , *, Koksal Ceyhan d , Vedat Sansoy b , Omer Basar a , Burak Erer a , Omer Uysal c , e ¨ Gulay Hergenc¸ a

Departments of Cardiology and Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey b Cardiology Institute, Istanbul University, Istanbul, Turkey c Division of Biostatistics, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey d Ersek Center for Cardiovascular Surgery, Istanbul, Turkey e ` ` Technical University, Istanbul, Turkey Department of Biochemistry, Yıldız Received in revised form 6 March 2002; accepted 6 April 2002

Abstract Background: Levels of plasma insulin have been recognized as a weak risk indicator for coronary or cardiovascular risk in the general population with ethnic background and gender modifying this relationship. We assessed whether insulin concentrations are associated with or would serve as a marker of prevalent coronary heart disease risk in a cross-sectional study of a population having low cholesterol levels (just under 5 mmol / l) but higher prevalence of components of the metabolic syndrome. Methods: In 688 participants of the Turkish Adult Risk Factor Survey in 2001, plasma insulin values as well as other risk variables were evaluated, and coronary heart disease was diagnosed based on clinical findings and Minnesota coding of resting electrocardiograms. Nearly equal numbers of men and women (.30 years of age) constituted the population sample from the two largest regions of Turkey. Concentrations of insulin were determined by the chemiluminescent immunometric method. Results: Geometric mean value was 50 pmol / l (interquartile range 37–68 pmol / l), without revealing a significant difference in genders. Fasting insulin was correlated in both genders with many variables, notably those involving central obesity, triglycerides, blood pressure, physical inactivity and, inversely, with high-density lipoprotein (HDL)-cholesterol. In a regression model, waist circumference and body mass index were strongly associated with log insulin, after controlling for age and presence of coronary heart disease. The age- and obesity-adjusted odds ratio for coronary heart disease in the highest as opposed to the lowest quartile was 2-fold in both genders (P,0.05). Even after adjustment for dyslipidemia, blood pressure, glucose intolerance, physical activity and smoking status, an over 2-fold increased coronary heart disease risk still persisted with regard to hyperinsulinemia ($10 mU / l, 69.5 pmol / l). When C-reactive protein which was correlated with fasting insulin only in women, was added to the model, the impact of hyperinsulinemia on coronary heart disease risk remained unchanged. Conclusion: Hyperinsulinemia (i) may provide information on the coronary heart disease likelihood over and above that provided by the other risk factors, including HDL-cholesterol, and (ii) may contribute, within the frame of insulin resistance, to the coronary heart disease risk independently of the classical risk factors.  2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hyperinsulinemia; Coronary heart disease; Inflammation; Risk assessment

1. Introduction q

From the Turkish Society of Cardiology, Istanbul, Turkey. *Corresponding author. Present address: Nisbetiye cad. 37 / 24, Etiler 80630, Istanbul, Turkey. Tel.: 190-212-288-4455; fax: 190-212-2884433. E-mail address: [email protected] (A. Onat).

Postmeal or fasting hyperinsulinemia has been shown to be associated with increased coronary or cardiovascular risk [1–3]. As concluded in a review

0167-5273 / 02 / $ – see front matter  2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00190-0

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[4], while older prospective studies of endogenous (postmeal) insulin levels in non-diabetic adults found significantly increased coronary heart disease risk, few subsequent studies have done so [5,6]. Overall, it has been considered in a meta-analysis as a weak risk indicator for the occurrence of cardiovascular disease [7]. More recently, several studies on fasting insulin levels have reported a positive association with coronary heart disease risk either in men [8–10], or among women but not in men [11]. Uncertainty prevails on its value in risk prediction among women and in the elderly [12,13]. It is generally agreed that the relationship between hyperinsulinemia and cardiovascular risk is modified by ethnic background [7,14]. Paucity of information exists with regard to populations of developing countries and, in particular, to populations having normal cholesterol levels but a high prevalence of the metabolic syndrome. We report our findings and analysis in a cross-sectional study with respect to fasting hyperinsulinemia as a risk factor for prevalent coronary heart disease in an unselected population sample of non-diabetic Turkish adults. Distribution of insulin levels and their interrelation with other risk factors in a general population having distinguishing features in risk profile [15,16] will also be described.

