This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Burchfiel, C. M. Articles by Yano, K. Search for Related Content PubMed PubMed Citation Articles by Burchfiel, C. M. Articles by Yano, K.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:2213-2221.)
© 1995 American Heart Association, Inc.

Articles

Distribution and Correlates of Insulin in Elderly Men

The Honolulu Heart Program

Cecil M. Burchfiel; J. David Curb; Dan S. Sharp; Beatriz L. Rodriguez; Richard Arakaki; Po-Huang Chyou; Katsuhiko Yano

From the Honolulu Epidemiology Research Unit, Field Studies and Clinical Epidemiology Scientific Research Group, Epidemiology and Biometry Program, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute (C.M.B., D.S.S.), the Honolulu Heart Program, Kuakini Medical Center (J.D.C., B.L.R., P.-H.C., K.Y.), and the John A. Burns School of Medicine, University of Hawaii at Manoa (J.D.C., B.L.R., R.A.), Honolulu, Hawaii.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Abstract The role of insulin in cardiovascular disease is uncertain, and studies in elderly or minority populations are infrequent. Fasting and 2-hour insulin concentrations and their cross-sectional associations with cardiovascular risk factors were examined in 3562 elderly (aged 71 to 93 years) Japanese American men from the Honolulu Heart Program who were reexamined between 1991 and 1993. Insulin distributions were skewed (mean and median: 16.8 and 12 µU/mL for fasting; 117.2 and 93 µU/mL for 2-hour); fasting but not 2-hour insulin levels declined significantly with age (P<.0001 and P=.54, respectively). Factors most strongly correlated with insulin included measures of obesity, fat distribution, and levels of triglyceride, glucose (r=.38 to r=.50 fasting, r=.21 to r=.27 2-hour), and HDL cholesterol (r=-.41 and r=-.22, respectively). Other correlates included fibrinogen, hematocrit, heart rate, blood pressure, cigarettes per day (all positive), alcohol, physical activity, and forced vital capacity (negative). Associations were also evident across risk factor quintiles. Insulin levels were significantly elevated in men with hypertension and diabetes. In multiple linear regression analyses, log₁₀ fasting insulin was positively and independently associated with body mass index, triglycerides, glucose, fibrinogen, hematocrit, heart rate, diabetes, and hypertension and negatively associated with HDL cholesterol, physical activity, and forced vital capacity. In general, results were similar for log₁₀ 2-hour insulin and when subjects who fasted <12 hours or had diabetes were excluded. Substitution of medication use and blood pressure for hypertension indicated independent associations of medication use but not blood pressure with insulin. These findings suggest that fasting and 2-hour insulin levels are associated with several key features of insulin resistance syndrome in elderly Japanese American men.

Key Words: Asian Americans • hypertension • insulin • lipoproteins • obesity

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The role of insulin as an independent risk factor for cardiovascular disease is uncertain. Several early prospective studies of three cohorts of middle-aged men demonstrated that elevated insulin levels are associated with an increased risk of CHD independent of other cardiovascular risk factors.^{1 2 3} However, more recent evidence does not support these findings.^{4 5 6 7 8} Thus, whether hyperinsulinemia directly enhances cardiovascular risk is now less certain.⁹

Several investigations have indicated that certain cardiovascular risk factor profiles tend to be observed in individuals more frequently than would be expected by chance. The hypothesis has been raised that insulin resistance and the hyperinsulinemia associated with it may be responsible for the clustering of hypertension, glucose intolerance, and dyslipidemia, recently referred to as "syndrome X"¹⁰ or insulin resistance syndrome.^{11 12 13} However, others suggest that the evidence does not support this hypothesis.¹⁴ Both insulin levels and the characteristics associated with them have been infrequently examined in elderly populations, particularly in specific ethnic groups such as Asian Americans.

A recent reexamination of elderly Japanese American men from the Honolulu Heart Program provided the opportunity to examine fasting and 2-hour insulin concentrations and their cross-sectional associations with a number of lifestyle, anthropometric, physiological, and metabolic risk factors. Multivariate regression models were used to identify correlates that were independently associated with fasting and postload insulin levels.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
The Honolulu Heart Program was initiated in 1965 to identify risk factors for CHD and stroke among a population-based cohort of 8006 Japanese American men who resided on Oahu at that time and were born between 1900 and 1919.¹⁵ There have been four examinations of the entire cohort. The baseline examination, between 1965 and 1968, was followed by three subsequent examinations occurring approximately 2 years (1968 to 1970), 6 years (1971 to 1975), and 25 years (1991 to 1993) later. Details of recruitment and study design for the baseline examination have been published previously.^{15 16 17 18}

Study Population
Among 8006 men who were initially examined, 3845 were reexamined or completed an extended telephone interview between 1991 and 1993. The men ranged in age from 71 to 93 years, and those examined (n=3741) represented 80% of the men who were alive and thus eligible at that time. Of those examined, a majority were seen in a clinic setting (86%); the remaining men completed slightly abbreviated examinations in their homes (13%) or nursing homes (1%). A total of 3573 men provided fasting blood specimens, 3562 had fasting insulin measurements performed, and 2160 men had insulin measured 2 hours after a 75-g glucose load. Among the subjects who did not have a 2-hour insulin measurement (n=1413), 415 were not offered an oral glucose tolerance test because they were examined in a nonclinic setting. Subjects were also excluded by protocol from this test if they were diabetic and taking insulin (n=61); had a stomach resection, active ulcer, or stomach cancer (n=363); had severely elevated blood pressure (systolic >200 mm Hg or diastolic >115 mm Hg, n=31); fasted <8 hours (n=8); or met more than one of these conditions (n=32). A total of 458 men preferred not to take the test, and 2-hour insulin values were not available for an additional 45 men.

