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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2852-2858
Copyright © 2004 by The Endocrine Society

The Relationship of Fasting Serum Radioimmune Insulin Levels to Incident Coronary Heart Disease in an Insulin-Treated Diabetic Cohort

Richard A. Kronmal, Joshua I. Barzilay, Russell P. Tracy, Peter J. Savage, Trevor J. Orchard and Gregory L. Burke

Department of Biostatistics, University of Washington (R.A.K.), Seattle, Washington 98115; Kaiser Permanente of Georgia and Division of Endocrinology, Emory University (J.I.B.), Atlanta, Georgia 30082; Department of Pathology and Biochemistry, University of Vermont College of Medicine (R.P.T.), Colchester, Vermont 05446; Division of Epidemiology and Clinical Applications, National Heart, Lung, Blood Institute, National Institutes of Health (P.J.S.), Bethesda, Maryland 20892; Department of Epidemiology, Graduate School of Public Health (T.J.O.), University of Pittsburgh, Pittsburgh, Pennsylvania 15251; and Department of Public Health Sciences, Wake Forest University School of Medicine (G.L.B.), Winston-Salem, North Carolina 27157

Address all correspondence and requests for reprints to: Richard A. Kronmal, Ph.D., University of Washington, Department of Biostatistics Cardiovascular Health Study Coordinating Center Building 29, Suite 310, 6200 NE 74th Street, Seattle, Washington 98115. E-mail: kronmal{at}u.washington.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
It is not known whether insulin levels, in the setting of insulin treatment, are an independent risk factor for coronary heart disease (CHD). We studied a cohort of 116 insulin-treated individuals, 65 yr or older, who were followed for 5.6–9 yr. All were free of CHD at baseline.

There were 47 incident CHD events. In Cox proportional hazards modeling, with fasting immune-reactive insulin levels as a continuous variable, the hazard ratio for CHD was statistically significant (P < 0.0001). When insulin levels were divided into intervals, those in the third interval [43–150 µU/ml (258–900 pmol/liter)] had an adjusted 30% increased relative risk (95% confidence interval, 0.57, 2.98) compared with those in the first interval [<20 µU/ml (<120 pmol/liter)]. Those in the fourth interval [151–400 µU/ml (906–2400 pmol/liter)] had an adjusted 5.6-fold increased risk (2.3–13.1; P < 0.0001). Approximately 15% of the cohort had such elevated insulin levels. Immune-reactive insulin levels were strongly correlated with specific insulin, proinsulin, and insulin antibody levels.

Markedly elevated fasting immune-reactive insulin levels were an independent risk factor for CHD in this study of insulin-treated older adults. These observational findings should be confirmed through larger prospective studies, given their implications for insulin therapy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRIOR STUDIES OF the relationship of serum insulin levels with incident coronary heart disease (CHD) have been done largely in nondiabetic populations or in untreated diabetic cohorts. Results have been inconsistent. Several studies have shown an independent role for elevated insulin levels, whereas others have not (reviewed in Refs.1, 2, 3). Part of this uncertainty derives from the fact that elevated insulin levels have a close physiological link to the insulin resistance syndrome and its components of dyslipidemia, hypertension, and inflammation (2). The latter are risk factors for CHD, making it difficult to separate out an independent role for insulin levels as a risk factor for CHD.

Insulin-treated diabetes mellitus (DM) is associated with insulin resistance and a high risk of CHD (4, 5). Whether insulin levels in this setting are a risk factor for CHD has not been determined. Exogenous insulin therapy may result in high serum insulin levels (6, 7). In the present observational study, we examine the relationship of serum insulin levels with incident CHD in an insulin-treated diabetic cohort. Participants were 65 yr or older and members of the Cardiovascular Health Study (CHS), a longitudinal, observational study of older adults whose purpose is to identify factors related to the onset and course of CHD and stroke (8). Elderly individuals have the highest incidence of DM and CHD in the population and therefore are an appropriate population for such a study. We hypothesize that elevated insulin levels have an independent association with incident CHD after adjustment for CHD risk factors, including those related to insulin resistance.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Recruitment methods for the CHS have been published (8). Briefly, participants were recruited in two stages: an original cohort (n = 5201) in 1989–1990, and an African-American cohort (n = 687) in 1993–1994. Informed consent was obtained on study entry. Together, there were 179 participants receiving insulin therapy at baseline, representing 19.3% of the total CHS diabetic cohort (n = 921). Of these insulin-treated individuals, 116 were free of CHD at enrollment, and 114 of the 116 had complete data for analysis. All had fasting blood chemistries drawn before morning insulin treatment (9).

