From the Department of Medicine, University of Texas Health Science
Center at San Antonio, Texas (S.M.H.); the Department of Public Health
Sciences, Winston-Salem, NC (R.D'A.); the Department of Clinical
Biochemistry, University of Cambridge, Cambridge, UK (C.N.H.); the National
Heart, Lung and Blood Institute, Division of Epidemiology and Clinical
Applications, Bethesda, Md (P.J.S.); the Department of Physiology and
Biophysics, University of Southern California School of Medicine, Los Angeles,
Calif (R.N.B.); the Department of Radiology, Tufts University School of
Medicine, Boston, Mass (D.O'L.); the Department of Preventive Medicine
and Biometrics, University of Colorado Medical School, Denver, Colo (M.R.);
Kaiser Permanente, Division of Research, Oakland, Calif (J.S.); the Department
of Pathology, University of Vermont School of Medicine, Burlington, Vt (R.T.);
and the Department of Medicine, University of California at Los Angeles School
of Medicine, Los Angeles, Calif (M.F.S.).
Methods—We examined the relation between fasting proinsulin,
fasting split proinsulin, fasting and 2-hour insulin (after oral
glucose load), and intima-media wall thickness (IMT) in the common
carotid artery (CCA) and internal carotid artery (ICA) in 985
nondiabetic subjects from the Insulin Resistance
Atherosclerosis Study, a multiethnic study of insulin
resistance and atherosclerosis.
Results—In the overall population, a weak but significant
relation between proinsulin and CCA IMT was observed
(r=0.07, P=0.029). However, the relation
between proinsulin and IMT was stronger in Hispanics and non-Hispanic
whites than in African Americans. In non-Hispanic whites and Hispanics,
significant correlations between CCA and proinsulin
(r=0.087) and between ICA and proinsulin
(r=0.101), split proinsulin (r=0.092),
and fasting insulin (r=0.087) were observed. The
significant correlations became more attenuated (and nonsignificant)
after adjustment for cardiovascular risk factors,
especially plasminogen activator
inhibitor-1 (PAI-1).
Conclusions—The association between proinsulin and IMT, while
weak, appears to be stronger than the association between insulin and
IMT. Adjustment for PAI-1 markedly attenuated the association between
proinsulin and IMT, suggesting a possible mediating role for PAI-1 in
this association. It is possible that proinsulin may represent
a marker of atherosclerosis rather than a causal factor
for atherosclerosis. Studies of the insulin resistance
syndrome and atherosclerosis that use insulin as a
surrogate for insulin resistance should consider the use of specific
insulin assays as well as determination of proinsulin concentrations.
Insulin concentration has been considered to be fairly well correlated
with insulin resistance (r=-0.60) in nondiabetic
subjects.11 12 Although no studies have examined
insulin resistance in relation to the incidence of
cardiovascular disease, a number of studies have shown
that subjects with atherosclerosis are more insulin
resistant.13 14 15 16 Insulin concentrations
have been used as a surrogate for insulin resistance in studying the
association of insulin with atherosclerosis, since the
use of direct methods to assess insulin sensitivity, such as the
hyperinsulinemic euglycemic clamp or the
frequently sampled intravenous glucose tolerance (FSIGT)
test, are expensive and time-consuming and have only limited patient
acceptance. One potential problem with the use of insulin
concentrations as a surrogate for insulin resistance is that most
commercial assays for insulin cross-react with proinsulin. Proinsulin
is increased relative to insulin in subjects with type 2 diabetes in
all studies17 18 19 20 21 22 23 and elevated in subjects with
impaired glucose tolerance in most23 24 but not
all20 studies. Increased proinsulin has been more
strongly correlated with cardiovascular risk factors
than insulin in both diabetic25 26 and
nondiabetic27 28 29 subjects. Relatively few data
are available on the relation of proinsulin to
cardiovascular disease or
atherosclerosis. Kahn et al30
found a relation of insulin (but not proinsulin) to prevalent
coronary heart disease (CHD) in 170 Japanese Americans. In
contrast, Båvenholm et al31 found a significant
relation between both insulin and proinsulin with CHD in 62 men; these
associations were no longer significant after adjustment for body mass
index (BMI). Yudkin et al32 found modest (but
significant) relations between both insulin and proinsulin and
prevalent CHD; these results were no longer significant after
adjustment for BMI. In the longitudinal study,32
no significant relation between insulin or proinsulin and CHD was
observed. In small studies of proinsulin with