existing. Out of a total of 541 men and 581 women, plasma insulin levels were assayed in the non-fasting state in 15 subjects and under fasting conditions in 745 individuals. When 57 subjects with diabetes were also excluded, 320 non-diabetic men and 368 women remained who formed the study population for analysis of fasting insulin levels. The field study protocol included a questionnaire on the past history of cardiovascular disease, smoking habits, levels of physical activity, and family income, while physical examination of the cardiovascular system including measurement of blood pressure, a set of anthropometric measurements, recording of a resting electrocardiogram and appropriate collection and shipment of blood samples. Diagnosis of coronary heart disease was based on the presence of angina pectoris, of a history of myocardial infarction with or without accompanying Minnesota codes of electrocardiograms [18], or on a history of myocardial revascularization. Among women typical angina before age 45 and atypical angina at any age precluded the diagnosis. Isolated typical angina in women and atypical angina in men were considered as suspect diagnoses. These criteria resulted from the fact that electrocardiographic changes of ‘ischemic type’ (codes 1.1–3, 4.1–3, 5.1– 3, 7.1) were absent in only one-third of all patients (in seven men and 17 women).

2. Materials and methods

2.1. Measurement of risk factors and validation Participants of this study form part of the cohort of the Turkish Adult Risk Factor Study, a prospective survey on the prevalence of cardiac disease and risk factors in adults in Turkey carried out periodically since 1990 in seven geographical regions of the country [15,17]. The last follow-up in May 2001 was confined to the cohort residing in the two largest regions of Turkey, namely the Marmara and the Central Anatolian regions which make up 43% of the entire sample population surveyed. These regions are slightly more developed in terms of urbanization and industrialization than the remaining regions of the country. Participants were 31 years of age or older, and 95% of the people invited were tracked, while 78% of those invited were examined. All subjects gave informed consent. The survey is representatively stratified for sex and age, with rural distribution slightly more preponderant (45%) than currently

Blood pressure was measured with an aneroid sphygmomanometer in the sitting position on the right arm, and the mean of two recordings 3 min apart was recorded. Waist circumference was measured with the subject standing and wearing only underwear, at the level midway between the lower rib margin and the iliac crest, while that of the hip was measured at the level of the great trochanters. Body mass index was calculated by the computer as weight divided by height squared (kg / m 2 ). With regard to cigarette smoking, non-smokers, past smokers and three increments of current smoking formed the five categories. Physical activity was graded by the participant himself into four categories of increasing order with the aid of the following scheme: grade 1: white-collar worker, sewing-knitting, walking #1 km daily; grade 2: repair worker, house work, walking

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1–2 km daily; grade 3: mason, carpenter, truck driver, cleaning floors and windows, walking 4 km daily; grade 4: heavy labor, farming, regular sports activity [15]. Blood samples were centrifuged at 2000 rpm for 15 min within 30 min after collection. Serum partitioned to aliquots was kept at 4 8C and sent to Istanbul the same day at 4–8 8C where it was kept in a freezer at 280 8C for less than 1 month until measurements. Serum concentrations of total cholesterol, triglycerides and glucose were measured using enzymatic Roche Diagnostics kits (Mannheim, Germany) with Hitachi 902 autoanalyzer. Direct automated HDL-cholesterol measurements (Roche Diagnostics homogeneous ‘HDL-C plus’ kit which uses PEG-modified enzymes, sulfated a-cyclodextrin and dextran sulfate) were done with homogeneous enzymatic colorimetric test. Plasma concentrations of insulin were determined by the chemiluminescent immunometric method using Diagnostic Products kits and the autoimmunanalyzer Immulite (Los Angeles, CA). All insulin measurements were performed on the same day. Calibrators and controls were supplied by the manufacturer. Calibration range was up to 400 mIU / l and analytical sensitivity 2 mIU / l. Values of high-sensitivity C-reactive protein were measured with the Dade-Behring nephelometer system using N Latex CRP mono reagent by particle-enhanced immunonephelometric method (Behring Werke, Marburg, Germany). Both the reference laboratory and the laboratory in which the measurements were done participated in external quality control programs of the College of American Pathologists. Within run coefficients of variation for insulin regarding normal and pathological control samples were 4.2 and 5.3%, respectively; for the remaining variables, they ranged between 1.3 and 2.4%. Day to day coefficients of variation for glucose, total cholesterol, HDL-cholesterol, triglycerides, insulin and Creactive protein were 1.5–3%. Plasma apolipoprotein B values were measured by the turbidimetric method (Turbitimer, Behring) in a previous survey 10 months before. Mean values for concentrations of insulin and C-reactive protein are geometric means6S.D. calculated from the log-transformed distribution. Insulin values were also provided in pmol / l whereby 1 mU / l was converted to 6.945 pmol / l. External quality control was performed