Baseline serum insulin levels were measured by competitive RIA (Coat-A-Count Insulin; Diagnostic Products Corp., Malvern, PA). There is no cross-reactivity with C-peptide or glucagon with this assay. There is, however, 40% cross-reactivity with proinsulin. The normal range for fasting insulin in nonobese subjects is 0–30 µU/ml (0–180 pmol/liter), and is 7–74 µU/ml (42–444 pmol/liter) in obese subjects. The lower detection limit of the assay is 1.2 µU/ml (7.2 pmol/liter), and the assay range is 5–400 µU/ml (30–2400 pmol/liter). The interassay coefficient of variance (CV) range is 4.9–10.0%.

In 2003, baseline samples, which were frozen at –70 C, were assayed for insulin fractions for the 179 insulin-treated diabetic participants. Proinsulin was measured by RIA (Human Proinsulin RIA; Linco Research, Inc., St. Charles, MO). This assay does not cross-react with insulin or C-peptide and measures only proinsulin. The minimum detectable level is 0.3 µU/ml (1.8 pmol/liter), and intra- and interassay CVs range from 1.5–6.9% and 1.5–10.1%, respectively. Normal fasting values are 1.3 ± 0.5 µU/ml (7.8 ± 3.0 pmol/liter). Specific human insulin was also measured by RIA (Human Insulin Specific RIA; Linco Research, Inc.). This assay does not cross-react with proinsulin, but it can cross-react with insulin antibodies, thereby giving falsely elevated insulin levels. The minimal detectable level is 2 µU/ml (12 pmol/liter). The normal fasting range is 5–15 µU/ml (30–90 pmol/liter). The intraassay and interassay CVs range from 2.2–4.4% and 2.9–6.0%, respectively. Antiinsulin antibodies (IgG) were measured using an enzyme immunoassay (Anti-insulin-G EIA; ALPCO Diagnostics, Windham, NH). It does not cross-react with insulin (Tracy, R. P., oral communication). The minimum detectable level is 1.0 U/ml (6 µmol/liter), and the assay range is 5.0–300.0 U/ml (30.0–1800 µmol/liter). The intraassay and interassay CVs range from 2.9–9.4% and 3.9–8.4%, respectively. The normal range is estimated to be less than 15 U/ml (<90 µmol/liter), and a positive result for the presence of antiinsulin antibodies is estimated to be more than 15 U/ml (>90 µmol/liter).

After blood was drawn, participants underwent cardiovascular testing: 1) resting electrocardiogram (ECG); 2) ankle and arm blood pressures, from which an ankle/arm blood pressure index was derived; and 3) carotid ultrasound, which measured intimal-medial thickness (IMT) (10). During the clinic visit, details of past medical history were obtained.

Prevalent and incident CHD was defined as myocardial infarction (MI), angina pectoris, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, and/or deaths attributable to CHD. This composite (and not MI alone) was chosen because CHD is aggressively managed nowadays, and MI alone would underestimate the prevalence or incidence of CHD. In the event that a diagnosis of CHD was unclear, it was adjudicated by committee (11).

As a standard against which to gauge the effects of serum insulin levels on CHD, a measure of normal insulin levels for this age group was derived. A subset of the CHS cohort was chosen that did not have characteristics known to influence insulin levels: individuals with a body mass index less than 25 kg/m2; normal oral glucose tolerance test using World Health Organization criteria (12); no hypoglycemic agent use; no prevalent CHD or stroke; and fasting overnight for 9 h or more. There were 959 participants meeting these criteria. The upper 5% of the distribution was defined as hyperinsulinemia.

Analysis

Baseline characteristics (continuous variables) of the cohort, categorized by insulin levels, were compared using ANOVA. Categorical variable comparisons were done using the {chi}2 test. The effect of serum insulin levels on time to incident CHD was examined using Cox proportional modeling with adjustment for significant risk factors selected by stepwise regression from the variables shown in Table 1Go (except for the special assay variables). Initial modeling was done with insulin levels treated as a continuous variable. When subsequent examination for nonlinearity revealed that most of the elevated risk was in participants with very high insulin levels, insulin was categorized into four intervals for the entire cohort based on quartiles of the insulin distribution of the participants with new CHD events and modeled as a categorical variable. This ensures that the number of incident CHD events occurring in each interval is approximately one fourth of the total number of events. This is an objective way of defining the intervals that allows for a sufficient number of events in each interval so that statistically stable estimates of the hazard ratios can be obtained. All analyses were done using SPSS, version 11.0 (SPSS Inc., Chicago, IL).


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  		TABLE 1. Characteristics of the CHS insulin-treated diabetic cohort divided by intervals of fasting insulin level

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The distribution of fasting immune-reactive insulin levels in the 179 insulin-treated participants is shown in Fig. 1Go. Of these participants, 65.4% had levels less than 50 µU/ml (<300 pmol/liter); 13.4% had levels between 51 and 100 µU/ml (306–600 pmol/liter); 4.5% had levels between 101 and 150 µU/ml (606–900 pmol/liter); and 16.8% had levels of at least 151 µU/ml (906 pmol/liter). The mean insulin level was 87 µU/ml (522 pmol/liter), and the median level was 33 µU/ml (198 pmol/liter). A normal fasting immune-reactive insulin level for this age group, among healthy nondiabetic participants (see Subjects and Methods for definition), was less than 18 µU/ml (108 pmol/liter). By this definition, only 20% of the insulin-treated cohort had normal fasting insulin levels.



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  		FIG. 1. Distribution of fasting immune-reactive insulin levels (microunits per milliliter) in the insulin-treated diabetic cohort of the CHS.

 
Baseline characteristics of the 179 participants in the insulin-treated cohort, by insulin levels, are shown in Table 1Go. There were no significant differences between groups with respect to demographic factors, duration of known DM, factors related to insulin resistance (waist-to-hip ratio, blood pressure, glucose level, uric acid level), kidney function, vascular inflammation [type-1 plasminogen activator inhibitor (PAI-1)], markers of generalized inflammation (fibrinogen, C-reactive protein, factor VII, albumin, and white blood cell count), daily energy expenditure, measures of subclinical cardiovascular disease (ankle/arm index and major ECG changes), measures of atherosclerosis (common and internal carotid artery IMT), and prior cerebrovascular disease. Those with the lowest immune-reactive insulin levels were older, weighed less, and had higher high-density lipoprotein (HDL) cholesterol and lower triglyceride levels than those in the other groups.

Levels of specific insulin, proinsulin, and insulin antibodies were related to immune-reactive insulin levels (Table 1Go). The correlation between them and immune-reactive insulin was 0.68, 0.58, and 0.75, respectively (P < 0.001 for each). Among those in the top interval of immune-reactive insulin, 15 of 17 were also in the top interval of specific insulin, 10 of 13 were in the top interval of proinsulin, and 10 of 12 were in the top interval of antiinsulin antibodies.

Median follow-up was approximately 7.6 yr (maximum, ~9 yr) for the original cohort and approximately 5.2 yr (maximum, ~5.6 yr) for the new cohort. There were 47 incident CHD events in the 116 participants without prevalent CHD. A total of 114 were analyzed, owing to missing data in two participants. There was little difference in event rate in the two lowest intervals of fasting immune-reactive insulin levels [7–19 µU/ml (42–114 pmol/liter) and 20–42 µU/ml (120–252 pmol/liter)], 5.7 and 5.8 per 100 person-years, respectively. The rate was moderately higher, 9.0 per 100 person-years, for those in the third interval [43–150 µU/ml (258–900 pmol/liter)]. The rate was dramatically higher, 19.5 per 100 person-years, in those with the highest insulin levels [151–400 µU/ml (906–2400 pmol/liter)]. Cumulative CHD incidence is shown in Fig. 2Go. The estimated cumulative rate of incident CHD at 9 yr of follow-up in participants in the highest baseline immune-reactive insulin level interval was 82%, compared with a rate of 40% in those in the lowest interval.



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  		FIG. 2. Cumulative incidence of CHD categorized by baseline intervals of fasting radioimmune insulin levels (intervals in microunits per milliliter shown to the right of each curve).

 
In Cox proportional hazards modeling, with immune-reactive insulin as a continuous variable, the hazard ratio for insulin levels was statistically significant (P < 0.0001). When insulin levels were divided into four intervals based on quartiles of the distribution of the participants with new CHD events (Table 2Go), those in the third interval had an approximately 30% increased relative risk compared with those in the first interval (P value, nonsignificant). Those in the fourth interval had a 5.6-fold increased risk [95% confidence interval (CI), 2.3, 13.1; P < 0.0001] compared with those in the first interval. When Cox proportional hazards modeling was done using specific insulin levels as a predictor, the highest level [45–202 µU/ml (270–1212 pmol/liter)] was not significantly associated with incident CHD on unadjusted analysis (relative risk, 1.78; 95% CI, 0.78, 4.06). With adjustment, the highest level was a significant predictor of CHD (relative risk, 4.09; 95% CI, 1.63, 10.24; P = 0.003). Proinsulin levels were not associated with CHD in adjusted or unadjusted analyses, nor were antiinsulin antibodies.


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  		TABLE 2. Cox proportional hazards regression analysis relating fasting immune-reactive insulin levels, specific insulin, proinsulin and antiinsulin antibodies to CHD risk in the insulin-treated diabetic cohort in CHS that was free of CHD at baseline

 
When both immune-reactive insulin levels and specific insulin levels were included in the same model, specific insulin levels were not a significant predictor of CHD, nor did this affect the strength of association of the other covariates with CHD (data not shown). High immune-reactive insulin levels remained strongly predictive of CHD.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To our knowledge, this is the first analysis to demonstrate that elevated fasting immune-reactive insulin levels are of prognostic importance for incident CHD in insulin-treated individuals. One prior study reported a relationship between the dose of exogenous insulin and CHD event rate (5). Those who developed CHD had higher insulin levels and dose requirements compared with those without incident CHD (13). Two other studies. which included small numbers of diabetic subjects on hypoglycemic therapy but did not present data specifically for those using insulin, suggested that high insulin levels may be associated with prevalent CHD (14, 15). Lastly, the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes showed a trend toward increased cardiovascular events in individuals receiving intense hypoglycemic therapy, including insulin therapy, compared with those receiving less intense therapy (16). Unlike these other studies, the present study controlled for numerous CHD risk factors, including those related to insulin resistance (hypertension, waist-to-hip ratio, and uric acid, PAI-1, triglyceride, and HDL cholesterol levels).

Prior studies of the effects of elevated insulin levels on CHD risk in nondiabetic individuals or untreated diabetic individuals have given contradictory results. A metaanalysis concluded that insulin levels may be an independent risk factor for CHD (reviewed in Ref.1), but other studies do not support such a role (reviewed in Ref.3). In all of these studies, insulin levels were lower than those found to be associated with CHD in this study. Similar to prior studies, we did not find an association between CHD and insulin levels less than 18 µU/ml (108 pmol/liter), the upper limit of normal insulin for this age cohort (data not shown). Like the Veterans Affairs High-Density Lipoprotein Intervention Trial, an approximately 30% elevated risk of CHD was found for fasting immune-reactive insulin greater than 42 µU/ml (>252 pmol/liter) (17). In the British Regional Heart Study (14), a specific insulin level greater than 35 µU/ml (>210 pmol/liter) was associated with increased CHD risk. In our study, an increased risk was present for a level greater than 45 µU/ml (>270 pmol/liter). In the Rancho Bernardo study, with a mean age of 67.5 yr, high fasting immune-reactive insulin levels [e.g. >100 µU/ml (>600 pmol/liter)] were present in the elderly, including those without a diagnosis of DM (18). Our results, therefore, are in agreement with prior studies.

Almost all studies that have examined the relationship of serum insulin levels and CHD have used a RIA. This assay reacts with specific insulin, proinsulin, and insulin antibodies. Our analysis showed a strong correlation between immune-reactive insulin and these subfractions. Those in the highest interval of radioimmune insulin had the highest levels of all subfractions. We did find that specific insulin was an independent predictor of CHD, suggesting that insulin per se, at high levels, is a CHD risk factor. Nonetheless, the assay for specific insulin cross-reacts with insulin antibodies, so it cannot be said with certainty that what was measured was not a combination of specific insulin and insulin antibodies. In multivariate analysis, immune-reactive insulin was more strongly related to CHD risk than was specific insulin, suggesting that it is the combination of insulin, proinsulin, and insulin antibodies that is related to CHD risk.

There are several explanations as to how high insulin levels accumulated in the blood. First, kinetic studies show that insulin clearance is inversely related to the percentage of body fat and directly related to muscle mass (19). Given the age of the cohort and the diminished muscle mass that is associated with aging, it is possible that elevated insulin levels were due in part to diminished clearance. Second, studies have shown that there is wide variation in absorption of injected insulin, based on sc blood flow (20), site of injection (21), dose of insulin (5), and circadian rhythms (22). These factors can lead to variation in the duration of insulin in the serum. Lastly, elevated levels may have been due to a combination of exogenous administration and endogenous production. In the entire CHS diabetic cohort, insulin levels greater than 150 µU/ml (>900 pmol/liter) were present only in those receiving insulin therapy and not in those on oral hypoglycemic agents or diet therapy (our unpublished data). This makes it clear that serum levels greater than 150 µU/ml (>900 pmol/liter) are related to insulin therapy. On the other hand, those with the highest insulin levels also had the highest proinsulin levels, suggesting that production of insulin was still present.

This study has deficiencies. The data are observational, and the size of the cohort is small. The dose and type of insulin used were not recorded. Only one measurement of insulin was taken at a variable time from the administration of the last dose of insulin. The variability of insulin levels over time in insulin-treated individuals is unknown but is likely considerable. It is possible that the mean or maximum insulin level over a 24-h period would be an even stronger predictor of CHD risk than a single measure taken in the morning, as was done in the CHS. The cohort excluded those with illnesses with short life expectancies. This would have the effect of excluding the sickest and possibly underestimating the risk of CHD associated with high insulin levels. Lastly, although there were no differences between those with and without high insulin levels with regard to factors associated with insulin resistance (blood pressure, uric acid, waist-to-hip ratio), exact measures of insulin resistance were not done in this study. It is therefore not possible to exclude the possibility that high insulin levels were not related to degree of insulin resistance.

Advantages of the study include testing done in a central laboratory with high quality standards, as well as long and nearly complete follow-up. Lastly, unlike most studies, women were included in these analyses (reviewed in Ref.18).

Several mechanisms may explain how elevated fasting insulin levels are associated with CHD in this older population. These include a direct atherogenic effect on the arterial muscle or endothelium (23), increased thrombogenesis (24, 25), impaired fibrinolysis (26), or an additive effect on the morning surge in blood pressure and heart rate that are associated with increased risk of CHD (27). Whatever the mechanism, we believe our findings are provocative and should be retested. Factors to be considered are the timing and dose of exogenous insulin and the kinetics of insulin absorption and clearance.

Given the high rate of CHD (82% in <9 yr) in those with markedly elevated insulin levels, our results suggest that it may be worthwhile to measure insulin levels in elderly diabetics receiving exogenous insulin therapy.


   Footnotes
 
This work was supported by contracts NO1-HC-85079 through NO1-HC-85086, NO1-HC-35129, and NO1-HC-15103 from the National Heart, Lung, and Blood Institute.

Abbreviations: CHD, Coronary heart disease; CHS, Cardiovascular Health Study; CV, coefficient of variance; DM, diabetes mellitus; ECG, electrocardiogram; HDL, high-density lipoprotein; IMT, intimal-medial thickness; MI, myocardial infarction; PAI-1, type-1 plasminogen activator inhibitor.

Received October 21, 2003.

Accepted March 9, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals