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Insulin-Like Growth Factor (IGF) I, -II, and IGF Binding Protein-3 and Risk of Ischemic Stroke

Department of Clinical Epidemiology (S.P.J., H.H.H., H.T.S., K.O.) and Medical Department M (Endocrinology and Diabetes) and Institute of Experimental Clinical Research (H.Ø., J.O.L.J.), Aarhus University Hospital, DK-8000 Aarhus, Denmark; Center for Cardiovascular Research (S.P.J., K.O.), Aalborg Hospital, Aarhus University Hospital, DK-9100 Aalborg, Denmark; and Institute of Cancer Epidemiology (A.T.), Danish Cancer Society, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Søren Paaske Johnsen, Ph.D., Department of Clinical Epidemiology, Aarhus University Hospital, Ole Worms Allé 150, DK-8000 Aarhus C, Denmark. E-mail: spj{at}dce.au.dk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background: Low IGF-I levels may be associated with the development of stroke; however, prospective data appear to be unavailable.

Methods: This was a nested case-control study within a Danish follow-up study, including 57,053 men and women. Baseline data included circulating IGF-I, IGF-II, and IGF binding protein (IGFBP)-3 concentrations as well as lifestyle factors and medical history. We identified 254 cases with incident ischemic stroke and 254 gender- and age-matched controls.

Results: Participants in the bottom quartiles of IGF-I and IGFBP-3 levels (median concentrations, 72 and 2937 ng/ml, respectively) were at increased risk of ischemic stroke, e.g. adjusted odds ratios (ORs) of 2.06 [95% confidence interval (CI), 1.05–4.03] and 2.29 (95% CI, 1.17–4.49), respectively, when compared with participants in the top quartiles (median concentrations, 125 and 4835 ng/ml, respectively). A negative, although weaker, association was also found for IGF-II (adjusted OR 1.44, 95% CI 0.79–2.64) when comparing the bottom quartile with the top quartile. No substantial associations were seen for IGF-I and IGF-II when also adjusting for IGFBP-3; adjusting IGFBP-3 for IGF-I and -II had only a minor impact on the risk estimates.

Conclusion: These findings give some support to the hypothesis that the IGF axis is involved in the pathogenesis of ischemic stroke.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE IGF AXIS includes IGF-I and IGF-II, specific receptors, and at least six IGF binding proteins (IGFBPs) (1, 2). The system is involved in the regulation of growth and cellular proliferation in numerous target tissues through endocrine, paracrine, and autocrine mechanisms. IGF-I is an important mediator of the anabolic effects of growth hormone in both the pre- and postnatal periods (2). IGF-II also plays a role during prenatal development, whereas its physiological postnatal role in humans remains unclear (2). The levels of free bioactive of IGF-I and –II is influenced by the IGFBPs, in particular IGFBP-3, which determines the efflux of circulating IGFs through the capillary barrier as well as the binding of IGFs to tissue receptors. In addition, some of the IGFBPs, including IGFBP-3, also appear to exert IGF-independent effects (3). Thus, IGFBP-3 has been shown to inhibit cellular proliferation and to enhance apoptosis through specific binding sites on the cell membrane (3).

Animal studies and observational studies on humans have suggested an association between the (IGF) axis, in particular IGF-I and risk of stroke. Thus, IGF-I stimulates nitric oxide production from the endothelium and vascular smooth muscle cells, and low tissue IGF-I levels and reduced IGF-I receptor expression have been found in atherosclerotic plaques (1). Furthermore, hypopituitary adults with GH deficiency and low IGF-I levels have increased intima-media thickness and a higher prevalence of atheromatous plaques in the common carotid arteries (4). A more than 2-fold increased mortality due to cerebrovascular diseases in hypopituitary patients has been reported in some (5, 6, 7) although not all studies (8, 9). Moreover, relatively low levels of serum IGF-I and IGFBP-3 have been found in patients with a recent stroke and may be related to the clinical outcome after stroke (10, 11). However, because the underlying disease may have affected the IGF axis, it is difficult to draw conclusions about causality (10). Recently low-baseline serum IGF-I and high IGFBP-3 levels have been reported to be associated with a subsequent increased risk of fatal and nonfatal ischemic heart disease and congestive heart failure (12, 13, 14, 15). To our knowledge, however, no prospective data on the association between the IGF system and risk of stroke have been reported.

With this background, we hypothesized that low circulating concentrations of IGF-I, IGF-II, and IGFBP-3 at baseline would be associated with an increased risk of ischemic stroke.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Design and study population

We conducted this nested case-control study within the Danish follow-up study "Diet, Cancer, and Health" (16). Eligible cohort members were born in Denmark, resided in the Copenhagen or Aarhus areas, and did not have a previous cancer diagnosis registered in the Danish Cancer Registry. From December 1993 through May 1997, 80,996 men and 79,729 women aged 50–64 yr were invited to participate in the study. A total of 27,177 men (33.6%) and 29,876 women (37.5%) accepted the invitation.

All cohort members completed questionnaires on education and lifestyle factors. At baseline, anthropometric measures, blood pressure, and serum total cholesterol were measured. Furthermore, samples of biological material were obtained and stored in a biorepository.

Participants were followed up in the Danish National Registry of Patients and the Civil Registration System using the civil registry number, a personal identification number given to all Danish citizens at birth or on immigration.

Information on death or emigration was obtained using the Civil Registration System that has kept data of all changes in vital status of the entire Danish population since 1968, including changes in address, dates of emigration, and date of death.

Information on hospitalizations was retrieved from The Danish National Registry of Patients, which was established in 1977 and records 99.4% of all discharges from nonpsychiatric hospitals in Denmark (17). The data include the dates of admission to and discharge from the hospital, the surgical procedures, and up to 20 discharge diagnoses, classified according to the Danish version of the International Classification of Diseases, 8th revision (ICD-8), until 1993 and subsequently according to ICD-10 (17).

We excluded 2500 (4.4%) participants who had been hospitalized before enrollment with cardiovascular diseases, i.e. stroke, transient ischemic attack, ischemic heart disease, or peripheral arteriosclerosis (ICD-8: 410–414, 430–438, 440; and ICD-10: G45, I20–25, I60–70) to ensure that IGF levels and possible confounding factors were not influenced by prevalent cardiovascular disease at baseline. Furthermore, we also excluded 47 participants (0.08%) who left 10 or more items blank on the questionnaires or who had seven or more items with implausible values.

Cases and controls

We defined potential cases as participants with a discharge diagnosis of stroke or transient ischemic attack (ICD-10: I60–69.8 and G45). Cases were identified through 1998 for persons living in the Copenhagen area and through 1999 for persons living in the Aarhus area. Medical records were reviewed by a single reviewer using a detailed standardized form to verify the diagnosis (18). The review was based on all the available information in the medical records including the written radiology reports, results from laboratory tests, etc. The actual brain imaging films were not reinterpreted.

The World Health Organization’s definition of stroke was used, i.e. an acute disturbance of focal or global cerebral function with symptoms lasting more than 24 h or leading to death of presumed vascular origin (19). The distinction among ischemic stroke, intracerebral hemorrhage, and subarachnoidal hemorrhage was based on a computed tomography or magnetic resonance scan, a spinal fluid examination, or an autopsy or surgical report. All cases had undergone computed tomography or magnetic resonance scanning. We subclassified all cases of ischemic stroke on the basis of the presumed etiology according to the Trial of Org 10172 (a low-molecular-weight heparinoid) in Acute Stroke Treatment classification: large-artery atherosclerosis, cardioembolism, small-vessel occlusion, stroke of other determined etiology, and stroke of undetermined etiology (20). This classification is based on clinical features, i.e. cortical or cerebellar dysfunction and lacunar syndrome, and data (e.g. location and size of infarct) collected by tests such as brain imaging, cardiac imaging, duplex imaging of extracranial arteries, arteriography, and laboratory assessments for a prothrombotic state.

Only cases of ischemic stroke were included in this study because the number of participants with intracerebral hemorrhage or subarachnoidal hemorrhage was too small for further analyses.

We selected one control for each case, matched by gender and age (within 5 yr) using the risk set sampling technique (21).

Measurements of IGFs and IGFBP-3

Plasma total IGF-I and IGF-II were determined after acid ethanol extraction using noncompetitive time-resolved monoclonal immunofluorometric assays as previously described (22). Plasma IGFBP-3 was measured by an immunoradiometric assay (Diagnostic System Laboratories, Inc., Webster, TX). All measurements were performed in duplicate within the same assay. All intra- and interassay coefficients of variation were less than 5 and 10%, respectively.

"Diet, Cancer, and Health" and the substudy reported here were approved by the regional ethical committees and the Danish Data Protection Agency.

Statistical analyses

We categorized the levels of IGF-I, IGF-II, and IGFBP-3 into quartiles based on the distribution among cases, and risk of ischemic stroke was compared using the highest quartile as reference level. We used conditional logistic regression to estimate odds ratios (ORs) adjusted for several possible confounding variables, i.e. smoking status (current, former, and never smoker), systolic and diastolic blood pressure at baseline (included as continuous variables), total nonfasting cholesterol level at baseline (6 mmol/liter cf. > 6 mmol/liter), self-reported history of diabetes mellitus (yes/no), body mass index (BMI) (included as a continuous variable), alcohol intake (14 cf. > 14 U of alcohol per week for women and 21 cf. > 21 U of alcohol per week for men), and length of school education (7, 8–10, and > 10 yr). IGF-I and -II were also analyzed further adjusted for IGFBP-3, and IGFBP-3 was further adjusted for IGF-I and -II.

We also examined the association between the IGF-axis and risk of ischemic stroke with second-degree fractional polynomial regression to obtain smooth representations of the ORs as continuous functions of IGF-I, -II, and IGFBP-3 levels (23). The median values of IGF-I, -II, and IGFBP-3 were used as reference values in these analyses.

Analyses were done separately for different subtypes of ischemic stroke. Finally, we repeated the analyses after excluding participants with a self-reported history of diabetes mellitus to examine whether the possible association was mediated through development of that disease because low IGF-I levels have been linked with the risk of diabetes (24).

Throughout the analyses, 95% confidence intervals (CIs) were calculated for all ORs. All analyses were done using Stata Statistical Software (release 7.0; Stata Corp., College Station, TX).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Characteristics of cases and controls

A total of 266 study participants were hospitalized with a verified diagnosis of acute ischemic stroke. This study included 254 cases who had provided plasma samples at baseline and 254 controls. We found no substantial differences in baseline characteristics when comparing the 14 excluded cases of ischemic stroke without available serum samples with the remaining 254 cases. Median length of follow-up was 3.1 yr (range 0.0–5.1 yr). Table 1 shows characteristics of the cases and controls. Data on all variables were available for 498 persons (98.0%).

Crude ORs of 1.70 (95% CI 0.99–2.89) for IGF-I and 2.26 (95% CI 1.31–3.89) for IGFBP-3 were found when comparing the bottom with the top quartile (Table 2). The association for IGF-II was weaker, with an OR of 1.30 (95% CI 0.79–2.12).

No substantial associations with ischemic stroke were seen for IGF-I and -II when we adjusted for IGFBP-3 (Table 2). In contrast, adjusting IGFBP-3 for IGF-I and -II had only a minor impact [OR 2.18 (95% CI 0.89–5.33)].

The association between levels of IGF-I, -II, and IGFBP-3 and risk of ischemic stroke did not appear to follow monotonic dose-response patterns (Fig. 1). Indications of possible threshold patterns were seen for both IGF-I and IGFBP-3, although the relatively wide confidence intervals in the extremes of the curves indicate that caution is needed when interpreting the shape of the curves.

View larger version (18K): [in this window] [in a new window]   FIG. 1. OR of ischemic stroke according to concentration of circulating IGF-I, -II, and IGFBP-3. Median concentration was used as reference. Data were adjusted for smoking, systolic and diastolic blood pressure, diabetes, BMI, hyperlipidemia, alcohol intake, and years of school education.

Restricting the analyses to participants without a self-reported history of diabetes mellitus did not change the risk estimates (data not shown).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We found inverse associations between levels of IGF-I and IGFBP-3 and the risk of ischemic stroke. An inverse but weaker association was also noted for IGF-II. The highest risk estimates were found for ischemic stroke due to large-artery atherosclerosis or of undetermined etiology; however, these subgroup analyses should be interpreted with caution due to the small numbers of cases.

The strengths of our study included the prospective design; the complete follow-up through nationwide, population-based registries, which limited the risk of selection and surveillance bias; the standardized and detailed assessment of all registered stroke events; and the detailed information on a number of possibly confounding factors.

For the identification of potential cases of stroke, we relied on the coding of cerebrovascular diagnoses by hospital physicians at the time the patients were discharged. Thus, we were able to include only strokes that led to hospitalization. However, given the age profile of our study cohort, it is likely that most patients with clinical symptoms of acute stroke were referred to a hospital for further evaluation and that any loss to follow-up was independent of levels of IGF-I, -II, and IGFBP-3. Handling of possible confounding in observational epidemiological studies is still somewhat hampered by the lack of detailed knowledge concerning the mechanisms linking the IGF axis with risk of ischemic stroke. Thus, it is possible that diabetes and BMI may, in fact, be intermediate steps in the causal pathway rather than independent risk factors. Inclusion of intermediate variables into the analyses could seriously influence the interpretation of the obtained risk estimates; however, our findings appeared consistent independently of how the multivariate models were constructed. Furthermore, the median length of follow-up in our study was relatively short. Thus, it is likely that some pathophysiologic processes, e.g. development of asymptomatic atherosclerosis in extra- or intracranial arteries, may already have been present at baseline among some of the cases. Finally, it should be noted that the precision of our risk estimates was moderate as indicated by the relatively broad confidence intervals analyses. Caution is therefore emphasized when interpreting the results.

The findings of our study are in accordance with data linking the IGF axis with vascular disease (12, 13, 14, 15, 25, 26, 27). In a case-control study, Juul et al. (13) found a low baseline level of IGF-I to be associated with a relatively high risk, i.e. 1.94 (95% CI 1.03–3.66), of ischemic heart disease during a follow-up period of 15 yr when comparing the bottom with the top quartile (13). In contrast to our findings concerning ischemic stroke, the inverse association between levels of circulating IGF-I and risk of ischemic heart disease was present after adjustment for IGFBP-3. Furthermore, high rather than low IGFBP-3 levels were associated with an increased risk of ischemic heart disease (13). This discrepancy could indicate that the effects of IGF-I and IGFBP-3 may differ within the vascular system, a hypothesis that is also somewhat supported by our analyses on different subtypes of ischemic stroke.

The IGF axis is involved in the regulation of growth and cellular proliferation in numerous target tissues through endocrine, paracrine, and autocrine mechanisms. However, the exact biological mechanisms linking the IGF axis with risk of vascular disease, including stroke, are not yet firmly established. Because GH is a recognized stimulator of IGF-I production and serum IGF-I levels are low in GH deficiency and elevated in active acromegaly, one could hypothesize that the reported associations reflected effects of GH rather than independent effects of IGF-I. In healthy adults, however, GH status only accounts for 30% of the variation in circulating IGF-I (28, 29), whereas a substantial genetic contribution has been reported (12, 30). Abnormalities in the lipoprotein metabolism are well documented in patients with hypopituitarism and may be one of the possible pathways linking the IGF axis with ischemic stroke and other manifestations of ischemic cardiovascular disease (31). However, IGF-I may also mediate development of atherosclerosis directly through its effects on nitric oxide production, vascular smooth muscle cell migration, and proliferation and monocyte behavior and function (25) or indirectly through an association with insulin sensitivity and risk of developing diabetes (24). Furthermore, IGF-I as well as IGFBPs cross the blood-brain barrier and are present in the cerebrospinal fluid and can therefore affect aspects of neuronal metabolism (11). Indeed, in vitro and animal experiments have found IGF-I to have a protective effect against hypoxic injuries (11, 32, 33).

The complexity of the IGF axis remains a challenge when studying its role in development of human disease. This is illustrated by the fact that high levels of IGF-I and IGFBP-3 have recently been associated with an increased risk of several forms of cancer (34), i.e. the opposite scenario of the findings in our study. It is undoubtedly an oversimplification to suggest that estimation of circulating IGFs, either bound or free, integrates all of the highly complex actions of the IGF axis at the tissue level.

We found indications of inverse associations between levels of IGF-I and IGFBP-3 and the risk of ischemic stroke. An inverse but weaker association was also noted for IGF-II. These findings lend further support to the hypothesis that the IGF axis is involved in the pathogenesis of vascular disease including ischemic stroke. The biological mechanisms behind these associations remain to be clarified before it is possible to examine any potential clinical implications.

	Footnotes

 
This work was supported by The Danish Cancer Society, Europe Against Cancer, and The Danish Medical Research Council through Vestdansk Sundhedsvidenskabeligt Forskningsforum.

First Published Online August 30, 2005

Abbreviations: BMI, Body mass index; CI, confidence interval; IGFBP, IGF binding protein; OR, odds ratio.

Received October 22, 2004.

Accepted August 18, 2005.

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