atherosclerosis, no significant associations were
observed.9 10
In this report, we examine the association between insulin, proinsulin,
and atherosclerosis as determined by B-mode imaging of
the carotid artery intima-media thickness (IMT) in 985 nondiabetic
subjects in a large multicenter, multiethnic study, the Insulin
Resistance Atherosclerosis Study
(IRAS).33 This imaging technique has been shown
to reflect histopathologically verified
atherosclerosis34 35 and
therefore has been widely used as a noninvasive method for assessing
atherosclerosis.36 37 Because
proinsulin levels have been associated with
cardiovascular risk factors, we also assess whether
relations between proinsulin and atherosclerosis may be
attributed to cardiovascular risk factors. We have
previously reported the relationship of insulin sensitivity to
atherosclerosis in the
IRAS.16
A total of 1625 individuals participated in the IRAS (56%
women).33 The final study sample included 613
non-Hispanic whites (NHW), 548 Hispanics (HIS), and 464 African
Americans (AA). FSIGT tests were successfully performed in 94%
(1525/1625) of IRAS participants overall. Individuals with normal
glucose tolerance constituted the largest segment of the study sample
(44%) (NHW, n=291; AA, n=187; and HIS, n=241), followed by diabetic
subjects (33%) (NHW, n=177; AA, n=176; and HIS, n=241) and persons
with impaired glucose tolerance (23%) (NHW, n=145; AA, n=101; and HIS,
n=123). The distribution of insulin sensitivity has been recently
described in nondiabetic40 and
diabetic41 subjects from the IRAS.
Race and ethnicity were assessed by self-report. Hispanic ethnicity was
defined by the US census question, "Are you of Spanish or Hispanic
descent?" Height, weight, and girth (minimum waist, waist at the
umbilicus and hips) were measured following a standardized protocol.
BMI in weight/height2
(kg/m2) was used as an estimate of overall
adiposity. The ratio of waist circumference was used as an estimate of
body fat distribution.
The IRAS examination required 2 visits (
Plasma glucose was measured with the glucose oxidase technique on an
automated autoanalyzer (Yellow Springs Equipment Co). Insulin
was measured using the dextran-charcoal
radioimmunoassay.45 This insulin assay
cross-reacts with proinsulin. Glucose and insulin levels in all samples
were measured at the central IRAS laboratory at the University of
Southern California, Los Angeles. The split-pair coefficient of
variation (CV) for insulin was 15% in the IRAS (n=86).
Fasting serum intact proinsulin and 32-33 split proinsulin were
determined from samples stored at -70°C for an average of 3.3 years
(35 to 44 months) by means of highly specific 2-site monoclonal
antibody–based immunoradiometric assays.46 The
split-pair CV was 14% for proinsulin (n=98) and 18% for 32-33 split
proinsulin (n=98). There was no detectable cross-reactivity of insulin
or 32-33 split proinsulin in the intact proinsulin assay. Insulin did
not significantly cross-react in the assay for 32-33 split proinsulin,
and the cross-reactivity of intact proinsulin in this assay was 84%.
Assay values of 32-33 split proinsulin were corrected for this by
subtraction of the corresponding proinsulin cross-reactivity. The assay
of 32-33 split proinsulin cross-reacts equally with 32-33, des-32, and
des-31-32 split proinsulins. We used the term 32-33 split proinsulin to
indicate the sum of these 3 molecules, the majority of which are
des-31-32 split proinsulin.47 The sensitivity
limit of the intact proinsulin and 32-33 split proinsulin assays was
1.25 pmol/L (3 SDs from zero). Intact proinsulin and 32-33 split
proinsulin were determined at the laboratory of the Department of
Clinical Biochemistry at Addenbrook's Hospital, Cambridge, UK.
Plasma lipoprotein measurements were obtained from single fresh fasting
plasma samples using Lipid Research Clinic methods. VLDL was isolated
by preparative ultracentrifugation, and VLDL (top) and
bottom fractions were measured for cholesterol and
triglyceride concentrations. HDL cholesterol
was measured after precipitation of apolipoprotein B–containing
lipoproteins with MnCl2 and heparin. The
cholesterol content in the supernatant was measured in a
separate autoanalyzer channel set to measure low
cholesterol values. LDL cholesterol was
calculated as the difference between the HDL cholesterol
and the bottom cholesterol. Triglycerides were
measured enzymatically after correction for free glycerol.
Fibrinogen was measured in citrated plasma with a modified clot-rate
assay using the Diagnostica STAGO ST4 instrument as
described.48 This is based on the original method
of Clauss,49 with a CV of 3.0%.
Plasminogen activator inhibitor-1
(PAI-1) was also measured in citrated plasma,50
using a 2-site immunoassay that is sensitive to free PAI-1 but not to
PAI-1 complex with tissue plasminogen
activator.51 The citrate sample was
centrifuged for a minimum of 30 000g minutes
to make certain that there was no contamination from platelet
PAI-1; the CV was 6.0%.
High-resolution B-mode carotid ultrasonography was performed with
Toshiba SSA-270A imaging units (Toshiba America Medical Systems) to
provide an index of
atherosclerosis.34 35 52 53 The
scanning and reading protocols were identical to those used in the
Cardiovascular Health Study.54
All studies were recorded on super VHS tape and sent weekly to a
central reading center. The high-resolution images of the common (CCA)
and internal (ICA) carotid arteries were analyzed using a
specially designed computer program to calculate far-wall IMT. To
quantify the degree of thickening of the carotid artery walls, the
measures of IMT were summarized into 2 variables, 1 for the CCA and
1 for ICA. Because of the geometry of the artery and the physics of
ultrasound assessment, measurements of the far wall are considered both
more reliable and valid35 and were the focus of
these analyses. The maximum IMT of the CCA was defined as the
mean of the maximum IMT for the far wall on both the left and right
sides (1 view). The maximum IMT of the ICA was defined similarly: 3
views from each side were averaged, and the mean of the right and left
averages was used in the analysis. The number of measurements
available for averaging thus ranged from 1 to 2 for the CCA and 1 to 6
for the ICA. A subset of 43 participants were rescanned for an
assessment of intrasonographer variability; the correlation coefficient
between scans was 0.95 and 0.94 for CCA IMT and ICA IMT,
respectively.
Statistical Analyses
In these models, we examined whether there were any interactions
between proinsulin and either sex or ethnicity. There were no
significant interactions with sex; however, significant interactions of
proinsulin and ethnicity were observed, such that African Americans had
a different relationship of proinsulin and IMT than non-Hispanic whites
and Hispanics. Because there was no significant difference in the
relation between proinsulin and IMT for non-Hispanic whites and
Hispanics, these groups were pooled together in the
analyses.
Therefore, in Table 3
After further adjustment for LDL cholesterol, HDL
cholesterol, triglycerides, LDL size, and
PAI-1, the associations between proinsulin and IMT were no longer
statistically significant (data not shown). Proinsulin was most
strongly associated with PAI-1 (r=.414,
P<0.001). After adjustment for PAI-1 only (in addition to
ethnicity, clinic, age, sex, and smoking status), the relation between
proinsulin and CCA and ICA IMT was no longer statistically significant
(data not shown). In contrast, after further adjustment for BMI and
WHR, the relation between proinsulin and CCA and ICA IMT remained
statistically significant (data not shown).
In our data, the relation between levels of insulin and proinsulin and
carotid IMT was no longer statistically significant after adjustment
for cardiovascular risk factors. Previous work has
suggested that proinsulin may be strongly associated with
cardiovascular risk factors in both
diabetic25 26 and
nondiabetic27 28 subjects. When
cardiovascular risk factors were adjusted for 1 at a
time, adjustment for PAI-1 markedly attenuated the association between
proinsulin and IMT, suggesting a possible role for PAI-1 in mediating
this association. Proinsulin (at very high concentrations) has been
shown to increase PAI-1 in an in vitro
system.55 56 Increased levels of PAI-1 have been
associated with myocardial infarction.57 58
The relation of proinsulin to CHD is controversial. Small
cross-sectional studies have found inconsistent relations
between proinsulin and CHD, with some studies reporting significant
results31 32 and 1 study reporting no significant
association.30 In 1 longitudinal
study,32 no significant relations were found
between proinsulin and CHD.32
The explanation for the possible role of proinsulin in
atherosclerosis is not clear. Proinsulin is present
in low concentrations except in diabetic
subjects.17 18 19 20 21 22 23 24 Furthermore, the activity of
proinsulin either in vitro or in vivo is only 8% to 10% of that of
insulin,59 so these low concentrations are
unlikely to have a biological insulin-like effect. Recently, Alessi et
al60 have reported increased production
of PAI-1 by visceral fat, suggesting that visceral fat may affect both
insulin resistance and increased PAI-1. The above study may suggest
that a common factor (perhaps visceral fat) increases
proinsulin, PAI-1, and IMT, rather than suggesting that increased
proinsulin might lead to increased PAI-1, which in turn might lead to
increased IMT. However, when we adjusted for the effect of BMI and WHR,
the relation between proinsulin and IMT remained significant,
suggesting that the relation between proinsulin and IMT is at least
partially independent of adiposity.
Another possibility for the association between proinsulin and IMT
might be autonomic dysfunction. Autonomic dysfunction has been shown to
predict cardiovascular
mortality.61 62 Recently, increased proinsulin
levels have been associated with the sympathovagal balance of the
autonomic nervous function in both non–insulin-dependent diabetes
mellitus patients and control subjects.63
In conclusion, we have shown a significant (but modest) association
between proinsulin and atherosclerosis that may be
mediated in part by higher PAI-1 levels. The association between
proinsulin and IMT appears to be stronger than that of insulin and IMT.
The biological significance of the association between proinsulin and
IMT is unknown, and thus it is possible that the relation between
proinsulin and atherosclerosis may be an epiphenomenon.
Further work on the biological basis of this association is
necessary.
Received January 29, 1998;
revision received April 29, 1998;
accepted May 22, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Proinsulin and Insulin Concentrations in Relation to Carotid Wall Thickness
Insulin Resistance Atherosclerosis Study
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Insulin
resistance and hyperinsulinemia have been
associated with atherosclerosis. Recent attention has
focused on the possible role of proinsulin because most
radioimmunoassays for insulin cross-react with proinsulin. Therefore,
it is not known which of the two, insulin per se or
proinsulin, is more strongly related to atherosclerosis.
Key Words: atherosclerosis • insulin • plasminogen activator inhibitor-1 • proinsulin
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Insulin
concentrations have been related to the incidence of
cardiovascular disease in
many1 2 3 4 but not all
studies.5 6 7 Fasting insulin concentrations were
also related to atherosclerosis in the carotid artery
in the large Atherosclerosis Risk in Communities
Study.8 In smaller Finnish9
and American10 studies, insulin concentrations
were not related to atherosclerosis.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
A detailed description of the design and methods of the IRAS has
been published.33 In brief, this study was
conducted at 4 clinical centers. Clinical centers in Oakland and Los
Angeles, Calif, studied non-Hispanic whites and African Americans
recruited from Kaiser Permanente, a nonprofit health
maintenance organization. Clinical centers in San Antonio, Tex,
and San Luis Valley, Colo, studied non-Hispanic whites and Hispanics
recruited from 2 ongoing population-based studies (San Antonio Heart
Study38 and San Luis Valley Diabetes
Study39 ). Diabetic subjects taking insulin were
not eligible for the IRAS. Of all eligible subjects, 48% contacted
completed the 2-day IRAS examination. Diabetic subjects with a fasting
glucose level 
300 mg/dL (16.7 mmol/L) were excluded. The
fasting glucose levels of Hispanic, African American, and non-Hispanic
white diabetic and nondiabetic subjects in the IRAS were similar to
those of their counterparts in the NHANES
survey.33 
1 week apart; range, 2 to 28
days), each lasting approximately 4 hours. Oral glucose tolerance tests
and FSIGT tests were performed during the first and second visits,
respectively. Participants were asked before each visit to fast for 12
hours, to abstain from heavy exercise and alcohol for 24 hours, and to
refrain from smoking the morning of the examination. For the oral
glucose tolerance test, a 75-g glucose load (Orangedex, Custom
Laboratories) was administered in <10 minutes. Blood was
collected before ingestion and at 2 hours after the glucose load.
Glucose tolerance was classified according to the World Health
Organization criteria.42 Insulin sensitivity was
assessed by the FSIGT test43 with minimal model
(MINMOD) analyses.44
Means and standard deviations were presented for the
clinical characteristics of the subjects studied. These descriptive
statistics were presented separately for each of the 3 ethnic
groups studied (Table 1
). Next,
analyses were performed using correlation and ANCOVA techniques
(SAS version 6.08, SAS Institute). Because many of the key
variables were not normally distributed (ie, insulin, proinsulin,
triglycerides, and PAI-1), we used predominantly
nonparametric correlation analyses (Spearman rank
correlations) for statistical testing. The initial model adjusted for
demographic variables (age, sex, ethnicity, clinic, and smoking
status). Further adjustment (using continuous variables) was made
for blood pressure, lipid levels (LDL, HDL, triglycerides),
LDL size, waist circumference, and PAI-1 in the second model.
Because of the large number of comparisons made (especially in Table 2), the nominal probability values should
be interpreted with caution.
View this table:
[in a new window]
Table 1. Clinical Characteristics of Nondiabetic Subjects by
Ethnic Group
View this table:
[in a new window]
Table 2. Overall Spearman Correlations (P)
With IMT of Carotid Arteries, Adjusted for Age, Clinic, Ethnic Group,
Sex, and Smoking
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Table 1
shows the characteristics of the nondiabetic subjects by
ethnicity. Table 2 shows Spearman correlations (in the overall group)
of proinsulin and insulin with IMT, adjusted for age, clinic, ethnic
group, sex, and smoking. Proinsulin was significantly correlated with
CCA IMT (P=0.029) and borderline significantly correlated
with ICA IMT (P=0.057). Split proinsulin, fasting insulin,
2-hour insulin, and fasting proinsulin/fasting insulin ratio were not
significantly correlated with IMT. Because previous analyses
from the IRAS16 suggest a stronger relation
between insulin sensitivity and IMT in non-Hispanic whites or Hispanics
than African Americans, we next tested whether the relation between
proinsulin and IMT might differ between the ethnic groups. The
probability value for overall ethnicityxproinsulin interaction was
significant for CCA (P=0.017) but not for ICA
(P=0.256). However, there was no significant interaction for
insulin or proinsulin in relation to IMT between Hispanics and
non-Hispanic whites. , we show
correlations separately in Hispanics and non-Hispanic whites compared
with African Americans. These data were adjusted for age, sex,
ethnicity, clinic, and smoking status. Proinsulin, split proinsulin,
and fasting insulin were significantly correlated with ICA IMT, whereas
proinsulin was significantly correlated with CCA IMT in Hispanics and
non-Hispanic whites. In contrast, in African Americans, neither insulin
nor proinsulin was significantly correlated with IMT.
View this table:
[in a new window]
Table 3. Spearman Correlations (P) With
IMT of Carotid Arteries Separately for Non-Hispanic Whites and
Hispanics Combined and African Americans, Adjusted for Age, Clinic,
Sex, and Smoking Status
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
In this report, we found a significant association between
proinsulin concentrations and carotid IMT. The relation of intact
proinsulin to atherosclerosis was stronger than the
relation of insulin or split proinsulin to
atherosclerosis. The association between proinsulin and
IMT was stronger in Hispanics and non-Hispanic whites than in African
Americans. In fact, the correlation between proinsulin and IMT was
inverse in African Americans, although these results were not
statistically significant. (It is possible that if a specific insulin
assay was used, the relation of insulin to IMT might have been even
weaker.) In a previous report from the IRAS study, decreased insulin
sensitivity was related to atherosclerosis in Hispanics
and non-Hispanic whites but not in African
Americans.16 We do not have a biologically
plausible explanation why the relationship of insulin resistance,
insulin, and proinsulin to atherosclerosis should
differ in African Americans, but we have shown previously that
nondiabetic African Americans are very insulin
resistant,40 and possibly a plateau might
characterize the association of insulin or proinsulin to
atherosclerosis. Two previous small studies have
examined the relation of proinsulin to atherosclerosis.
Katz et al10 did not find a significant relation
between proinsulin and insulin and atherosclerosis (as
assessed by coronary angiography) in a predominantly African
American population. Niskanen et al9 also did not
find an association between proinsulin concentrations and IMT in a
Finnish population. The differences in the studies may all relate to
the error in the assay for proinsulin or insulin and the number of
participants, since both will have relatively large effects on
associations as assessed by correlation analyses. This might be
especially true if the r values are as small as they are
here. However, in the IRAS the precision of the proinsulin and insulin
assays were similar as determined by the split-pair CVs.
Acknowledgments
This work was supported by the National Heart, Lung, and Blood
Institute (grants HL47887, HL47889, HL47890, HL47892, and HL47902) and
the General Clinic Research Centers Program (grants NCRR GCRC, M01
RR03431, and M01 RR01346).
Footnotes
Reprint requests to Steven M. Haffner, MD, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284-7873.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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A. J.G. Hanley, G. McKeown-Eyssen, S. B. Harris, R. A. Hegele, T. M.S. Wolever, J. Kwan, P. W. Connelly, and B. Zinman Cross-Sectional and Prospective Associations Between Proinsulin and Cardiovascular Disease Risk Factors in a Population Experiencing Rapid Cultural Transition Diabetes Care, July 1, 2001; 24(7): 1240 - 1247. [Abstract] [Full Text] [PDF]
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B. Frauchiger, H. P. Schmid, C. Roedel, P. Moosmann, and D. Staub Comparison of Carotid Arterial Resistive Indices With Intima-Media Thickness as Sonographic Markers of Atherosclerosis Stroke, April 1, 2001; 32(4): 836 - 841. [Abstract] [Full Text] [PDF]
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