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in a reference laboratory in a random selection of 3% of participants. Plasma measurements and coronary heart disease diagnosis were executed in an entirely blinded fashion. Collected survey data were checked by the primary investigator before and after being included in the database to ensure data quality and completeness. Individuals with diabetes mellitus or glucose intolerance were identified using the criteria of World Heart Organization [19].

2.2. Statistical analysis The significance of the correlation between log insulin values and other variables was assessed using the Spearman test. Concentrations of fasting insulin were statistically analyzed by quartiles. Tests for trend were used to assess any relation of increasing insulin values and risk of coronary heart disease after dividing the study sample into quartiles. Linear regression models were fit for log insulin as a dependent variable, and variables of interest as independent variables to demonstrate their contribution. Likelihood estimates of coronary heart disease and confidence intervals were obtained by use of logistic regression analyses. Adjusted odds ratios were obtained for these models that accounted for confounding variables. A value of P,0.05 (twotailed) was considered statistically significant. Multiple regression analyses of the data were carried out using STATA 5-0 for Windows package.

3. Results The clinical characteristics of the sample population are shown in Table 1 separately for men and women. The mean ages of 320 men and 368 women were almost identical (51612 years). Tendency to obesity (mean body mass index 28.3 kg / m 2 ), in particular to central obesity (mean waist circumference 91 cm) is clearly apparent among women and is suggested in men. This is paralleled by high systolic and diastolic pressures in women and by high plasma triglyceride levels in both genders. The most striking features of the study sample are the low mean levels of total cholesterol (|192 mg / dl, or 4.97 mmol / l), LDL-cholesterol (around 121 mg / dl or 3.15 mmol / l), and especially HDL-cholesterol (1.06 mmol / l), dis-

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Table 1 Characteristics of the non-diabetic study population (n5688) Men (n5320)

Age, years Waist circumference, cm Body mass index, kg / m 2 Systolic BP, mmHg Diastolic BP, mmHg Total cholesterol, mg / dl HDL-cholesterol, mg / dl Triglycerides, mg / dl Apolipoprotein B a , mg / dl Fasting glucose, mg / dl Fasting insulin, pmol / l C-reactive protein, mg / l Current smokers, % Physical activity grade

Women (n5368)

n

Mean

S.D.

n

Mean

S.D.

320 318 306 320 320 318 318 317 116 317 320 289 320 307

51.6 89.2 27.5 130.9 82 187.9 37.4 158.6 110.6 78.3 60.2 b 4.11 b 43.8 2.44

12.6 9.8 4.2 23.1 13.2 36.7 8.8 87.3 33.7 12.9 7.66 14.1

368 361 360 367 367 367 367 367 222 367 368 335 367 350

50.5 92.5 29.1 139.6 85 196.2 45 130.7 118.1 77.6 60.8 b 3.99 b 16.6 2.08

12 10.8 5.3 29 14.3 37.6 9.8 65.6 49 12.1 5.6 5.3

0.7

0.47

BP, blood pressure. a Values from 2000. b Arithmetic means.

tinctly lower than in Western populations. In addition, smoking is prevalent among men (44%) and sedentary lifestyle among women. Altogether in 74 subjects (35 men, 39 women) in this study, coronary heart disease was considered to be prevalent at the time of the survey, including 16 subjects (5 men, 11 women) with suspect coronary heart disease diagnosis.

