Association of Insulin Levels with Lipids and Lipoproteins in Elderly Japanese-American Men

Association of Insulin Levels with Lipids and Lipoproteins in Elderly Japanese-American Men CECIL M. BURCHFIEL, PhD, ROBERT D. ABBOTT, PhD, J. DAVID CURB, MD, DAN S. SHARP, MD, PhD, BEATRIZ L. RODRIGUEZ, MD, PhD, RICHARD ARAKAKI, MD, AND KATSUHIKO YANO, MD

PURPOSE: Elevated insulin levels have been associated with cardiovascular disease, but the relationship of insulin with other risk factors and its position in the atherosclerotic pathway is uncertain. A cross-sectional study was conducted to determine whether insulin concentrations were associated with lipids and lipoproteins independently of adiposity and other cardiovascular risk factors. METHODS: Subjects included 3417 Japanese-American men from the Honolulu Heart Program who completed a follow-up examination between 1991 and 1993 and were 71–93 years of age. Men were categorized by quintiles of fasting and 2-hour insulin concentration. RESULTS: Age-adjusted mean high-density lipoprotein (HDL) cholesterol and triglyceride levels varied significantly across quintiles of fasting and 2-hour insulin (P , 0.001, tests for trend), but insulin was not related to total cholesterol and low-density lipoprotein (LDL) cholesterol. HDL cholesterol decreased from 59.3 to 43.7 mg/dL and triglycerides increased from 95.6 to 175.8 mg/dL comparing lowest to highest quintiles of fasting insulin, respectively. These associations were slightly stronger in lean than obese subjects and in nondiabetic versus diabetic individuals particularly for 2-hour insulin levels. Multiple linear regression analysis adjusting for several adiposity measures separately (body mass index (BMI), subscapular skinfold thickness, waist circumference, and waist/hip ratio) and other cardiovascular risk factors attenuated associations slightly but they still remained statistically significant. Estimated differences in HDL cholesterol across extreme quintiles of fasting insulin were reduced slightly from 15.6 mg/dL with adjustment for age to 12.5 mg/dL with adjustment for age and BMI, and to 11.3 mg/dL with adjustment for age, BMI, and cardiovascular risk factors. CONCLUSIONS: Insulin concentration was strongly and independently associated with HDL cholesterol and triglycerides in this cohort of elderly Japanese-American men. Since this study was crosssectional, further investigation is required to determine whether elevated insulin levels are causally related to dyslipidemia. Ann Epidemiol 1998;8:92–98. Published by Elsevier Science Inc. KEY WORDS:

Asian Americans, Insulin, Lipoproteins, HDL Cholesterol, Obesity, Triglycerides.

INTRODUCTION Insulin has been identified as an independent predictor of cardiovascular disease in several studies (1–7), but recent evidence has been less consistent. It is possible that insulin may increase risk of cardiovascular disease directly by enhancing atherosclerosis, indirectly through adverse effects

From the Honolulu Epidemiology Research Unit, Epidemiology and Biometry Program, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Honolulu, HI (C.M.B., D.S.S.); Division of Biostatistics, University of Virginia School of Medicine, Charlottesville, VA (R.D.A.); Honolulu Heart Program, Kuakini Medical Center (R.D.A., J.D.C., B.L.R., K.Y.); and Department of Medicine, the John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI (R.D.A., J.D.C., B.L.R., R.A.). Address reprint requests to: Cecil M. Burchfiel, Ph.D., Division of Epidemiology and Clinical Applications, NHLBI, NIH, II Rockledge Centre, 6701 Rockledge Dr. MSC 7934, Bethesda, MD 20892-7934. Received June 11, 1997; revised August 21, 1997; accepted August 25, 1997. Published by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010

on other cardiovascular risk factors, or perhaps through a combination of these direct and indirect effects. Some investigators have proposed that insulin promotes atherosclerosis directly through its proliferative effects on smooth muscle cells in the arterial wall (8–10). Adverse effects of insulin on lipid and lipoprotein levels could provide an indirect mechanism that may partially account for the increased risk of cardiovascular disease experienced by individuals who have conditions characterized by insulin resistance and hyperinsulinemia such as glucose intolerance. Recent prospective evidence suggests that mechanisms other than adverse changes in lipids and blood pressure may also be involved in associations of hyperinsulinemia and ischemic heart disease (7). Insulin has been associated with lipids and lipoproteins in several studies (7, 11–15), but investigations among the elderly and minority populations are uncommon. Evidence for an association of insulin with lipids and lipoproteins appears biologically plausible. Hyperinsulinemia is thought to stimulate hepatic production of very-low-density 1047-2797/98/$19.00 PII S1047-2797(97)00167-1