Data Collection
A comprehensive examination of the Honolulu Heart Program cohort was conducted between 1991 and 1993 and included demographic, lifestyle (smoking, alcohol, physical activity), medical history, medication use, and psychosocial information as well as anthropometric, physiological, and laboratory measurements from standardized procedures. Questionnaires and methods of measurement were consistent with previous examinations for a majority of these variables and have been described previously.¹⁷ A physical activity index was estimated from the number of hours spent in five different activity levels during a 24-hour period weighted by the estimated oxygen consumption required for each activity level,¹⁹ analogous to methods used in studies from Framingham²⁰ and Puerto Rico.²¹ The mean of two standard blood pressure measurements was used, and hypertension was considered present if blood pressure exceeded 160/95 mm Hg or if antihypertensive medications were taken. Spirometry was performed using standardized recommendations from the American Thoracic Society²² and included intensive technician training and quality control assessment, consistent with methods used in the Cardiovascular Health Study.²³ Variables measured for the first time in this cohort included waist and hip circumference, fibrinogen, and fasting and 2-hour concentrations of glucose and insulin.

Participants were instructed to fast overnight for at least 12 hours. Blood specimens were obtained and shipped to the University of Vermont for standard measurements of levels of total cholesterol, HDL cholesterol, triglyceride, glucose (fasting and 2-hour), and fibrinogen. After the fasting blood specimen was drawn, a 75-g glucose load was administered, and a second specimen was drawn 2 hours later. Fasting and 2-hour insulin concentrations were measured subsequently in the Diabetes Endocrinology Research Center Core Radioimmunoassay Laboratory, Northwest Lipid Research Laboratories, at the University of Washington after being stored at -70°C for up to 2 years. A double antibody polyethylene glycol accelerated radioimmunoassay method was used.²⁴ The lowest limit of detection for this assay was 3 µU/mL. There were five subjects with insulin values below this level, and they were assigned values of 1.5 µU/mL, midway between 0 and 3. Quality control assays were performed using two levels of reconstituted commercial lyophilized human immunoassay control serum specimens (Lyphochek, Bio-Rad Laboratories). These assays, which involved 540 pairs at both relatively low (mean±SD, 21±1.9 µU/mL) and high (82±6.6 µU/mL) insulin concentrations, yielded a coefficient of variation of 9% and 8%, respectively.

Statistical Analysis
Because of the skewed nature of the fasting and 2-hour insulin distributions, a log₁₀ transformation of insulin values was used for assessment of statistical significance. Mean insulin concentrations were derived by calculating antilogarithms of log₁₀ insulin to facilitate presentation of the findings. Spearman's correlation coefficients were used to assess univariate associations between continuous variables and untransformed insulin. A general linear model procedure was used to calculate age-adjusted mean insulin levels across quintiles of continuous variables and across specified levels of categorical variables.^{25 26} On the basis of these results, multiple linear regression was used to identify factors that were independently associated with insulin. Log₁₀ transformations of fasting and 2-hour insulin were used as dependent variables in these multivariate models. Additional analyses were conducted after exclusion of subjects with diabetes and those who fasted <12 hours (4% of subjects).

To estimate the magnitude of impact that each of the independent variables had on the mean insulin concentration, the absolute and percent change in mean insulin level associated with a specified change in each independent variable was calculated using regression coefficients from these models. First, the predicted mean log₁₀ insulin concentration was calculated for the overall population using mean levels of each independent variable and their respective regression coefficients. The antilog of this value provided the predicted mean insulin concentration (12.77 µU/mL for fasting insulin in this population). The percent change in fasting insulin level associated with, for example, a 10-mg/dL change in HDL cholesterol was calculated as e^ß(10)-1 and converted to a percentage, where ß is the regression coefficient for HDL cholesterol in the log₁₀ transformed fasting insulin model, analogous to a method described previously.²⁷ The predicted absolute change in mean insulin level was then calculated by multiplying the predicted mean insulin level by the percentage of change in mean insulin level.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The distributions of fasting and 2-hour insulin concentration were positively skewed, with a mean and median of 16.8 and 12 µU/mL for fasting insulin and 117.2 and 93 µU/mL for 2-hour insulin, respectively (Fig 1). Mean insulin levels declined slightly with increasing age, with the trend being statistically significant for fasting insulin but not for 2-hour insulin (Table 1).

View larger version (16K): [in this window] [in a new window]   Figure 1. Bar graphs show distribution of fasting insulin and 2-hour insulin concentrations in the study population.

View this table: [in this window] [in a new window]   Table 1. Insulin Concentrations by Age1

A number of potential correlates of insulin were examined univariately (Table 2). Spearman's correlation coefficients that were .05 or .05 were statistically significant at the P<.01 level. In general, associations were stronger for correlates of fasting insulin than for correlates of 2-hour insulin. Several measures of obesity and body fat distribution, as well as lipids and lipoproteins, were strongly correlated (HDL cholesterol negatively) with fasting (r=.41 to r=.50) and 2-hour (r=.22 to r=.27) insulin. Among the obesity and fatness indices, BMI, waist circumference, and subscapular skinfold thickness were somewhat more strongly correlated with both fasting and 2-hour insulin than WHR, triceps skinfold thickness, and subscapular to triceps ratio. Relatively strong correlations were also observed for fasting glucose (with fasting insulin only), 2-hour glucose, and hematocrit levels. Somewhat weaker but statistically significant correlations were found for age (negative), alcohol (negative), physical activity (negative), systolic and diastolic blood pressure (positive), heart rate (positive), FVC (negative), and fibrinogen (positive).

View this table: [in this window] [in a new window]   Table 2. Spearman's Correlation Coefficients for Insulin and Cardiovascular Risk Factors

Age-adjusted mean insulin levels were significantly higher in men with hypertension and in those who reported taking antihypertensive medication (Table 3). Men who reported taking diabetic medication or were told they had diabetes by a physician had significantly higher fasting and significantly lower 2-hour insulin levels. Smoking status and education were not associated with insulin levels (data not shown).

View this table: [in this window] [in a new window]   Table 3. Age-Adjusted Mean Insulin Concentrations by Level of Categorical Variables1

Age-adjusted mean fasting and 2-hour insulin levels were also compared across quintiles of selected continuous variables (Fig 2). Results are presented for three anthropometric indices and three metabolic or hematologic variables, all of which exhibited Spearman's correlation coefficients of .2 (or -.2) for both fasting and 2-hour insulin. Mean fasting and 2-hour insulin levels increased in a stepwise fashion with increasing quintiles of BMI, WHR, and subscapular skinfold thickness, with the steepest gradient occurring across BMI quintiles. Similarly, mean fasting and 2-hour insulin levels showed a stepwise decrease across quintiles of HDL cholesterol and increases across quintiles of triglyceride and hematocrit level. In general, gradients involving fasting insulin tended to be stronger than those involving 2-hour insulin, and all tests for linear trend across quintiles were significant at P<.0001.

View larger version (42K): [in this window] [in a new window]   Figure 2. Bar graphs show age-adjusted mean fasting insulin (solid bars) and 2-hour insulin (hatched bars) concentrations by quintiles of selected variables. Mean insulin levels were calculated as antilogarithms of the means of log10 insulin.

Variables that were significantly associated with fasting and 2-hour insulin in univariate or bivariate analyses were included in multiple linear regression models with log₁₀ transformations of insulin as the dependent variable. Regression coefficients for four separate models are presented with their respective probability values in Table 4. In the first model including all subjects, hypertension, triglyceride, use of diabetic medication, fasting glucose, BMI, heart rate, fibrinogen, and hematocrit were positively associated with log₁₀ fasting insulin after adjustment for other variables. HDL cholesterol, physical activity, and FVC were negatively associated with fasting insulin, independent of other variables in the model. When subjects with diabetes and those who fasted <12 hours were excluded, results were nearly identical except that fibrinogen and FVC were of borderline significance (P<.10). Triglyceride, BMI, WHR, heart rate, and hematocrit were positively associated with log₁₀ 2-hour insulin, whereas HDL cholesterol, fasting glucose, use of diabetic medication, physical activity, and FVC were negatively associated with log₁₀ 2-hour insulin. Results were again similar in nondiabetic subjects except for fasting glucose, which was significant at a borderline level (P=.075), and fibrinogen, which became significant (P=.033). In general, correlates of fasting and 2-hour insulin were similar with only a few exceptions: hypertension was associated with fasting but not 2-hour insulin, WHR was associated with 2-hour insulin but not fasting insulin, and diabetic medication use as well as fasting glucose were negatively associated with 2-hour insulin but positively associated with fasting insulin. In addition, FVC was more strongly associated with 2-hour than fasting insulin. Overall, these independent variables accounted for 41.2% and 19.2% of the variability in log₁₀ transformed fasting and 2-hour insulin levels, respectively.

View this table: [in this window] [in a new window]   Table 4. Multiple Linear Regression Analysis for Correlates of Log10 Fasting and 2-h Insulin1

Several additional multiple regression models were also considered. When hypertension was replaced with diastolic blood pressure and use of antihypertensive medication in these models, diastolic blood pressure was not significantly related to either fasting or 2-hour insulin, whereas medication use was independently related to fasting insulin only among nondiabetic subjects (P<.02). In addition, diastolic blood pressure was not associated with insulin when subjects taking antihypertensive medications were excluded. Because WHR and BMI were moderately correlated (r=.48), these multiple regression analyses were also repeated after exclusion of WHR, and similar results were observed.

To examine the magnitude of the multivariate associations presented in Table 4 for fasting insulin in particular, the estimated absolute and percent changes in the predicted mean fasting insulin levels for the entire population are presented based on a specified change in each independent variable (Table 5). For example, an estimated increase in HDL cholesterol of 10 mg/dL from the population mean (50.9 mg/dL) was associated with a predicted decrease of 0.37 µU/mL in mean fasting insulin for the overall population (from 12.77 to 12.40 µU/mL), and this corresponds to a 2.9% decrease in the predicted fasting insulin level. Similarly, use of medication for diabetes was associated with a 9.2% higher mean fasting insulin level, and an increase of 2 U in BMI was associated with a 5.8% increase in fasting insulin.

View this table: [in this window] [in a new window]   Table 5. Predicted Effects of Changes in Independent Variables on Mean Fasting Insulin1

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Insulin concentrations and their cross-sectional correlates were examined in this population-based cohort of elderly Japanese American men in Hawaii. Fasting insulin levels were similar to those reported in Finland²⁸ and Rancho Bernardo,²⁹ lower than levels reported among Pima Indians³⁰ and Nauruans,³¹ and somewhat higher than levels reported in other populations.^{3 32 33 34 35} Postchallenge insulin concentrations were somewhat higher relative to most other studies^{3 28 31 33} but not all.^{29 30} However, comparisons across populations may be complicated by the use of different insulin assay methods and differences in age and in use of exclusion criteria such as diabetic status. The possibility of cross-reactivity between insulin measured by conventional immunoreactive methods and proinsulin has also been raised as a potential limitation.¹⁴ However, associations between insulin concentrations and cardiovascular risk factors were recently shown to be similar for conventional insulin assays and a more direct measurement of insulin that was free of any cross-reactivity with proinsulin.³⁶

In general, several correlates of insulin concentration identified in this study were consistent with those found in other studies.^{8 28 34 35 37 38 39 40} Although most of these studies evaluated associations of insulin with measures of obesity and fat distribution, lipids and lipoproteins, blood pressure, and several lifestyle variables, relatively few examined postload insulin levels separately⁸ or in conjunction with fasting levels,^{35 38 40} and few included fibrinogen,³⁷ heart rate,^{37 41} hematocrit, and FVC.⁴² In addition, the absolute and percent change in mean insulin level associated with changes in these factors was relatively small when considered individually, but these effects may be notably larger when these factors are considered collectively.

Measures of obesity and fat distribution were among the variables most strongly associated with insulin. These associations are consistent with prior evidence linking obesity and excess body fat, particularly in abdominal and upper-body regions, with hyperinsulinemia and an underlying insulin-resistant state.⁴³ Also consistent with these strong relations, hyperinsulinemia may be associated with the clustering of not only hypertension, glucose intolerance, and hypertriglyceridemia but also upper-body obesity, which have been referred to as the "deadly quartet," in individuals who were found to be at increased risk of cardiovascular disease.⁴⁴

The strong independent associations of levels of HDL cholesterol (inverse) and triglyceride (direct), but not total cholesterol (data not shown), with fasting and 2-hour insulin levels in the present study were consistent with the characteristic dyslipidemia component of insulin resistance syndrome. The joint occurrence of these lipid abnormalities has been specifically linked to elevated insulin levels,⁴⁵ and these associations were evident in a number of other epidemiological studies.^{8 13 28 34 35 37 38 39 40}

Both diabetes and fasting glucose level were independently associated with insulin concentration. When analyses were confined to nondiabetic subjects, fasting glucose remained significantly and directly associated with fasting insulin level, consistent with several other studies.^{8 13 37 34} Subjects who took diabetic medication were likely to have lower 2-hour insulin levels compared with nondiabetic men. Fasting glucose was also inversely associated with 2-hour insulin levels in all subjects combined but reached borderline significance in nondiabetic subjects. These findings suggest that diabetic subjects receiving medication had elevated fasting levels of insulin and were less able to generate an insulin response to the glucose challenge, compatible with an insulin-resistant state and impaired insulin secretion.

The evidence linking hypertension and insulin is less consistent. Several recent reviews provide evidence of a possible association,^{33 46 47} and additional prospective studies have been recommended.^{9 46} Findings from several studies support an independent association between blood pressure and insulin,^{34 40 47 48 49 50} but a number of other reports indicate no association,^{29 30 31 51} provide supportive evidence only in some ethnic groups but not in others,^{52 53} or suggest reasons for a noncausal relation.⁵⁴

In this study, hypertension was independently associated with fasting but not 2-hour insulin concentrations. However, diastolic blood pressure was not associated with fasting or 2-hour insulin level when use of antihypertensive medication was taken into account separately or when analyses were limited to subjects not receiving antihypertensive treatment. These findings may also be consistent with adverse effects of some antihypertensive agents (eg, thiazide diuretics and ß-blockers) on insulin resistance,⁵⁵ which could be worse in diabetic subjects. In a recent prospective study by Haffner and associates,¹³ fasting insulin levels were significantly and independently related to the incidence of hypertension, particularly in lean subjects (defined as a BMI <27 kg/m²). Approximately 90% of the men from the Honolulu Heart Program were below this cut point and thus were relatively lean.

Associations of several less frequently examined risk factors were also evaluated. In contrast to several recent reports,^{56 57} smoking and alcohol were not independently related to insulin levels. The inverse association of physical activity with insulin level is consistent with several other studies that suggest beneficial effects of physical activity on insulin sensitivity and resistance.^{58 59} The positive association between heart rate and insulin observed in this study is consistent with findings from other studies^{37 41} that indicate a relation with factors involved in control of the systemic circulation (eg, increased sympathetic activity). Findings from the present study concerning fibrinogen were in agreement with those from the Zutphen Study³⁷ and provide support for involvement of factors associated with hemostasis or an inflammatory response in the insulin resistance syndrome as well.⁶⁰ FVC was also inversely and independently related to insulin levels, particularly postload insulin, and this association was not materially affected when nonsignificant effects of cigarette smoking were also controlled. An inverse relation between FVC and insulin level has also been observed in a study of young adults; however, an independent association was no longer evident after adjustment for subscapular skinfold thickness.⁴²