3.1. Insulin values by sex The distribution of insulin values ranged from ,2 to 95 mU / l. The median (and interquartile) values of fasting insulin in men were 6.8 mU / l (47.2 pmol / l) (5.02 and 9.22 mU / l, or 35–64 pmol / l). Respective values among women were higher by 12%, namely, 7.6 mU / l (53 pmol / l) (5.63 and 10.26 mU / l, or 39–71.3 pmol / l), P.0.05. Some 24% of men and 27% of women had concentrations $10 mU / l.

3.2. Relationship of insulin values with other risk parameters Pearson correlation coefficients and significance between associations of logarithm of fasting insulin on the one hand and 12 parameters measured or estimated in the 688 non-diabetic men and women under study are shown in Table 2. These correlations

were uniformly highly significant in both genders with the exception of total cholesterol and apo B. Associations of insulin levels were inverse, as expected, with regard to physical activity and HDLcholesterol. Correlation was strongest with waist circumference, men exhibiting a powerful correlation (r50.45 vs. 0.33). Smoking status was significantly associated inversely with log insulin levels in men but not in women. This unadjusted finding would lose its significance or reverse the relation when adjustment was made for the difference of 5.3 cm in waist girth and nearly 7 years in age between male smokers and non-smokers, a difference which in our analysis would account for a variation of 26% in insulin concentrations and thus be in agreement with the experience that chronic smoking is associated with high age- and body mass index-adjusted plasma insulin levels [20]. Apo B was measured in one-half of all participants, in three-fifths of those with hyperinsulinemia. Among the latter group of 97 subjects (insulin levels$10 mU / l), 39 had apo B$ 120 mg / dl (and 30 subjects presumably had combined hyperlipidemia as indicated by the presence of levels of apo B$120 mg / dl combined with triglycerides$1.5 mmol / l). Prevalence of apo B$ 120 mg / dl in the 242 remaining subjects was lower (32.6%), interaction between insulin and apo B levels existing only in men, and not in women.

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Table 2 Partial correlation coefficient (r) and significance (P) between log fasting insulin and 12 risk parameters in 688 Turkish men and women, aged .30 years Versus a

Waist circumference (cm), n5318 / 361 Body mass index (kg / m 2 ), n5306 / 360 Triglycerides (mg / dl), n5317 / 367 Diastolic blood pressure (mmHg) Systolic blood pressure (mmHg) Smoking status HDL-cholesterol (mg / dl), n5318 / 367 Age C-reactive protein, n5309 / 362 Apolipoprotein B (mg / dl), n5116 / 222 Total cholesterol (mg / dl), n5318 / 367 Physical activity grade a

Both genders

Men, n5320

Women, n5368

r

P,

r

P,

0.390 0.366 0.276 0.191 0.172 20.124 20.165 0.127 0.095 0.08

0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.001 0.014 0.141 NS 0.000

0.449 0.442 0.262 0.178 0.186 20.165 20.211 0.133 0.094 0.151

0.000 0.000 0.000 0.001 0.001 0.005 0.000 0.001 0.1 0.105 NS 0.1

20.160

20.099

r

P, 0.333 0.311 0.337 0.194 0.151

20.202 0.128 0.126

20.117

0.000 0.000 0.000 0.000 0.004 NS 0.000 0.014 0.017 NS NS 0.039

n indicates number of men and women with present data.

Log C-reactive protein concentrations were significantly associated (F53.61, P50.014, ANOVA) with insulin quartiles, geometric means ranging from 1.73, 1.53, 2.01 and 2.65 mg / l from the lowest to the highest quartile, respectively. When separately analyzed for genders, the association was not significant in men, but was of borderline significance in women. In a multiple linear regression model (F535, P, 0.001) body mass index in men and, particularly, waist circumference (P,0.02) in both genders were significantly and independently associated with log insulin concentrations, after adjustment for age which did not appear to affect these levels independently of central obesity (Table 3).

3.3. Odds ratios for fasting insulin associated with coronary heart disease When concentrations of fasting insulin of the entire sample comprising 659 subjects were divided into quartiles, the number of those with prevalent coronary heart disease rose with each quartile, and after adjustment for age, obesity and glucose intolerance, the odds ratio for coronary heart disease in the upper quartile (hyperinsulinemia) rose abruptly to 1.93 as compared to the lowest quartile. Adjustment for the ten covariates of fasting insulin concentrations in the model led to the retainment of the odds ratio just over 2 and suppressed the emergence of any salient modifiable variable, other than systolic blood pressure in men (Table 4 and Fig. 1). The covariates in the model were such strong variables as dyslipidemia,

(diastolic) blood pressure, central obesity, smoking habit and physical activity grade. When the effect of log C-reactive protein was further included into this model (Table 5), logistic regression revealed that the association between hyperinsulinemia and coronary heart disease was unchanged among women and marginally weakened in men. Overall, the independent association with coronary heart disease risk was somewhat stronger in hyperinsulinemic men than women. Included in addition in the logistic regression model were: sex, waist circumference, diastolic presTable 3 Obesity correlates of log fasting insulin adjusted for age and presence of coronary heart disease (n5659) Coeff. b

S.E.

Std b

Adults Waist circumference Body mass index Presence of CHD Age

0.0054 0.0073 0.0668 0.00117

0.001 0.003 0.028 0.001

F535.2; P,0.001 0.251 0.000 0.158 0.008 0.090 0.017 0.064 0.094

Men Waist circumference Body mass index Presence of CHD Age

0.00617 0.0122 0.0685 0.00132

0.002 0.006 0.041 0.001

F523; P,0.001 0.255 0.013 0.214 0.036 0.090 0.093 0.069 NS

Women Waist circumference Body mass index Presence of CHD Age

0.0041 0.0059 0.0609 0.00112

0.002 0.003 0.038 0.001

F513.4; P,0.001 0.205 0.009 0.148 0.056 0.085 0.111 0.063 NS

Std, standardized.

P,

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Table 4 Odds ratios a and 95% confidence intervals for prevalent coronary heart disease by quartiles of fasting insulin (n5644) Quartiles of insulin

Parameter estimates

b Adults Lowest, ,5.5 mU / l Second, 5.6–7.3 mU / l Third, 7.4–9.9 mU / l Highest, .10 mU / l Age Systolic blood pressure Men, n5303 Lowest, ,5.5 mU / l Second, 5.6–7.3 mU / l Third, 7.4–9.9 mU / l Highest, .10 mU / l Age Systolic blood pressure Women, n5341 Lowest, ,5.5 mU / l Second, 5.6–7.3 mU / l Third, 7.4–9.9 mU / l Highest, .10 mU / l Age

0.707 0.056 0.016

0.802 0.054 0.037

0.700 0.054

Confidence intervals

S.E.

OR

0.245 0.016 0.009

P trend 0.034 1 0.85 NS 1.04 NS 2.03 1,25; 3,28 1.058 1,02; 1,09 1.016 0,999; 1,034

0.376 0.026 0.015

P trend 0.127 1 0.85 NS 1.04 NS 2.23 1,664; 4,66 1.056 1,002; 1,112 1.038 1,008; 1,069

0.348 0.022

P trend 0.157 1 0.85 NS 1.04 NS 2.01 1,018; 3,98 1.056 1,01; 1,10

a

Included in the logistic regression model were in addition: sex, waist circumference, diastolic pressure, total cholesterol, triglycerides, HDLcholesterol, glucose intolerance, smoking status and physical activity grade. Model comprised 64 subjects with CHD (male 31, female 33).

sure, total cholesterol, triglycerides, HDL-cholesterol, glucose intolerance, smoking status and physical activity grade. The model included 63 subjects with CHD (male 30, female 33). A cut-off point of 10.0 mU / l for hyperinsulinemia included 30 patients with coronary heart disease out of 388 subjects (18.2%), whereas there were only 38 coronary heart disease patients among 494 individuals (7.7%) below the cut point, resulting in an unadjusted 2.4-fold discrimination in coronary heart disease likelihood.

4. Discussion The present cross-sectional population-based study evaluated the distribution of and the association with coronary heart disease risk of fasting plasma insulin concentrations in a general population which differed in the risk profile from those studied to date in highly industrialized communities. In a study population

which comprised women as well as men and middleaged and elderly participants, hyperinsulinemia proved to be significantly and independently associated with prevalent coronary heart disease. The study is only of intermediate size though one of few studies on women examining the relationship between insulin levels and coronary heart disease risk, along with the ARIC [11], the San Luis Valley [21] and the Kuopio [13] studies. In adults aged 31 or over, we found geometric mean fasting insulin values of 51 pmol / l (with interquartile ranges 38–68 pmol / l) which did not differ significantly with regard to gender. These values are slightly lower than those (mean 68 pmol / l) reported in several recent surveys [13,22], though higher than that obtained in the Helsinki Policemen study [2], and similar to the population samples reported by Hergenc¸ et al. [23]. Previous studies utilizing non-specific immunoassays may have somewhat overestimated insulin values; furthermore, rather than the absolute levels in a community, the relative concentrations are critical in assessing the impact on the risk of coronary heart disease. Similar to previous studies [11,21,24,25], insulin levels were correlated with numerous risk variables of the insulin resistance syndrome in our cohort in both genders, namely with measures of (central) obesity, blood pressure, triglycerides and, inversely with HDL-cholesterol and physical activity. Waist circumference was the best correlate of fasting insulin levels as noted by others [25]. Though the relation to apo B did not attain statistical significance which may be ascribed to the determination of these levels only in part of our cohort, interaction between hyperinsulinemia and hyper-apo B did exist among men. A significant but weak correlation (r50.15) was obtained between levels of insulin and apo B in a cross-sectional study of elderly men [26]. C-reactive protein, also related to the insulin resistance syndrome, was significantly though weakly correlated with insulin levels in women, as it was, in a previous analysis of our cohort [27], the variable having the strongest correlation with prevalent coronary heart disease. Our finding that the addition of the variable C-reactive protein to the logistic regression model failed to attenuate insulin’s association with coronary heart disease among women, suggests that hyperinsulinemia is closely associated with the subclinical inflammatory marker. The hypothesis that

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Fig. 1. Odds ratio in each quartile (Qtl) of fasting insulin level adjusted for nine risk factors: 2-fold distinction of risk in the quartile$10 mU / l is obtained. The aggregate number of men and women in each quartile is indicated in the abcissa.

chronic subclinical inflammation is part of the insulin resistance syndrome [28,29] seems supported in our population having a different ethnicity. It should be emphasized that the main limitation of our study is its being cross-sectional in nature which does not allow definition of the time sequence of Table 5 Independent associations on the likelihood of prevalent CHD of quartiles of fasting insulin, C-reactive protein and other variables (n5628) Quartiles of insulin

Parameter estimates

b Adults Lowest, ,5.5 mU / l Second, 5.6–7.3 mU / l Third, 7.4–9.9 mU / l Highest, .10 mU / l Age Systolic blood pressure

0.707 0.053 0.018

Confidence intervals

S.E.

OR

0.245 0.017 0.009

P trend 0.056 1 0.84 NS 1.02 NS 1.95 1,20; 3,16 1.054 1,02; 1,09 1.018 1,001; 1,036

events and causal relations. Final confirmation that hyperinsulinemia is a predictor of CHD in Turkish adults can only be obtained from a prospective study. Adjustment for antihypertensive medication was not made. The size of the population sample is smaller than many (but not all) related previous studies. Nevertheless, possibly due to the risk profile of the cohort, this did not preclude the emergence of a clear result. It should be pointed out that any potential bias in terms of inaccuracy in the insulin assays or of coronary heart disease diagnosis would tend to dilute rather than augment the association. The association between fasting hyperinsulinemia and coronary heart disease tended to exhibit a threshold effect (at insulin level $10 mU / l) rather than exhibiting gradedness across the quartiles. Among the strengths of this study are that adjustment for HDL-cholesterol was made and all diabetics diagnosed by the World Health

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Organization criteria were excluded. Moreover, fasting insulin has been used which according to insulin clamp studies correlates better with insulin resistance than postchallenge insulin [4]. The odds ratio of hyperinsulinemia on the likelihood of coronary heart disease was more conspicuous than in most previous studies, namely 2-fold between the highest and lowest quartiles (representing a gradient of 60 pmol / l), and this pertained to both genders. In a meta-analysis of 12 prospective studies published up to 1996 on the relationship between insulin and cardiovascular disease [7], the summary relative risk corresponding to the interquartile range was 1.17 (95% CI, 1.09–1.26). The greater odds ratio obtained herein may partly be due to a substantial proportion of the cohort being insulin-resistant participants which non-diabetic Turkish adults presumably often are. Yet, the Helsinki Policemen study [2] in men also reported a high relative risk as did the large biracial ARIC study [11] in the female hyperinsulinemic groups when not fully adjusted for conventional factors. Finally, it is considered that most recent investigations using sensitive and specific insulin assays give higher risk ratios than older studies [30] which applies to our study. Thus the strength of the stated association might be ascribed to the assumption that the contribution of hyperinsulinemia and / or insulin resistance to atherogenesis in a population with low mean cholesterol levels but with a higher prevalence of the insulin resistance syndrome [31] might be greater than in communities exhibiting high LDL-cholesterol levels. The role of hyperinsulinemia as a coronary risk factor remains controversial. Most investigators shared the opinion that, since the modest association between hyperinsulinemia and the raised coronary heart disease risk often disappeared after adjustment for dyslipidemia, obesity and hypertension, hyperinsulinemia, instead of being an independent coronary risk factor, increases the coronary heart disease risk through these factors [4,30,32,33]. Indeed, an editorial concluded that neither hyperinsulinemia, nor insulin resistance is a major risk factor for the development of atherosclerotic cardiovascular disease in the absence of other risk factors [34]. However, workers of the Quebec Cardiovascular study recently voiced the view that the relation of hyperinsulinemia to coronary heart disease may be largely independent of alterations in body weight, blood pressure and plasma

lipoprotein concentrations [8], to which our results lend support. Related findings of the Health Professionals Follow-up Study also suggested that the relationship between obesity and cardiovascular risk factors is partly mediated by plasma insulin [26]. To which mechanisms may a possible impact of hyperinsulinemia on coronary heart disease risk be ascribed? Aside from the recently described acylation stimulating protein that determines the rate of fatty acid uptake by adipocytes during lipolysis, insulin is a prime determinant of the effectiveness of the processes of fatty acid uptake and retention, which has been designated by Sniderman and coworkers [35] as fatty acid trapping. Ineffective fatty acid trapping leads to an excess fatty acid flux to the muscles and the liver. Increased fatty acid flux to the liver enhances the rate of secretion of VLDL particles leading to hypertriglyceridemic hyperapoB with accompanying raised vascular risk. Increased fatty acid flux to skeletal muscle results in reduced utilization of glucose by muscle and augments muscle triglyceride content with concomitant reduced insulin sensitivity [36] and diminished insulin removal by the liver. This process further promotes insulin resistance and hyperinsulinemia. Our findings suggest that hyperinsulinemia (i) may provide information on the coronary heart disease likelihood over and above that provided by the other risk factors, including HDL-cholesterol, and (ii) may contribute to the coronary heart disease risk independently of the classical risk factors. This knowledge may have implications for prevention inasmuch as increased physical activity and reduction and control of obesity are known to lead to a decline in elevated plasma insulin levels and underlying insulin resistance.

Acknowledgements This study was supported in part by the Pfizer and Astra companies (both Istanbul, Turkey).

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