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Selected Abbreviations and Acronyms HDL 5 high-density lipoprotein LDL 5 low-density lipoprotein BMI 5 body mass index VLDL 5 very-low-density lipoprotein

lipoprotein (VLDL) cholesterol and lead to an elevation of triglycerides (16, 17) and a reduction in high-density lipoprotein (HDL) cholesterol levels (18). In addition, data indicate that insulin normally stimulates lipoprotein lipase activity which increases catabolism of chylomicrons and VLDL (19), but the enzyme stimulation may be less efficient in the insulin resistant state leading to decreased lipoprotein lipase activity and thus higher triglyceride levels (15). A recent examination of elderly Japanese-American participants from the Honolulu Heart Program provided the opportunity to examine the cross-sectional associations of fasting and 2-hour insulin levels with total cholesterol, HDL cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides. The potential roles of obesity, body fat distribution and other cardiovascular risk factors in these associations were also evaluated. Relations between insulin and these lipids were examined in subjects who were relatively lean and in those who had greater adiposity using indices of body mass index (BMI), subscapular skinfold thickness, waist circumference, and waist-hip ratio. Associations were also compared in subjects categorized by diabetic status and several lifestyle characteristics (smoking status, alcohol intake, and physical activity). The primary objective of this investigation was to determine whether associations between insulin and lipid levels were independent of other cardiovascular risk factors including several measures of adiposity.

METHODS The Honolulu Heart Program is a prospective epidemiologic study designed to identify risk factors for coronary heart disease and stroke among 8006 Japanese-American men who were initially examined between 1965 and 1968. The entire surviving cohort has been reexamined an average of two (1968 to 1970), six (1970 to 1974), and 25 (1991 to 1993) years after the initial baseline examination. Previous reports describe details of recruitment and study design (20, 21). This investigation involves data collected from the recent examination performed between 1991 and 1993. Study Population Of 8006 subjects initially examined, 3845 completed an examination or telephone interview between 1991 and 1993. These men ranged in age from 45 to 68 years at baseline and 71 to 93 at the later examination. Recently

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examined men (n 5 3741) constituted 80% of participants who were alive at that time. Of the examined men, 86% participated in a clinic setting, 13% in their homes, and 1% in nursing homes. A total of 3573 subjects provided a fasting blood specimen and 3444 fasted for at least 12 hours. Fasting insulin levels were measured in 3417 of these men, and total cholesterol levels were available in 3416. Similarly, insulin levels, measured 2 hours after a glucose challenge, and total cholesterol were available for 2114 of the men. Slightly fewer measurements were available for the other lipids and lipoproteins. Reasons for the fewer 2-hour insulin measurements were described in detail previously (22); the most common reasons included: 1) examination in a nonclinic setting where glucose challenge was not offered; 2) stomach resection, active ulcer, or cancer; and 3) preference to avoid taking the test. In addition, subjects who had diabetes and were taking insulin (n 5 61), a relatively small proportion of the cohort (1.8%), were excluded by protocol from the oral glucose tolerance test. Data Collection Participants completed a comprehensive examination that included demographic, lifestyle, medical history, medication use, and psychosocial information, as well as ECG, spirometry, and a variety of anthropometric and other laboratory measurements. Methods used in data collection were consistent, in general, with those used at the initial examination, approximately 25 years earlier (23). Briefly, smoking history was ascertained, and the average number of cigarettes smoked per day, as well as a pack-year summary variable, were created to reflect amount and duration of smoking for current and past smokers. Alcohol intake (mL/day) was estimated based on the usual frequency and amount of consumption of beer, wine, sake, and hard liquor. An index of physical activity was calculated from the number of hours spent in five activity levels during a 24-hour period weighted by the estimated oxygen required for each level of activity (24). Anthropometric measurements included BMI (weight in kg divided by height in meters squared), subscapular skinfold thickness determined with Lange calipers, and waist and hip circumferences. Information on diabetes was derived from several sources. A physician diagnosis of diabetes was reported in 17.4% of subjects, and 11.7% reported taking diabetic medications. In several analyses of nondiabetic and diabetic individuals, diabetes was considered present when subjects reported taking diabetic medications, or had elevated fasting (> 140 mg/dL) or post-load (> 200 mg/dL) glucose values (38.7% among those with post-load measurements). Blood specimens were collected after a recommended overnight fast of 12 hours. After the fasting specimen was drawn, a 75-g glucose load was administered, and a second specimen was drawn 2 hours later. A detailed description

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of the methods used for measurement of insulin (22), glucose (25), lipids and lipoproteins (26), and fibrinogen (27) have been published previously. Briefly, fasting and 2-hour insulin concentrations were measured using a double antibody radioimmunoassay method (28) after storage at 2708C for up to 2 years. Standard enzymatic measurements of total cholesterol, HDL cholesterol, and triglycerides were performed using an Olympus Demand System (Olympus Corp) and were standardized according to the Centers for Disease Control (29). LDL cholesterol was calculated for subjects with triglyceride levels < 400 mg/dL, based on the Friedewald method (30). Statistical Analysis Both fasting and 2-hour insulin concentrations were divided into quintiles. Age-adjusted mean levels of lipids and lipoproteins were then compared across quintiles of fasting and 2-hour insulin using general linear models with lipid levels as the dependent variable (31, 32). A test for trend in lipid values across quintiles of insulin was also performed. Since the distribution of triglycerides was skewed, a log10 transformation was used, and its antilogarithm was calculated for presentation of adjusted mean values. To determine whether associations between insulin and lipids might differ according to levels of other potentially important cardiovascular risk factors, these analyses were repeated stratifying on two levels of obesity and body fat distribution, diabetic status, age (, 80 versus > 80 years), alcohol intake, physical activity, and smoking status. Factors which could obscure associations of insulin with lipids and lipoproteins were also examined. Although not presented here, results of these analyses were nearly identical to those published recently in which correlates of insulin (24), lipids, and lipoproteins (26) were identified. Factors

related to both insulin and any of the lipids or lipoproteins were included in multivariate analyses; these variables included diabetic history, fasting glucose, alcohol intake, hematocrit, heart rate, fibrinogen, physical activity, and packyears of smoking. Multiple linear regression was used to assess whether associations of insulin with lipids and lipoproteins were independent of other cardiovascular risk factors. A series of models were used with successive addition of covariates: 1) age only; 2) age and BMI (or other measures of adiposity); 3) age, adiposity, and additional cardiovascular risk factors. To indicate the magnitude of the insulin-lipid associations, analysis of covariance was used to estimate adjusted mean levels of lipids and lipoproteins across quintiles of insulin concentration using the same three models (32).

RESULTS Age-adjusted mean levels of lipids and lipoproteins are presented in Table 1 by quintiles of fasting and 2-hour insulin concentrations. Strong associations were observed for HDL cholesterol and triglycerides (P , 0.001, tests for trend), but not with total and LDL cholesterol. Age-adjusted mean HDL cholesterol levels decreased from 59.3 mg/dL in the lowest fasting insulin quintile to 43.7 mg/dL in the highest quintile, while triglyceride levels increased from 95.6 to 175.8 mg/dL in the lowest compared with the highest insulin quintiles. Similar comparisons across quintiles of 2-hour insulin were strong but somewhat less striking; mean levels of HDL cholesterol and triglycerides decreased from 55.1 to 47.2 mg/dL and increased from 106.3 to 155.6 mg/dL, respectively. Subsequent analyses focus on associations of insulin with HDL cholesterol and triglycerides. Similar analyses were conducted separately for lean and obese subjects, and for

TABLE 1. Age-adjusted mean 6 SE lipid levels (mg/dL) by quintiles of fasting and 2-hr insulin, 1991–93 na

Total cholesterol

HDL cholesterol

LDL cholesterol

Triglyceridesb

Fasting insulin (mU/mL) 1.5–7.9 8–10 11–14 15–20 21–1164 Test for trend

676 637 772 675 656

186.8 6 1.3 191.6 6 1.3 191.3 6 1.2 191.5 6 1.3 189.2 6 1.3 P 5 0.25

59.3 6 0.5 53.7 6 0.5 50.2 6 0.4 47.6 6 0.5 43.7 6 0.5 P , 0.001

106.7 6 1.2 112.8 6 1.2 113.0 6 1.1 111.4 6 1.2 108.1 6 1.2 P 5 0.73

95.6 6 1.0 115.0 6 1.0 129.5 6 1.0 149.3 6 1.0 175.8 6 1.0 P , 0.001

2-hour insulin (mU/mL) 2.7–56 57–81 82–107 108–150 151–960 Test for trend

424 424 421 421 424

189.1 6 1.6 192.5 6 1.6 193.8 6 1.6 192.8 6 1.6 192.0 6 1.6 P 5 0.21

55.1 6 0.6 51.5 6 0.6 51.1 6 0.6 48.7 6 0.6 47.2 6 0.6 P , 0.001

110.3 6 1.5 113.5 6 1.5 115.4 6 1.5 113.8 6 1.5 110.9 6 1.5 P 5 0.75

106.3 6 1.0 124.4 6 1.0 125.2 6 1.0 139.2 6 1.0 155.6 6 1.0 P , 0.001

Insulin quintiles

a b

Numbers of subjects are provided for total cholesterol; slightly fewer subjects were available for other lipids. Values for triglycerides are antilogarithms of mean 6 SE of log10 transformation.

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FIGURE 1. Age-adjusted mean levels of HDL cholesterol and triglycerides by fasting insulin quintiles for lean and more obese subjects. Triglyceride values are antilogarithms of mean 6 SE of the log10 transformation. All tests for trend were significant at P , 0.001.

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those with measures of body fatness in the lower 3 compared with the upper 2 quintiles of the distribution. Fasting insulin was inversely associated with HDL cholesterol and directly associated with triglycerides in both lean and obese subjects (P , 0.001), with similar but perhaps slightly stronger associations apparent in those with a lean body mass than in those who were more obese (Figure 1). Subjects who had less upper body obesity (subscapular skinfold , 17 mm) and less central obesity (waist/hip ratio , 0.96) showed similar statistically significant patterns (data not shown), with slightly stronger gradients of HDL cholesterol and triglycerides across quintiles of fasting insulin than subjects who had greater upper body and central obesity (upper 2 quintiles). Similar patterns were also evident when age-adjusted mean HDL cholesterol and triglyceride levels were compared across 2-hour insulin quintiles (data not shown). Similar stratified analyses showed that associations of fasting insulin with HDL cholesterol and triglycerides were equally strong in nondiabetic and diabetic (taking diabetic medication, having elevated fasting (> 140 mg/dL), or 2-hour (> 200 mg/dL) glucose values) subjects (data not shown). Associations of 2-hour insulin with HDL cholesterol and triglycerides were stronger in nondiabetic subjects and less evident although still significant in diabetic subjects. Comparable analyses (data not shown) indicated that relations of insulin with HDL cholesterol and triglycerides were similar when subjects were further stratified by age (, 80 and > 80 years of age), alcohol intake (, 30 and > 30 mL/d), physical activity (lower 3 and upper 2 quintiles), and current cigarette smoking (data not shown). Results of multiple linear regression analysis are presented in Table 2 with fasting and 2-hour insulin levels as the primary independent variables, and HDL cholesterol and log10 triglycerides as dependent variables. Fasting insulin was inversely associated with HDL cholesterol and directly associated with triglycerides adjusting for age only (P , 0.001). The regression coefficients were attenuated slightly when BMI, subscapular

TABLE 2. Multiple linear regression coefficients for association of insulin with HDL cholesterol and triglycerides, 1991–93a HDL cholesterol Adjustment variables Age Age and BMI Age and subscapular skinfold Age and waist Age and waist/hip Age, BMI, and othersd Age, subscapular skinfold, and others Age, waist, and others Age, wasit/hip, and others a d

Triglycerides (log10)

Fasting insulin

2-hour insulin

Fasting insulin

2-hour insulin

20.053 20.043 20.049 20.042 20.061 20.025b 20.033c 20.026c 20.042

20.027 20.018 20.019 20.017 20.024 20.020 20.021 20.019 20.026

0.00100 0.00090 0.00095 0.00090 0.00112 0.00060 0.00065 0.00063 0.00078

0.00060 0.00049 0.00048 0.00047 0.00053 0.00048 0.00048 0.00047 0.00053

All associations were significant at P , 0.0001 except b P , 0.01 and c P , 0.001. Other variables included diabetic history, fasting glucose, alcohol intake, hematocrit, heart rate, fibrinogen, physical activity, and pack-years of smoking.

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skinfold, and waist circumference were included separately as covariates compared with the models adjusting for age alone; however associations remained highly significant (P , 0.001). With additional adjustment for other cardiovascular risk factors (diabetic history, fasting glucose, alcohol intake, hematocrit, heart rate, fibrinogen, physical activity, and smoking), regression coefficients were reduced further but remained statistically significant. Adjustment for waist/hip ratio tended to attenuate associations to the least extent while adjustment for BMI and waist circumference along with other risk factors accounted for somewhat more of this association. In general, associations involving 2-hour insulin were somewhat weaker but still statistically significant. However, in all cases fasting and 2-hour insulin concentrations were independently associated with HDL cholesterol and triglycerides. The impact of adjustment on the associations of fasting insulin with HDL cholesterol and triglycerides is depicted in Figure 2, and is based on analysis of covariance models. While associations are attenuated slightly with progressive adjustment for additional variables, associations remain relatively strong and independent. To illustrate the magnitude of these differences, estimated age-adjusted mean levels of HDL cholesterol were 15.6 mg/dL higher in the lowest quintile of fasting insulin compared with the highest quintile, adjusting for age alone (59.3–43.7). These differences across extreme quintiles were reduced slightly to 12.5 mg/dL with additional adjustment for BMI, and to 11.3 mg/dL with further adjustment for other cardiovascular risk factors. Similarly, differences in triglyceride levels between the lowest and highest fasting insulin quintiles were 80.2 mg/dL, 73.7 mg/dL, and 64.5 mg/dL adjusting for age only, age and BMI, and age, BMI, and other cardiovascular risk factors, respectively.

DISCUSSION Fasting insulin levels, and to a slightly lessor extent 2-hour insulin levels, were strongly and independently associated with HDL cholesterol and triglycerides, but not with total and LDL cholesterol in this elderly population of JapaneseAmerican men from the Honolulu Heart Program. Stronger associations of insulin with HDL cholesterol and triglycerides, compared to those involving total and LDL cholesterol, were identified in a population-based study of young adults (11). In several other cross-sectional studies, insulin levels were associated with HDL cholesterol (7, 14, 33, 34) and triglycerides (7, 14, 33), independent of generalized obesity. Prospective findings from the San Antonio Heart Study indicated that fasting insulin was significantly and independently related to an incidence of low HDL cholesterol and elevated triglyceride concentrations, whereas fasting insulin was not associated with total and LDL cholesterol (35). A recent prospective study of elderly subjects in eastern Fin-

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FIGURE 2. Mean levels of HDL cholesterol and triglycerides by fasting insulin quintiles adjusted for age, age and BMI, and age, BMI, and multiple cardiovascular risk factors (diabetic history, fasting glucose, alcohol intake, hematocrit, heart rate, fibrinogen, physical activity, and pack-years of smoking). Triglyceride values are antilogarithms of mean 6 SE of the log10 transformation. All tests for trend were significant at P , 0.001.

land demonstrated that baseline hyperinsulinemia was associated with incidence of hypertriglyceridemia; associations with incidence of low HDL cholesterol were not significant, perhaps due to an insufficient number of incident cases (36). Results from the latter two studies are in general consistent with our findings and provide support for an association in which hyperinsulinemia leads to dyslipidemia. Associations of insulin with HDL cholesterol and triglycerides were similar but perhaps slightly stronger among relatively lean subjects compared with those who were more obese. This pattern is consistent with the findings from the Atherosclerosis Risk in Communities Study where associations of insulin with several cardiovascular risk factors including HDL cholesterol and triglycerides were stronger in

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lean than in obese subjects (37). Since obesity may also contribute to hyperinsulinemia, these investigators suggested that a greater genetic susceptibility to hyperinsulinemia may account for the stronger associations in lean individuals. The same potential explanation might account for the similar findings among subjects with less central and upperbody obesity. In the current study, associations of fasting insulin with HDL cholesterol and triglycerides were similar for diabetic and nondiabetic subjects. However, somewhat weaker associations involving 2-hour insulin were evident among those with diabetes compared with nondiabetic subjects, consistent with a diminished capacity to respond to an oral glucose load (impaired insulin secretion). In another cross-sectional study, associations of fasting insulin with HDL cholesterol and triglycerides were slightly stronger in nondiabetic than diabetic subjects (14). Recent evidence indicates that fasting insulin levels are a reasonably good marker for insulin resistance, with fasting insulin being preferable to post-load insulin levels in subjects with abnormal glucose tolerance (38). In a cross-sectional study causal inferences cannot be made. Although the direction of relations may be uncertain, prior evidence is most consistent with elevated levels of insulin leading to adverse changes in lipids and lipoproteins. Dyslipidemic alterations as a result of hyperinsulinemia appear biologically plausible, although mechanisms of action have not been fully elucidated. Evidence indicates that insulin increases hepatic secretion of VLDL cholesterol and, consequently, plasma triglyceride levels rise (16, 17). In addition, enhanced hepatic lipase activity may accelerate removal of HDL cholesterol from the plasma and thus lower HDL cholesterol levels (39, 40). Lipoprotein lipase in adipose tissue may lose its responsiveness to insulin in insulin resistant states, and may lead to impaired postprandial triglyceride clearance and diminished HDL cholesterol levels (41). However, because both proatherogenic and antiatherogenic effects have been attributed to lipoprotein lipase (42), further clarification of its role is needed. In addition to the potential effects of insulin on these enzymes, it is possible that alterations in activities of cholesterol-ester transfer protein and lecithin cholesterol acyl transferase may also contribute to low HDL cholesterol levels (43). Another potential limitation of cross-sectional studies is that associations could be altered among individuals who have been treated for various conditions. For example, lipidlowering or antihypertensive medication might alter the strength of association between insulin and HDL cholesterol. It is also possible that use of antihypertensive medication might adversely affect lipid levels and therefore obscure true relations between insulin and HDL cholesterol or triglyceride levels. To address these possibilities we repeated analyses among subjects who were not taking medication to lower cholesterol levels (n 5 3032) and among those who were taking neither cholesterol-lowering nor antihyper-

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tensive medication (n 5 1957). Results were essentially unchanged when these exclusions were made. Age-adjusted mean levels of HDL cholesterol comparing lowest to highest fasting insulin quintiles were 15.6 mg/dL in the entire cohort, 15.3 mg/dL among subjects not taking cholesterol-lowering medication, and 15.3 mg/dL among those not taking medication to lower cholesterol or blood pressure. Similarly, differences in triglyceride levels across extreme fasting insulin quintiles were 80.2 mg/dL, 79.4 mg/dL, and 78.8 mg/dL, respectively. Thus, it appears unlikely that use of medication to lower cholesterol or blood pressure altered or confounded the associations of insulin with lipids and lipoproteins. In this study insulin concentration was inversely associated with HDL cholesterol and positively associated with triglyceride levels. The strength of associations might be underestimated in studies of older individuals since subjects with elevated insulin and a dyslipidemic profile might experience selective mortality (36). However, associations among this well-defined elderly population were strong and independent of adiposity and other cardiovascular risk factors. The association of fasting insulin with this dyslipidemic pattern is consistent with a central role for insulin resistance or compensatory hyperinsulinemia in “syndrome X” or the “insulin resistance syndrome” (17, 35). Given the crosssectional design of this study, further investigation such as that by Despres and colleagues (7) is needed to ascertain whether hyperinsulinemia is associated with increased cardiovascular disease risk through insulin’s potentially adverse effects on lipids and lipoproteins or through other mechanisms. This study was supported by contract NO1-HC-05102 from the National Heart, Lung, and Blood Institute, Bethesda, MD.

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