It is possible that insulin resistance, and the compensatory hyperinsulinemia that follows, may increase the risk of CHD directly through promotion of atherogenesis⁶¹ or indirectly through its adverse effects on other cardiovascular risk factors.^{56 62} Although evidence is limited, insulin may stimulate smooth muscle cell proliferation after disruption of the endothelial barrier^{61 63} and is associated with indices of arterial stiffness.⁶⁴ Associations of insulin with hypertension, although somewhat inconsistent, are plausible because insulin increases sympathetic nervous system activity⁶⁵ and promotes renal reabsorption of sodium.¹⁰ Insulin may enhance dyslipidemia through increased hepatic VLDL production¹⁰ and decreased catabolism of triglyceride-rich lipoproteins.⁶⁶ Moreover, insulin resistance may have multiple effects at molecular and cellular levels.^{62 67} For example, an increased risk of CHD associated with insulin level may be restricted to individuals with certain characteristics, such as the apolipoprotein E 3/2 phenotype.⁶⁸ While it is possible that hyperinsulinemia only serves as a marker for an adverse cardiovascular risk profile, insulin may be an important intermediate risk factor for cardiovascular disease.³⁴ The latter possibility is consistent with evidence from a recent prospective study demonstrating that hyperinsulinemia was associated with increased incidence of dyslipidemia and non–insulin-dependent diabetes mellitus.¹³

Several potential limitations of this investigation should be considered. As with other cross-sectional studies, it is not possible to discern whether elevated insulin concentrations are the cause or the result of adverse risk factor levels. Because this cohort represents survivors, it is possible that the magnitude of any associations observed between risk factors and insulin levels could be influenced by selective survival. Similarly, the observed decline in fasting and perhaps 2-hour insulin levels with increasing age, although in contrast with expected patterns,⁶⁹ could be explained by proportionally fewer men with higher insulin levels surviving to an older age. Some associations observed in this study could have been difficult to detect compared with those observed in other population groups, particularly if the factors involved were relatively uncommon in Japanese Americans. For example, associations between obesity and insulin level might be expected to be comparatively weaker in this relatively lean population. Despite this expectation, strong associations were observed. Strengths of this study include its relatively large sample size, low outmigration and high participation rates, and the wide range of potential correlates examined.

In this study, obesity, glucose intolerance, and lipid abnormalities were all strongly and independently associated with insulin levels. Other factors, including use of medication for hypertension, physical inactivity, heart rate, hematocrit, fibrinogen, and FVC, were also associated with insulin levels but somewhat less consistently. Although this study was cross-sectional, results suggest that insulin level is associated with an adverse risk factor profile, one that includes a number of the key features of the insulin resistance syndrome as well as several other less frequently examined factors. These findings extend previously reported associations between insulin and cardiovascular risk factors to a relatively elderly population of Japanese American men. Whereas several recent studies have provided evidence against an independent association between insulin and cardiovascular disease,^{4 5 6 7 8} the present study shows clear associations of insulin with an atherogenic risk factor profile. These relations are consistent with an indirect association where elevated insulin levels could adversely affect multiple cardiovascular risk factors. Further prospective studies are needed to clarify whether hyperinsulinemia acts as a marker of increased disease risk, adversely affects risk factor levels, or has a more direct and independent influence on risk of cardiovascular disease.

	Selected Abbreviations and Acronyms

 

BMI = body mass index CHD = coronary heart disease FVC = forced vital capacity WHR = waist to hip ratio

	Acknowledgments

 
This study was supported by contract NO1-HC-05102 from the National Heart, Lung, and Blood Institute, Bethesda, Md.

	Footnotes

 
Reprint requests to Dr Cecil M. Burchfiel, Honolulu Heart Program, National Heart, Lung, and Blood Institute, 347 North Kuakini St, Honolulu, HI 96817. E-mail buzz@hhs.cba.hawaii.edu.

Received July 25, 1995; accepted October 10, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Pyorala K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care. 1979;2:131-141. [Abstract]
2. Welborn TA, Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care. 1979;2:154-160. [Abstract]
3. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia. 1980;19:205-210. [Medline] [Order article via Infotrieve]
4. Welin L, Eriksson H, Larsson B, Ohlson LO, Svardsudd K, Tibblin G. Hyperinsulinaemia is not a major coronary risk factor in elderly men: the study of men born in 1913. Diabetologia. 1992;35:766-770. [Medline] [Order article via Infotrieve]
5. Hargreaves AD, Logan RL, Elton RA, Buchanan KD, Oliver MF, Riemersmaa RA. Glucose tolerance, plasma insulin, HDL cholesterol and obesity: 12-year follow-up and development of coronary heart disease in Edinburgh men. Atherosclerosis. 1992;94:61-69. [Medline] [Order article via Infotrieve]
6. Liu QZ, Knowler WC, Nelson RG, Saad MF, Charles MA, Liebow IM, Bennett PH, Pettitt DJ. Insulin treatment, endogenous insulin concentration, and ECG abnormalities in diabetic Pima Indians. Diabetes. 1992;41:1141-1150. [Abstract]
7. Collins VR, Dowse GK, Zimmet PZ, Tuomilehto J, Alberti KGMM, Gareeboo H, Nan L. Serum insulin and ECG abnormalities suggesting coronary heart disease in the populations of Mauritius and Nauru: cross-sectional and longitudinal associations. J Clin Epidemiol. 1993;46:1373-1393. [Medline] [Order article via Infotrieve]
8. Ferrara A, Barrett-Connor EL, Edelstein SL. Hyperinsulinemia does not increase the risk of fatal cardiovascular disease in elderly men or women without diabetes: the Rancho Bernardo Study, 1984-1991. Am J Epidemiol. 1994;140:857-869. [Abstract/Free Full Text]
9. Stern MP. The insulin resistance syndrome: the controversy is dead, long live the controversy! Diabetologia. 1994;37:956-958. [Medline] [Order article via Infotrieve]
10. Reaven GM. Banting Lecture 1988: role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607. [Abstract]
11. DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173-194. [Abstract]
12. Ferrannini E, Haffner SM, Mitchell BD, Stern MP. Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Diabetologia. 1991;34:416-422.[Medline] [Order article via Infotrieve]
13. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes. 1992;41:715-722. [Abstract]
14. Jarrett RJ. Why is insulin not a risk factor for coronary heart disease? Diabetologia. 1994;37:945-947. [Medline] [Order article via Infotrieve]
15. Worth RM, Kagan A. Ascertainment of men of Japanese ancestry in Hawaii through World War II Selective Service registration. J Chronic Dis. 1970;23:389-397. [Medline] [Order article via Infotrieve]
16. Rhoads GG, Kagan AM, Yano K. Usefulness of community surveillance for the ascertainment of coronary heart disease and stroke. Int J Epidemiol. 1975;4:265-270. [Abstract/Free Full Text]
17. Yano K, Reed DM, McGee DL. Ten-year incidence of coronary heart disease in the Honolulu Heart Program: relationship to biological and life-style characteristics. Am J Epidemiol. 1984;119:653-666. [Abstract/Free Full Text]
18. Kagan A, Popper JS, Rhoads GG. Factors related to stroke incidence in Hawaii Japanese men: the Honolulu Heart Study. Stroke. 1980;11:14-21. [Abstract/Free Full Text]
19. Burchfiel CM, Sharp DS, Curb JD, Rodriguez BL, Hwang L-J, Marcus EB, Yano K. Physical activity and incidence of diabetes: the Honolulu Heart Program. Am J Epidemiol. 1995;141:360-368. [Abstract/Free Full Text]
20. Kannel WB, Sorlie P. Some health benefits of physical activity: the Framingham Study. Arch Intern Med. 1979;139:857-861. [Medline] [Order article via Infotrieve]
21. Garcia-Palmieri MR, Costas R, Cruz-Vidal M, Sorlie PD, Havlik RJ. Increased physical activity: a protective factor against heart attack in Puerto Rico. Am J Cardiol. 1982;50:749-755. [Medline] [Order article via Infotrieve]
22. Gardner RM, Hankinson JL, Clausen JL, Crapo RO, Johnson RL, Epler GR. Standardization of spirometry—1987 update: official statement of the American Thoracic Society. Am Rev Respir Dis. 1987;136:1285-1298. [Medline] [Order article via Infotrieve]
23. Enright PL, Kronmal RA, Higgins M, Schenker M, Haponik EF. Spirometry reference values for women and men 65 to 85 years of age: Cardiovascular Health Study. Am Rev Respir Dis. 1993;147:125-133. [Medline] [Order article via Infotrieve]
24. Morgan CR, Lazarov A. Immunoassay of insulin: two antibody systems. Diabetes. 1963;21:115-126.
25. SAS Institute Inc. SAS/STAT User's Guide, Version 6. Cary, NC: SAS Institute Inc; 1990.
26. Lane PW, Nelder JA. Analysis of covariance and standardization as instances of prediction. Biometrics. 1982;38:613-621.[Medline] [Order article via Infotrieve]
27. Howard BV, Le NA, Belcher JD, Flack JM, Jacobs DR Jr, Lewis CE, Marcovina SM, Perkins LL. Concentrations of Lp(a) in black and white young adults: relations to risk factors for cardiovascular disease. Ann Epidemiol. 1994;4:341-350. [Medline] [Order article via Infotrieve]
28. Mykkanen L, Laakso M, Pyorala K. High plasma insulin level associated with coronary heart disease in the elderly. Am J Epidemiol. 1993;137:1190-1202. [Abstract/Free Full Text]
29. Asch S, Wingard DL, Barrett-Connor EL. Are insulin and hypertension independently related? Ann Epidemiol. 1991;1:231-244. [Medline] [Order article via Infotrieve]
30. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. Insulin and hypertension: relationship to obesity and glucose intolerance in Pima Indians. Diabetes. 1990;39:1430-1435. [Abstract]
31. Collins VR, Dowse GK, Finch CF, Zimmet PZ. An inconsistent relationship between insulin and blood pressure in three Pacific Island populations. J Clin Epidemiol. 1990;43:1369-1378. [Medline] [Order article via Infotrieve]
32. Burchfiel CM, Hamman RF, Marshall JA, Baxter J, Kahn LB, Amirani JJ. Cardiovascular risk factors and impaired glucose tolerance: the San Luis Valley Diabetes Study. Am J Epidemiol. 1990;131:57-70. [Abstract/Free Full Text]
33. Ferrannini E, Natali A. Essential hypertension, metabolic disorders, and insulin resistance. Am Heart J. 1991;121:1274-1282. [Medline] [Order article via Infotrieve]
34. Manolio TA, Savage PJ, Burke GL, Liu K, Wagenknecht LE, Sidney S, Jacobs DR Jr, Roseman JM, Donahue RP, Oberman A. Association of fasting insulin with blood pressure and lipids in young adults: the CARDIA Study. Arteriosclerosis. 1990;10:430-436. [Abstract/Free Full Text]
35. Ohmura T, Ueda K, Kiyohara Y, Kato I, Iwamoto H, Nakayama K, Nomiyama K, Ohmori S, Yoshitake T, Shinkawa A, Hasuo Y, Fujishima M. The association of the insulin resistance syndrome with impaired glucose tolerance and NIDDM in the Japanese general population: the Hisayama study. Diabetologia. 1994;37:897-904. [Medline] [Order article via Infotrieve]
36. Haffner SM, Mykkanen L, Valdez RA, Stern MP. Evaluation of two insulin assays in insulin resistance syndrome (syndrome X). Arterioscler Thromb. 1994;14:1430-1437. [Abstract/Free Full Text]
37. Feskens EJM, Kromhout D. Hyperinsulinemia, risk factors, and coronary heart disease: the Zutphen Elderly Study. Arterioscler Thromb. 1994;14:1641-1647. [Abstract/Free Full Text]
38. Zavaroni I, Bonora E, Pagliara M, Dall'Agio E, Luchetti L, Buonanno G, Bonati PA, Bergonzani M, Gnudi L, Passeri M, Reaven G. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med. 1989;320:702-706. [Abstract]
39. Burchfiel CM, Shetterly SM, Baxter J, Hamman RF. The roles of insulin, obesity and fat distribution in the elevation of cardiovascular risk factors in impaired glucose tolerance: the San Luis Valley Diabetes Study. Am J Epidemiol. 1992;136:1101-1109. [Abstract/Free Full Text]
40. Haffner SM, Fong D, Hazuda HP, Pugh JA, Patterson JK. Hyperinsulinemia, upper body obesity, and cardiovascular risk in non-diabetics. Metabolism. 1988;37:338-345. [Medline] [Order article via Infotrieve]
41. Stern MP, Morales PA, Haffner SM, Valdez RA. Hyperdynamic circulation and the insulin resistance syndrome (`syndrome X'). Hypertension. 1992;20:802-808. [Abstract/Free Full Text]
42. Higgins MW, Keller JB, Wagenknecht LE, Townsend MC, Sparrow D, Jacobs DR Jr, Hughes G. Pulmonary function and cardiovascular risk factor relationships in black and in white young men and women. Chest. 1991;99:315-322. [Abstract/Free Full Text]
43. Olefsky JM, Kolterman OG, Scarlett JA. Insulin action and resistance in obesity and non-insulin-dependent type II diabetes mellitus. Am J Physiol. 1982;243:E15-E30. [Abstract/Free Full Text]
44. Kaplan NM. The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med. 1989;149:1514-1520. [Abstract]
45. Laws A, King AC, Haskell WL, Reaven GM. Relation of fasting plasma insulin concentration to high-density lipoprotein cholesterol and triglyceride concentrations in men. Arterioscler Thromb. 1991;11:1636-1642. [Abstract/Free Full Text]
46. Donahue RP, Skyler JS, Schneiderman N, Prineas RJ. Hyperinsulinemia and elevated blood pressure: cause, confounder, or coincidence? Am J Epidemiol. 1990;132:827-836. [Free Full Text]
47. Denker PS, Pollock VE. Fasting serum insulin levels in essential hypertension: a meta-analysis. Arch Intern Med. 1992;152:1649-1651. [Abstract]
48. Fournier AM, Gadia MT, Kubrusly DB, Skyler JS, Sosenko JM. Blood pressure, insulin, and glycemia in nondiabetic subjects. Am J Med. 1986;80:861-879. [Medline] [Order article via Infotrieve]
49. Modan M, Halkin H, Almog S, Lusky A, Eshkol A, Shefi M, Shitrit A, Fuchs Z. Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. J Clin Invest. 1985;75:809-817.
50. Mitchell BD, Haffner SM, Hazuda HP, Valdez R, Stern MP. The relation between serum insulin levels and 8-year changes in lipid, lipoprotein, and blood pressure levels. Am J Epidemiol. 1992;136:12-22. [Abstract/Free Full Text]
51. Cambien F, Warnet J-M, Eschwege E, Jacqueson A, Richard JL, Rosselin G. Body mass, blood pressure, glucose, and lipids: does plasma insulin explain their relationships? Arteriosclerosis. 1987;7:197-202. [Abstract/Free Full Text]
52. Saad MF, Lillioja S, Nyomba BL, Castillo C, Ferraro R, De Gregorio M, Ravussin E, Knowler WC, Bennett PH, Howard BV, Bogardus C. Racial differences in the relation between blood pressure and insulin resistance. N Engl J Med. 1991;324:733-739. [Abstract]
53. Donahue RP, Donahue RD, Prineas RJ, Gutt M, Skyler JS, Schneiderman N, Goldberg RB. Insulin, ethnicity, and blood pressure: the Miami Community Health Study (MCHS). Am J Epidemiol. 1994;139:S57. Abstract.
54. Jarrett RJ. In defence of insulin: a critique of syndrome X. Lancet. 1992;340:469-471. [Medline] [Order article via Infotrieve]
55. Lithell HOL. Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism. Diabetes Care. 1993;14:203-209. [Abstract]
56. Facchini FS, Hollenbeck CB, Jeppesen J, Chen Y-DI, Reaven GM. Insulin resistance and cigarette smoking. Lancet. 1992;339:1128-1130. [Medline] [Order article via Infotrieve]
57. Feskens EJM, Loeber JG, Kromhout D. Diet and physical activity as determinants of hyperinsulinemia: the Zutphen Elderly Study. Am J Epidemiol. 1994;140:350-360.[Abstract/Free Full Text]
58. Regensteiner JG, Mayer EJ, Shetterly SM. Relationship between habitual physical activity and insulin levels among nondiabetic men and women: San Luis Valley Diabetes Study. Diabetes Care. 1991;14:1066-1074.[Abstract]
59. Donahue RP, Orchard TJ, Becker DJ, Kuller LH, Drash AL. Physical activity, insulin sensitivity, and the lipoprotein profile in young adults: the Beaver County Study. Am J Epidemiol. 1988;127:95-103. [Abstract/Free Full Text]
60. Reaven GM, Laws A. Insulin resistance, compensatory hyperinsulinaemia, and coronary heart disease. Diabetologia. 1994;37:948-952. [Medline] [Order article via Infotrieve]
61. Stout RW. Insulin and atheroma: 20-yr perspective. Diabetes Care. 1990;13:631-654. [Abstract]
62. Despres J-P, Marette A. Relation of components of insulin resistance syndrome to coronary disease risk. Curr Opin Lipidol. 1994;5:274-289.[Medline] [Order article via Infotrieve]
63. Stolar MW. Atherosclerosis in diabetes: the role of hyperinsulinemia. Metabolism. 1988;37(suppl 1):1-9.
64. Salomaa V, Riley W, Kark JD, Nardo C, Folsom AR. Non-insulin-dependent diabetes mellitus and fasting glucose and insulin concentrations are associated with arterial stiffness indexes: the ARIC Study. Circulation. 1995;91:1432-1443. [Abstract/Free Full Text]
65. Daly PA, Landsberg L. Hypertension in obesity and NIDDM: role of insulin and sympathetic nervous system. Diabetes Care. 1991;14:240-248. [Abstract]
66. Jeppesen J, Hollenbeck CB, Zhou M-Y, Coulston AM, Jones C, Chen Y-DI, Reaven GM. Relation between insulin resistance, hyperinsulinemia, postheparin plasma lipoprotein lipase activity, and postprandial lipemia. Arterioscler Thromb Vasc Biol. 1995;15:320-324. [Abstract/Free Full Text]
67. Moller DE, Flier JS. Insulin resistance: mechanisms, syndromes, and implications. N Engl J Med. 1991;325:938-948. [Medline] [Order article via Infotrieve]
68. Orchard TJ, Eichner J, Kuller LH, Becker DJ, McCallum LM, Grandits GA. Insulin as a predictor of coronary heart disease: interaction with apolipoprotein E phenotype. Ann Epidemiol. 1994;4:40-45. [Medline] [Order article via Infotrieve]
69. Fink RI, Kolterman OG, Griffin J, Olefsky JM. Mechanisms of insulin resistance in aging. J Clin Invest. 1983;71:1523-1535.

This article has been cited by other articles:

				Z. E. K. Pogson, T. M. McKeever, and A. Fogarty The association between serum osmolality and lung function among adults Eur. Respir. J., July 1, 2008; 32(1): 98 - 104. [Abstract] [Full Text] [PDF]

				T. M. McKeever, P. J. Weston, R. Hubbard, and A. Fogarty Lung Function and Glucose Metabolism: An Analysis of Data from the Third National Health and Nutrition Examination Survey Am. J. Epidemiol., March 15, 2005; 161(6): 546 - 556. [Abstract] [Full Text] [PDF]

				R. Peila, B. L. Rodriguez, L. R. White, and L. J. Launer Fasting insulin and incident dementia in an elderly population of Japanese-American men Neurology, July 27, 2004; 63(2): 228 - 233. [Abstract] [Full Text] [PDF]

				T. T. Fung, J. E. Manson, C. G. Solomon, S. Liu, W. C. Willett, and F. B. Hu The Association between Magnesium Intake and Fasting Insulin Concentration in Healthy Middle-Aged Women J. Am. Coll. Nutr., December 1, 2003; 22(6): 533 - 538. [Abstract] [Full Text] [PDF]

				H.-M. Lakka, T. A. Lakka, J. Tuomilehto, J. Sivenius, and J. T. Salonen Hyperinsulinemia and the Risk of Cardiovascular Death and Acute Coronary and Cerebrovascular Events in Men: The Kuopio Ischaemic Heart Disease Risk Factor Study Arch Intern Med, April 24, 2000; 160(8): 1160 - 1168. [Abstract] [Full Text] [PDF]

				K. L. Edwards, M. C. Mahaney, A. G. Motulsky, and M. A. Austin Pleiotropic Genetic Effects on LDL Size, Plasma Triglyceride, and HDL Cholesterol in Families Arterioscler. Thromb. Vasc. Biol., October 1, 1999; 19(10): 2456 - 2464. [Abstract] [Full Text] [PDF]

				N. Emanuele, N. Azad, C. Abraira, W. Henderson, J. Colwell, S. Levin, F. Nuttall, J. Comstock, C. Sawin, C. Silbert, et al. Effect of Intensive Glycemic Control on Fibrinogen, Lipids, and Lipoproteins: Veterans Affairs Cooperative Study in Type II Diabetes Mellitus Arch Intern Med, December 1, 1998; 158(22): 2485 - 2490. [Abstract] [Full Text] [PDF]

				P. W. F. Wilson, R. B. D'Agostino, D. Levy, A. M. Belanger, H. Silbershatz, and W. B. Kannel Prediction of Coronary Heart Disease Using Risk Factor Categories Circulation, May 19, 1998; 97(18): 1837 - 1847. [Abstract] [Full Text] [PDF]

				C. M. Burchfiel, D. S. Sharp, J. D. Curb, B. L. Rodriguez, R. D. Abbott, R. Arakaki, and K. Yano Hyperinsulinemia and Cardiovascular Disease in Elderly Men : The Honolulu Heart Program Arterioscler. Thromb. Vasc. Biol., March 1, 1998; 18(3): 450 - 457. [Abstract] [Full Text] [PDF]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar