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(Stroke. 2000;31:2936.)
© 2000 American Heart Association, Inc.
Original Contributions |
High Proinsulin Levels Precede First-Ever Stroke in a Nondiabetic Population
From the Department of Public Health and Clinical Medicine (B.L, M.E, G.H., B.S), Umeå University, Umeå, Sweden; Department of Medicine, Sunderby Hospital, Luleå, Sweden (M.E.); and Steno Diabetes Center, Gentofte, Denmark (B.D., M.R).
Correspondence to Bernt Lindahl, Behavioral Medicine, Department of Public Health and Clinical Medicine, Umeå University, SE-901 87 Umeå, Sweden. E-mail bernt.lindahl{at}medicin.umu.se
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Diabetic subjects have a 3- to 6-fold increased risk for stroke compared with nondiabetic subjects, and hyperinsulinemia shows strong and consistent associations with a cluster of cardiovascular risk factors. Methods separating proinsulin from (true) insulin have demonstrated proinsulin to be more strongly associated with cardiovascular disease than insulin. The present study evaluates the associations between first-ever stroke, proinsulin, and insulin.
Methods—In this incident case-referent study of a nondiabetic population, 94 cases of first-ever stroke (59 men and 35 women) were individually age- and sex-matched to 178 referents. Blood sampling was collected before the stroke event. Proinsulin and insulin were measured with highly sensitive 2-site sandwich enzyme-linked immunosorbent assays.
Results—In the study population, high proinsulin concentration more than tripled the risk for first-ever stroke after adjustments for total cholesterol, systolic blood pressure, smoking, body mass index, and insulin, with an odds ratio of 3.4 (95% CI, 1.4 to 8.4). In women the risk was even more pronounced, with an odds ratio of 13.7 (95% CI, 1.3 to 146). Synergy was found between proinsulin and systolic blood pressure. In women, synergy was also found between proinsulin and diastolic blood pressure as well as between insulin and both blood pressures.
Conclusions—High levels of proinsulin may predict later occurrence of first-ever stroke in a nondiabetic population.
Key Words: insulin • proinsulin • stroke
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The underlying cause of stroke in most cases is an atherosclerotic process in the blood vessels, and ischemic stroke accounts for approximately 80% of all stroke events.1 Next to age, hypertension is the most important risk factor for both hemorrhagic and ischemic strokes.2 3 Other important risk factors are smoking, diabetes, and hypercholesterolemia, but none of these are as important as hypertension. Men and women with diabetes have an excessive risk for cerebral infarction, while the risk for hemorrhage does not seem to be elevated.4 In the Framingham Study, 45- to 74-year-old diabetic men and women were found to have 2.5 to 3.5 times higher risk for cerebral infarction than nondiabetic individuals.5 The Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) study found a >4-fold higher risk for stroke in diabetic compared with nondiabetic men and nearly 6-fold higher risk for diabetic versus nondiabetic women.6 Recently, 2 prospective studies confirmed diabetes to be a strong risk factor for stroke. Furthermore, after exclusion of subjects with diabetes, both studies showed elevated fasting insulin levels to be associated with increased risk of future stroke.7 8
Ample evidence has been presented on the association between the insulin level and a cluster of cardiovascular risk factors. The risk factors that constitute the metabolic syndrome are obesity (especially abdominal), dyslipidemia with high triglyceride and low HDL cholesterol levels, hypertension, and low fibrinolytic activity. Often the syndrome also includes impaired glucose tolerance.9 10 11
The introduction of specific immunoradiometric12 or enzyme-linked immunosorbent assays (ELISA),13 14 which measure immunoreactivity from proinsulin and split proinsulin separately from true insulin, made it possible to independently examine the effect of proinsulin and true insulin on cardiovascular risk factors and cardiovascular disease. It has already been shown, in both diabetics and nondiabetics, that proinsulin and split proinsulin have a stronger association than insulin to dyslipidemia (high triglycerides and low HDL cholesterol), hypertension, and impaired glucose tolerance.15 It has also been shown in vitro that proinsulin, at least as strongly as insulin and independently of insulin, increases the level of plasminogen activator inhibitor type 1 (PAI-1) activity and thereby lowers fibrinolytic activity.16 17 Furthermore, the association between proinsulin and intima-media wall thickness in the common carotid artery was stronger than the corresponding association between insulin and intima-media wall thickness.18
The aim of the present study was to evaluate proinsulin and insulin as risk markers for first-ever stroke in a nondiabetic population.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Population
Since 1985, in Västerbotten County in northern Sweden, there has been an ongoing community intervention program for cardiovascular disease and diabetes, the Västerbotten Intervention Program (VIP).19 As a part of this program, all men and women were invited to a health survey at the age of 30, 40, 50, and 60 years. At the same time, the 2 northernmost counties in Sweden (Västerbotten and Norrbotten) joined the World Health Organization (WHO) MONICA study.20 Within this project, population-based health surveys were performed in 1986, 1990, and 1994. In total, 4725 men and women in the group aged 25 to 64 years participated. In both the VIP and the MONICA surveys, participants were requested to donate a blood sample to be stored at the Northern Sweden Medical Research Bank for future research purposes. In the present study a nested case-referent design has been used, in which incident cases of first-ever stroke were defined by the Northern Sweden MONICA incidence registry.21 The inclusion criteria for the cases were a first-ever stroke classified according to the MONICA criteria and identified during the period of January 1, 1985, through August 31, 1996. An additional criterion was the participation in the VIP or the MONICA survey and the presence of a blood sample in the Northern Sweden Medical Research Bank before the stroke event. One hundred twelve cases remained after the exclusion of individual cases with a previous acute myocardial infarction (n=15), stroke (n=9), or cancer diagnosis (n=13) and of cases in which the blood sample taken was inadequate for analysis (n=17).
Two referent subjects for each case were randomly selected among participants in the VIP or MONICA surveys. They were matched for sex, age (±2 years) and date (±1 year) of health survey, and geographic region. Individuals were excluded if they had died or had moved away from the region on or before August 31, 1996. The referent subjects were also excluded if they had an acute myocardial infarction, stroke, or cancer before the health survey. A questionnaire was sent to all referents to further ensure absence of stroke and/or acute myocardial infarction in their history.
For the present study all individuals (cases and
referents) with known (self-reported) diabetes (n=11) or unknown
diabetes (n=18) were excluded. Unknown diabetes was defined as having a
fasting plasma glucose at the health survey of 
7 mmol/L or a
2-hour plasma glucose during an oral glucose tolerance test (OGTT) in
the diabetic range, ie, 12.2 mmol/L in capillary plasma. An OGTT
was performed in >90% of the
participants.22
Twenty-nine diabetic subjects (18 cases and 11 referents) were excluded
along with the individually matched referents (n=36) to the stroke
cases with diabetes. Hence, 94 cases (59 men and 35 women) and 178
referents (113 men and 65 women) remained and formed the basis of the
present study.
Methods
At the health survey, blood pressure was measured
after the subject had rested for 5 minutes in the recumbent position.
Body weight was measured with the subject in light indoor clothing and
recorded to the nearest kilogram. Height was measured to the
nearest centimeter and without shoes. Body mass index was calculated as
weight (kilograms) divided by height (meters) squared. Smokers were
defined as those reporting daily smoking of cigarettes, cigarillos,
cigars, or a pipe. Ex-smokers and occasional smokers were classified as
nonsmokers. During the first years of the VIP health surveys, the
minimum fasting period before blood sampling was determined to be 4
hours. Since most of the health surveys were done in the morning, a
majority of the participants had an overnight fast. In 1992 and
subsequent years the requested minimum fasting period was changed to 8
hours. In a majority of the subjects (n=252), an abbreviated OGTT was
performed according to the WHO standard, with a 75-g anhydrous
glucose load and with measurement of plasma glucose after 2
hours.22 Venous
blood was taken in heparin tubes to obtain plasma for analyses
of proinsulin and insulin. The plasma samples were frozen within 1 hour
at -20°C and later during the day or within a week stored at
-80°C. Fresh serum was used for measurement of total
cholesterol.
Laboratory Procedures
Proinsulin was measured with the use of a highly
sensitive 2-site sandwich
ELISA.13 The assay
is based on 2 monoclonal antibodies, a mouse anti-human C-peptide
antibody (PEP-001) and a mouse anti-human insulin antibody (HUI-001).
The detection limit in human serum is 0.25 pmol/L. There was no
cross-reaction with human insulin and human C-peptide. However, the 4
major proinsulin conversion intermediates reacted in various
proportions ranging from 65% to 99%. Insulin was measured in a
similar manner with the use of another sensitive 2-site sandwich
ELISA.14 The assay
is based on 1 monoclonal antibody with its epitope near the C-terminal
end of the B-chain (OXI-005) and 1 monoclonal antibody with its epitope
centered around the A-chain loop (HUI-018). The detection limit is 5.0
pmol/L. The specificity of the assay excludes intact, split(32-33)-,
and des(31,32)-proinsulin. There was some cross-reaction with
split(65-66)-proinsulin (30%) and des(64,65)-proinsulin (63%).
Fasting plasma glucose, 2-hour plasma glucose during an OGTT, and total
serum cholesterol concentrations were measured with
Reflotron bench-top analyzers (Boehringer Mannheim
GmbH) at the time of the health
survey.23
The study was approved by the Research Ethics Committee at Umeå University, and the data handling procedures were approved by the National Computer Data Inspection Board.
Statistical Analysis
The Statistical Analysis System (SAS) version
6.12 and EGRET software version 1.01.10 were used. Our main
variables (proinsulin and insulin) had a skewed distribution. An
approximate normal distribution was achieved after logarithmic
transformation, and all statistical analyses assuming normal
distribution were performed on the transformed values. The sample was
divided into tertiles (proinsulin, insulin, systolic and
diastolic blood pressure) defined by the distribution of
these variables among the referent subjects. This procedure was
done separately for the whole study population as well as for men and
women. Univariate conditional logistic regression
analyses were performed to estimate odds ratios (ORs) and 95%
CIs of having a first-ever stroke for different levels of proinsulin,
insulin, and blood pressure. Multiple conditional logistic regression
analyses were conducted on the association between first-ever
stroke and proinsulin or insulin. Adjustments were made for
cardiovascular risk factors. The presence of synergy
was tested by dichotomizing and combining proinsulin or insulin and
blood pressure. A synergy index (SI) was calculated
(SI=RRAB-1/[RRAb-1]+[RRaB-1])
as proposed by
Rothman.24 Synergy
was indicated when SI exceeded the value of 1.
Five subjects (4 men and 1 woman) had missing values in the smoking variable, and an additional 6 subjects (2 men and 4 women) had missing values in the blood pressure variables and were excluded from the conditional logistic regression analyses. Four subjects (1 man and 3 women) had missing values in the insulin variable. Nine subjects (all men) had a missing value in body mass index. These subjects remained in the regression analyses, and their missing value in BMI was replaced by the mean of the male referents.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ninety-four cases (59 men and 35 women) with first-ever stroke together with 178 referents (113 men and 65 women) were included in the study. Basal characteristics are presented in Table 1
. In the whole study population, the
systolic and diastolic blood pressures along with
the proinsulin level were significantly elevated in the cases compared
with the referents. In men cases had higher blood pressure and higher
body mass index than referents, whereas in women cases had higher
proinsulin and insulin levels.
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Significant correlations between proinsulin, insulin, and
other study variables were found
(Table 2). In both men and women, proinsulin and insulin
correlated with body mass index. Proinsulin also correlated with
diastolic blood pressure. In women, proinsulin and insulin
correlated with systolic blood pressure. In general, the
correlations in women were stronger than in men.
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Using proinsulin as a continuous variable in the conditional logistic regression analyses showed in the whole study population a 4.8% increase in risk of first-ever stroke for every picomole per liter of elevation in proinsulin. In women the corresponding risk increase was 16%. The same kind of calculation using insulin was only marginally significant, with a risk increase for stroke in the whole population of 0.1% and in women of 0.6% for every picomole per liter of elevation in insulin.
To further estimate the relative risk of first-ever stroke
in subjects with high compared with low levels of proinsulin, insulin,
or blood pressure, the whole study population was divided into tertiles
on the basis of the distribution of the risk variable in the
referents. By conditional logistic regression analyses, crude
ORs and their 95% CIs were calculated
(Table 3). Values in the top tertile of proinsulin compared
with the bottom tertile indicated a more than doubled risk of future
stroke, with an OR of 2.6 (95% CI, 1.3 to 5.3). For insulin the OR was
2.0 (95% CI, 1.0 to 4.0). The corresponding estimate of top versus
bottom tertile for systolic blood pressure was more than 5
times higher, with an OR of 5.6 (95% CI, 2.2 to 13.8), and the
estimate for diastolic blood pressure was more than 10
times higher, with an OR of 10.2 (95% CI, 3.4 to 31.0). In women but
not in men, an excess risk for stroke due to elevated proinsulin or
insulin levels was seen
(Table 3).
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Multiple regression analyses were used to estimate
the association of proinsulin or insulin with first-ever stroke after
adjustment for potential confounders, such as smoking, total
cholesterol, body mass index, and systolic or
diastolic blood pressure. Proinsulin continued to explain
excess risk of stroke in the whole study population as well as in women
when systolic blood pressure was included in the regression
model. However, proinsulin disappeared as an explanatory variable
for stroke when systolic blood pressure was exchanged for
diastolic blood pressure. Adding insulin (as a continuous
variable) to the model resulted in minor changes in the ORs of
proinsulin and in slightly larger CIs. High levels of proinsulin still
indicated an excess risk for stroke in women as well as in the whole
study population
(Table 4). In women, insulin explained excess risk for
stroke when the top tertile was compared with the bottom tertile and
when systolic blood pressure, total cholesterol,
smoking, and body mass index were included in the model. The excess
risk disappeared when proinsulin was added to the model (data not
shown).
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To examine potential synergy between proinsulin and blood
pressure for the risk of first-ever stroke, 2 new variables were
created. The first of them combined proinsulin and systolic
blood pressure. Before this, proinsulin was dichotomized into the top
tertile versus the middle and bottom tertiles, and systolic
blood pressure was divided into 140 versus <140 mm Hg. Of the
4 possible contingencies, low proinsulin combined with low blood
pressure was used as reference. ORs and 95% CIs were calculated by
conditional logistic regression analyses. SI was manually
calculated. In the whole study population, as well as in men and women
separately, synergy was found between proinsulin and systolic
blood pressure, with SIs of 1.6 to 1.7. A corresponding interaction
variable was created between proinsulin and diastolic
blood pressure with a cutoff of 85 mm Hg. In women, synergy was
found with a SI of 1.7. In a similar way, positive interaction between
insulin and systolic or diastolic blood pressure
was tested. Synergy was found in the whole study group between insulin
and systolic blood pressure (SI 1.4). There was also an
interaction in women between insulin and both systolic and
diastolic blood pressures, with SIs of 2.1 and 1.3,
respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study indicates that high proinsulin levels may increase the risk for first-ever stroke. The association was seen in women as well as in the study population as a whole. The relation was clearly weaker and nonsignificant in men. The mean level of proinsulin among referents in this study of 7.0 pmol/L was similar to that of a healthy population from the same area of Sweden (6.9 pmol/L),25 suggesting that the referent group of this study on average has a normal level of proinsulin. Women having proinsulin levels
8.3
pmol/L (top tertile) compared with women with levels 
5.1
pmol/L (bottom tertile) were associated with a >4-fold increase in
risk of first-ever stroke. The corresponding risk in the whole study
group was more than doubled (OR 2.6). The risk factor status of
proinsulin in regard to first-ever stroke was still present after
controlling for the traditional cardiovascular risk
factors of total cholesterol, smoking, systolic
blood pressure, and body mass index. However, it disappeared when
diastolic blood pressure replaced systolic blood
pressure in the model. Additional control in the model for insulin did
not significantly change the result. Women with an insulin level >44
pmol/L (top tertile) compared with women with an insulin level <28
pmol/L (bottom tertile) showed a substantially increased risk for
first-ever stroke after adjustment for potential confounders, with an
OR of 27.4 (95% CI, 1.7 to 439). However, the excess risk disappeared
when proinsulin was added to the model. There was also indication of
synergy between proinsulin and systolic blood pressure, with a
SI of 1.6 to 1.7. The interaction effect was seen in the whole study
population as well as in men and women. Synergy between insulin and
systolic blood pressure was also found in the whole study
population as well as in women. The mechanisms by which proinsulin and possibly insulin may contribute to the development of first-ever stroke are incompletely understood. One leading hypothesis focuses on the role of hemostasis in general and especially on the associations with disturbed fibrinolysis. Proinsulin has been shown, at least as strongly as insulin and independently of insulin, to increase the level of PAI-1 activity, thereby lowering fibrinolytic activity.16 17 At the same time, we must realize that the low concentration of proinsulin in the circulation among nondiabetic individuals would contradict the hypothesis of a direct biological effect on stroke by proinsulin. Another possible, and perhaps more plausible, explanation for the relation between proinsulin and first-ever stroke is that the level of proinsulin acts indirectly as a sensitive marker of an underlying metabolic disturbance reflecting the actual demand on the ß cells.26
Our study supports earlier findings of a reduced sex-related difference in cardiovascular risk when diabetic or metabolically disturbed (high proinsulin levels) men and women are compared with metabolically normal men and women.5 27 In the 20-year follow-up of the Framingham Study, the incidence of every measured cardiovascular event was higher in normal men than in normal women. However, in the study diabetic women had a higher incidence of stroke than diabetic men.
It is important to emphasize the incident case-referent design of this study, implying that the exposure factors were measured before disease was developed. This minimizes recall and selection biases and excludes the possibility that high proinsulin levels were an effect of a previous stroke. The identification and definition of cases in a case-referent design are crucial, and it should be stressed that all stroke events in this study were strictly classified according to the MONICA criteria by the Northern Sweden MONICA stroke registry. Extensive quality assessments of the registry have been performed.21
It is not easy to compare the impact of different cardiovascular risk factors in the etiology of a first-ever stroke. In a multifactorial disease, several different causative mechanisms are present. In this mosaic of more or less related risk factors, some of them will be in the same causal path, while others will be joined in another causal path, and often we do not know the exact relations between our measured risk factor variables and to which causal path they belong.24 Proinsulin and insulin are secreted together from the ß cell and probably exert their biological effects in the body independently of each other. This does not exclude the possibility of coinciding effects later in the causal path of stroke (eg, PAI-1 activity). Therefore, when we examined the association between proinsulin and stroke, it seemed appropriate to include insulin in the regression model, and vice versa. However, the addition of 2 highly correlated variables, such as proinsulin and insulin, in the same model may create a situation of near collinearity. In our study the addition of insulin to the model only resulted in minor changes in the ORs of proinsulin on stroke, indicating that the multiple regression model chosen from a statistical point of view seemed robust enough for this procedure. Body mass index and proinsulin were also highly correlated, and it is certainly biologically plausible that these 2 variables act in the same causal path in the etiology of a first-ever stroke. The use of multiple regression analyses emphasizes the need of careful interpretation of the results as well as of which variables should be included in the regression models.
In conclusion, high concentrations of proinsulin in this incident case-referent study predicted a >2-fold increase, and in women a >4-fold increase, of first-ever stroke in nondiabetic individuals.
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Acknowledgments |
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This study was supported by grants from the Swedish Medical Research Council (27P-12314 and 27X-13077), Swedish Council of Forestry and Agricultural Research, Swedish Council for Planning and Coordination of Research, Joint Committee of the Northern Sweden Health Care Region, Heart and Chest Fund, Swedish Public Health Institute, Västerbotten County Council, and Norrbotten County Council. We thank Susanne Kjellberg Ishøy and Lis Arlington Ølholm for their technical assistance (proinsulin and intact insulin determinations). We also thank Hans Stenlund, Åsa Ågren, and Lars Weinehall for valuable contributions to the study.
Received May 25, 2000; revision received August 21, 2000; accepted September 5, 2000.
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