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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2295
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 4 1331-1338
Copyright © 2008 by The Endocrine Society

Associations of Insulin-Like Growth Factor (IGF)-I, IGF-II, IGF Binding Protein (IGFBP)-2 and IGFBP-3 with Ultrasound Measures of Atherosclerosis and Plaque Stability in an Older Adult Population

Richard M. Martin, David Gunnell, Elise Whitley, Andrew Nicolaides, Maura Griffin, Niki Georgiou, George Davey Smith, Shah Ebrahim and Jeff M. P. Holly

Departments of Social Medicine (R.M.M., D.G., E.W., G.D.S.) and Clinical Sciences (J.M.P.H.) at North Bristol, University of Bristol, Bristol BS8 2PR, United Kingdom; Vascular Screening and Diagnostic Centre (A.N., N.G.), 2368 Nicosia, Cyprus; Vascular Noninvasive Screening and Diagnostic Centre (A.N., M.G.), London W1G 7BZ, United Kingdom; Imperial College (A.N.), London, United Kingdom; Department of Biological Sciences (A.N.), University of Cyprus, 1678, Nicosia, Cyprus; and London School of Hygiene and Tropical Medicine (S.E.), London WC1E 7HT, United Kingdom

Address all correspondence and requests for reprints to: Dr. Richard M. Martin, Department of Social Medicine, University of Bristol, Bristol BS8 2PR, United Kingdom. E-mail: richard.martin{at}bristol.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Circulating IGF-I is inversely associated with ischemic heart disease incidence. Whether this association relates to alterations in plaque growth or stability, and the role of IGF-II and the major binding proteins [IGF binding protein (IGFBP)-2 and -3], is unclear.

Objective: Our objective was to test the hypothesis that circulating IGF-I is inversely, and IGF-II is positively, associated with subclinical atherosclerosis and plaque stability.

Design, Setting, and Participants: This was a cross-sectional analysis based on 310 participants in the United Kingdom-based Boyd Orr cohort who were aged 63–82 yr. Cohort members from Aberdeen, Bristol, Dundee, Wisbech, and London were invited to clinics for fasted venepuncture and arterial ultrasound examination.

Main Outcomes: Arterial intima-media thickness, arterial plaque prevalence, and computerized assessment of plaque echogenicity (a measure of stability), undertaken using the gray scale median, were calculated.

Results: In total, 269 of 310 (86.8%) participants had at least one carotid or femoral plaque. In models controlling for IGFBP-3, there was a 44% (95% confidence interval 12–64%) reduction in the odds of any plaque and a 28% lower (0–48%) odds of echolucent (unstable) plaques per SD increase in IGF-I. IGFBP-3 was positively associated with plaque instability (odds ratio: 1.38; 0.99–1.93). IGF-II was positively associated (0.05-mm increase per SD; 95% confidence interval 0.01–0.09), and IGFBP-2 was inversely associated, with carotid bifurcation intima-media thickness. Neither IGF-II nor IGFBP-2 was associated with plaque prevalence or echogenicity.

Conclusion: High-circulating IGF-I levels may promote arterial plaque stability. IGF-II and IGFBP-2 do not appear to play a role in plaque development or stability.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
The GH-IGF system plays a key role in somatic growth, cell proliferation, metabolic regulation, and apoptosis (1). The possibility that the IGF system influences atherosclerosis is supported by the adverse effects of GH deficiency on carotid intima-media thickness (IMT) (2) and ischemic heart disease (IHD) risk factors (3). These changes are reversed after GH replacement. Prospective and genetic studies suggest that increased IGF-I levels may protect against incident IHD and stroke (4, 5, 6, 7). Some studies using subclinical measures of atherosclerosis (e.g. IMT, angiographically defined plaques) have found null (8) or positive (9, 10, 11, 12) associations. IGF-I may play a different role in plaque growth compared with plaque rupture (9), but these studies did not distinguish stable from unstable plaques that are more vulnerable to rupture and cause acute coronary events. In vivo and in vitro findings indicate that IGF-II is proatherogenic (13), but epidemiological evidence is limited (9).

Common carotid and bifurcation IMT and the presence of carotid and femoral plaques are established measures of preclinical atherosclerosis that predict incident stroke and IHD (14, 15, 16). Plaques that appear echolucent (mainly black) on B-mode ultrasound are hemorrhage and lipid rich, whereas echogenic (uniformly white or calcified) plaques have a higher content of fibrous tissue and calcification (17, 18, 19). Echolucent carotid plaques are thought to be unstable and are associated with incident cardiovascular disease in prospective studies (20, 21, 22, 23). Computerized measurement of the gray scale median (GSM) of arterial plaques is a highly reproducible measure of echolucency (24), which is associated with unstable plaque and cardiovascular events (21, 22, 24, 25) and has been used as an outcome in etiological studies (26).

We have previously shown in the United Kingdom-based Boyd Orr cohort that childhood stature was inversely associated with the later development of IHD (27). Because IGF-I is positively associated with height (28), it is possible that the inverse associations between height and IHD may be have been mediated by height-related variations in IGF-I. In the Boyd Orr cohort, obesity and insulin resistance, major and related risk factors for IHD, were positively associated with IGF-II (29), suggesting that further investigation of the association of IGF-II with atherogenesis is warranted. Therefore, our primary aim was to investigate the hypothesis that circulating IGF-I is inversely associated, and IGF-II is positively associated, with ultrasound measures of atherosclerosis and unstable plaques in 63- to 82-yr-old participants of the Boyd Orr cohort (30). The roles of the binding proteins, IGF binding protein (IGFBP)-3, which binds over 90% of IGF-I and modulates its bioactivity and IGFBP-2, the second most abundant IGFBP (31), which particularly inhibits IGF-II actions and is a possible marker of insulin sensitivity (29), are currently unclear. Our secondary aim was to investigate the hypothesis that circulating IGFBP-3 is positively associated, and IGFBP-2 is inversely associated, with ultrasound measures of atherosclerosis and unstable plaques.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The original Boyd Orr cohort comprised 4999 children from 1343 families in 16 centers in the United Kingdom and Scotland who were surveyed when aged 0–19 yr between 1937 and 1939 (30). The National Health Service Central Register was used to trace 4379 (88%) of the study members. In 2002, 2563 of the original cohort were alive and living in the United Kingdom. We contacted all 732 participants who lived near clinics in Bristol, London, Wisbech, Aberdeen, and Dundee, and who had previously consented to the research. Overall, 405 participants responded (55% of those contacted) and underwent detailed clinical examination. All 405 were invited to a second clinic to have an arterial ultrasound scan, and 339 (46%) responded (30). Ethical approval was obtained from the Multicenter Research Ethics Committee for Scotland. All participants gave informed consent.

Full details of how the blood samples were processed and stored have been provided in a previous publication (32). Specifically, 93% of samples were obtained after participants had fasted overnight for 6 h or more. Total IGF-I, IGF-II, and IGFBP-3 levels were measured using in-house double-antibody RIAs as previously described (33). Total levels of IGFBP-2 were measured by one-step sandwich ELISAs (DSL-10-7100; Diagnostic System Laboratories, Inc., Webster, TX). The average coefficients of variation for intraassay variability for IGF-I, IGF-II, IGFBP-3, and IGFBP-2 were 6.7, 10, 3.9, and 5%, and for interassay variation were 9.7, 14, 8.1, and 7.1%, respectively.

Insulin resistance was estimated from fasting insulin and glucose levels by homeostasis model assessment (HOMA) (34). Weight and height were measured using a standard protocol (30), and body mass index (BMI) [weight (kg)/height (m)2] was calculated. Adult social class, cigarette smoking, exercise frequency and intensity, and alcohol consumption were determined by questionnaire. IHD was present if there was a self-reported doctor’s diagnosis of IHD, coronary surgery or angioplasty, or the Rose angina questionnaire (35) was positive.

Arterial ultrasound scan

The right and left carotid and common femoral arterial bifurcations were studied with an Advanced Technology Laboratories high-definition imaging 3000 duplex system (Advanced Technology Laboratories, Signal Hill, CA) using a high-resolution broadband width linear array transducer 7–4 MHz (Phillips Medical Systems, Reigate, UK). Measurements were made in both longitudinal and transverse sections of IMT and plaques, where present, by the same vascular technologist in all participants (blinded to all exposure variables, including IGF and IGFBP levels) as described previously (30). The common carotid IMT was measured at its thickest point 1.5- to 2-cm proximal to the flow divider, on the distal wall of the common carotid artery. Carotid bifurcation IMT was defined as previously described (30). In brief, the presence of a carotid plaque, its maximum thickness was measured, and this was taken as the carotid bifurcation IMT; in the absence of a plaque, the IMT measured at the carotid bulb origin was defined as the bifurcation IMT. Plaques were defined at the time of ultrasound measurements (30).

Images were saved on superVHS videotapes and magneto-optical disk (Sony). Images were then sent to A.N. for detailed computerized plaque analysis, as described previously (24). In brief, B-mode images of plaques are digitized and transferred to a personal computer. With the use of the software Adobe Systems, Inc., San Jose, CA Photoshop (version 3.0 or later) and the "histogram" facility, the GSM of the two reference points (blood and adventitia) in the original B-mode image is defined. Algebraic (linear) scaling of the image is performed with the "curves" option of the software so that in the resultant image, the GSM of blood equals 0–5 and that of the adventitia equals 185–195. In this way, the gray scale values of all the pixels in the image are adjusted according to the input and output values of the two reference points (blood: input value = measured GSM before linear scaling and output value = 0–5; and adventitia: input value = measured GSM before linear scaling and output value = 185–195). The GSM of the plaque (the median of the frequency distribution of the gray levels of the pixels in the plaque) in the normalized image (adjusted image using linear scaling) is used to quantify its echogenicity. In those with more than one plaque, the standardized GSM of the total plaque area was estimated as a weighted mean of the GSM value of each single plaque (26). The area of each plaque was divided by the total area of plaques in each person, and this fraction was multiplied with each plaque’s normalized GSM value. All scores were added to calculate the normalized GSM score for each person. Subjects with plaques that could not be classified because of too much echo shadowing or unsatisfactory image quality (n = 20) were excluded.

Analysis

Due to a skewed distribution, IGFBP-2 was loge transformed. Associations of IGFs and IGFBPs with IMT and GSM as continuous variables were investigated by multivariable linear regression. GSM was dichotomized at the median to generate a binary variable reflecting predominantly echolucent (GSM ≤ 37.53) vs. more echogenic (GSM > 37.53) plaques. Associations of IGFs and IGFBPs with arterial plaque prevalence and echolucency were investigated using multivariable logistic regression. Regression coefficients express the change in odds ratio (OR) (for plaques) or change in IMT or GSM associated with a SD change in IGF-I, IGF-II, IGFBP-3, or log IGFBP-2. Adjusting for possible within-family clustering made little difference to SEs, so model-based SEs are presented.

Multivariable regression models were based on subjects with complete data for IMT or plaque (n = 310) or GSM (n = 249) analyses and controlled for the following potential confounding factors: 1) age and sex; 2) a model additionally controlling for childhood factors (social class of the head of the child’s household, household food expenditure, and birth order), lifestyle factors in adulthood [adult social class, alcohol consumption, smoking status, and a validated exercise score (36)], and current BMI; 3) because IGFBPs are important regulators of IGFs, models were developed in which IGF-I and IGF-II associations were additionally adjusted for IGFBP-2 or IGFBP-3, and IGFBP-2 and IGFBP-3 associations [because IGFBPs may have IGF-independent actions (37)] were additionally adjusted for IGF-I or IGF-II; and 4) analyses controlling for HOMA insulin resistance (29). Associations of bifurcation IMT as an outcome controlled for whether or not a plaque was present. Interactions with sex were tested using the likelihood ratio test. Analyses were conducted using Stata 8 (StataCorp LP, College Station, TX).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The mean age of participants was 71 yr (SD 4.4; range 63–82), and 45% were male. The distribution of the main variables is shown in Table 1Go.


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  		TABLE 1. Characteristics of participants with complete data for analysis (n = 310 unless stated)

 
Representativeness

Study participants were representative of the remaining surviving survey members (n = 2563) in terms of sex, birth year, birth weight, father’s social class, and childhood BMI but were more likely, in childhood, to have been younger at the time of the baseline survey, taller, and to have come from families with greater per capita weekly food expenditure (30).

Association with plaques

In total, 269 of 310 (86.8%) participants had at least one carotid or femoral plaque [139 (51.7%) in women and 130 (48.3%) in men], 195 (62.9%) a carotid plaque, and 237 (76.5%) a femoral plaque. Table 2Go shows mean levels of IGF-I, IGF-II, IGFBP-2, and IGFBP-3 by the presence of any plaque, carotid or femoral plaques, and by plaque echogenicity. In models controlling for childhood and adulthood factors, there was an inverse association of IGF-I with the presence of any plaque (P = 0.02), which when stratified by anatomical location was observed for femoral (P = 0.03) but not carotid plaques (Table 3Go). The inverse association of IGF-I with any and femoral plaques was strengthened after controlling for IGFBP-3. Controlling for HOMA insulin resistance did not alter the observed associations. There was no evidence that IGF-I, IGF-II, IGFBP-2, or IGFBP-3 was associated with clinically evident IHD [e.g. OR per SD increase in IGF-I (fully adjusted) = 1.04 (0.71, 1.51); P = 0.9].


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  		TABLE 2. Circulating levels of IGF-I, IGF-II, IGFBP-2, and IGFBP-3 by the presence of plaques and by plaque echogenicity

 

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  		TABLE 3. Associations of measures of atherosclerosis per 1 SD difference in growth factor levels

 
Plaque stability (GSM)

Assessment of plaque GSM was available in 249 of 269 (93%) participants with either femoral or carotid plaque and complete data. GSM was normally distributed with overall mean (SD) 38.77 (15.78) and range 5.49–99.45. The GSM mean and SD within carotid plaques (17.14; SD = 15.96) was lower than in femoral plaques (29.88; SD = 15.87). In fully adjusted models, additionally controlling for IGFBP-3, increased IGF-I was associated with a lower risk of echolucent (unstable) plaques (Table 3Go and Fig. 1Go). In fully adjusted models, additionally controlling for IGF-I, there was some evidence that higher levels of IGFBP-3 were associated with a greater risk of unstable plaques. When analyses were stratified by plaque location, the association of IGF-I with GSM was seen for carotid (OR: 0.77; 0.52–1.14, n = 182) but not femoral (1.02; 0.72–1.43, n = 221) plaques. Controlling for HOMA insulin resistance did not alter the observed associations. Associations were similar in those with and without manifest IHD. There was some evidence that positive associations of IGF-I (P = 0.095) and inverse associations of IGFBP-3 (P = 0.13) with increasing plaque stability (higher GSM = greater stability) were observed across the distribution of GSM, in models controlling for IGFBP-3 or IGF-I, respectively (Table 3Go).


Figure 1
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  		FIG. 1. Mean levels of IGF-I by quartile of GSM. Means are adjusted for age, sex, social class in childhood, household food expenditure, birth order, social class in adulthood, alcohol consumption, smoking status, exercise, and IGFBP-3.

 
Association with IMT

There was no evidence that IGF-I or IGFBP-3 was associated with carotid bifurcation IMT or common carotid IMT (Table 3Go). IGF-II was positively associated (P = 0.03), and IGFBP-2 inversely associated (P = 0.06), with bifurcation IMT. There was minimal attenuation when the association of IGF-II with bifurcation IMT was controlled for IGFBP-3 (or IGFBP-2) and when that of IGFBP-2 was controlled for IGF-I (or IGF-II). There was no evidence that associations of IGF-II or IGFBP-2 with bifurcation IMT differed by whether or not plaques were present (all P interaction > 0.2). Controlling for HOMA insulin resistance hardly altered associations of IGF-II [coefficient = 0.06 mm; 95% confidence interval (CI) 0.01–0.11; P = 0.01] and IGFBP-2 (–0.06; –0.11 to –0.01; P = 0.02) with bifurcation IMT. The positive association of IGF-II with bifurcation IMT was only observed in those with clinically identified IHD (coefficient: 0.13 mm; 95% CI 0.05–0.22; P = 0.003), and not in those without IHD (0.01 mm; 95% CI –0.04 to 0.06; P = 0.7).

There was no evidence that the associations of the growth factors with bifurcation IMT, plaque presence, or plaque stability differed by male or female sex (all P interaction > 0.1).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Higher circulating IGF-I was associated with a lower risk of the presence of any arterial plaque and a lower risk of unstable plaques, but only after controlling for IGFBP-3, a major regulator of biologically available IGF-I. IGFBP-3 was positively associated with plaque instability, after controlling for IGF-I. IGF-II was positively associated with bifurcation IMT, but not with plaque prevalence or stability or carotid IMT. Stratification suggested an association of IGF-I with femoral but not carotid plaques, but the wide confidence limits indicate that these differing associations by location should be interpreted with caution. There was no association of IGF-I with common carotid and bifurcation IMT. The findings are in line with the hypothesis that associations of tall stature in childhood with lower risk of IHD observed in Boyd Orr (27) could, at least in part, be mediated by height-related variations in IGF-I.

Our results are in line with cohort studies reporting inverse associations of circulating IGF-I with clinical cardiovascular events (5, 6, 7) but are opposite of cross-sectional data showing positive associations of IGF-I with subclinical atherosclerosis (9, 10, 11). These studies (9, 11) could not discriminate between stable (thick fibrous component and small lipid pool) or vulnerable (thin fibrous cap, large lipid pool, and few smooth muscle cells) arterial lesions. Our data would suggest that inconsistent results from cohort studies, with clinical outcomes, compared with cross-sectional analyses based on subclinical atherosclerosis, could be partly explained because greater endocrine availability of IGF-I may play a role in stabilizing atherosclerotic plaques, so that they are less prone to rupture and subsequent acute cardiovascular events. Increased IGF-I may act to stabilize atherosclerotic plaques in a variety of ways (38). Apoptosis of plaque-derived vascular smooth muscle cells contributes to the depletion of collagen responsible for the mechanical integrity of plaques (39). IGF-I inhibits vascular smooth muscle cell apoptosis induced by TNF-{alpha} (40) and limits oxidized low-density lipoprotein-induced apoptosis through the phosphatidylinositol 3-kinase/Akt signaling pathway (41). Therefore, by acting as a survival factor for vascular smooth muscle cells, IGF-I may prevent the conversion of stable to unstable plaques (42, 43, 44). IGF-I also promotes insulin sensitivity (45), which may play a role in plaque stability (39). However, our results were not altered when we controlled for insulin resistance, suggesting that the possible plaque-stabilizing effect of IGF-I operates independently of insulin metabolism. Down-regulation of IGF-I receptor and increased expression of IGFBP-3 in carotid plaques has been associated with carotid plaque instability, perhaps mediated by inflammatory cytokines and oxidized low-density lipoprotein (46, 47). Recently, it has been shown that pregnancy associated plasma protein-A (PAPP-A) is abundantly expressed by macrophages in unstable plaques (48, 49) and predicts an adverse prognosis in patients with stable (50) and unstable (51) coronary artery disease. A positive association of PAPP-A with plaque instability would appear to contradict our data because it is an IGFBP-4 protease that is proposed to increase bioavailable IGF- I (52). However, PAPP-A is probably derived from the plaques themselves (49), and increased PAPP-A may reflect a local response to plaque instability and an attempted "repair" mechanism (38). In contrast, circulating IGF-I is mainly of hepatic origin and represents the host environment in which the plaque is developing. Our data are in line with the finding that higher circulating levels of PAPP-A were found in men with echogenic (stable) compared with echolucent (unstable) plaques (53). IGF-I is also synthesized locally in blood vessels and so can regulate cell growth by autocrine or paracrine mechanisms (43). The total concentration of IGFs to which cells in blood vessels are exposed will be partly derived from that in the circulation and partly from that that is locally synthesized. Due to the practicalities of this population-based study, we measured the circulating component, but the results need to be interpreted with consideration that variations in the locally produced component may also be important for atherosclerosis (43).

Plaque rupture is an important mechanism in small coronary arteries and less important in big femoral arteries. We found the association of IGF-I with plaque stability only in carotid plaques, though numbers were small, and this could be a chance finding.

The association of IGF-I with plaque stability was strengthened in models controlling for IGFBP-3, in line with the results of prospective studies showing inverse associations of IGF-I with IHD only after controlling for IGFBP-3 (5) or IGFBP-1 (6). The emergence of any association only after statistical adjustment indicates that caution is needed when interpreting the result. However, this finding is biologically plausible because IGFBP-3 carries more than 90% of circulating IGF, acting as a store for IGFs and restricting their extravascular transit. Thus, IGFBP-3 is a major modulator of IGF-I biological activity (37). IGFBP-3 was associated with unstable plaques, after controlling for IGF-I, in line with prospective data (5). Higher levels of IGFBP-3 may indicate reduced IGF-I bioavailability, leading to the development of unstable plaques, or could suggest an independent effect of IGFBP-3 on IHD risk.

IGF-II was positively, and IGFBP-2 inversely, associated with bifurcation IMT. There were no associations of IGF-II or IGFBP-2 with the presence of any, carotid or femoral plaques, plaque stability or carotid IMT. Therefore, our results add only very limited support to previous suggestions that IGF-II (or IGFBP-2) plays a role in cardiovascular disease (9, 13); at most these factors may be involved in the very early stages of atherogenesis at the carotid bifurcation.

Limitations of the present study include the fact that in older populations such as ours, the magnitude of associations may be disrupted by the known age-related decline in IGF-I levels or may be masked by other age-related confounding factors that we did not control for. However, this limitation would mask real associations rather than generate spurious effects. Our index of plaque stability was based on noninvasive arterial ultrasound assessment of echolucency (the GSM), which may have led to measurement error. However, GSM has been shown to be valid (17, 18, 19), reproducible (24), and predictive of future unstable cardiovascular events (21, 22, 24, 25). The studied sample represented less than 50% of the eligible population. However, it seems unlikely that associations of IGFs with plaque stability would differ between those who did and did not participate, unless the characteristics of the plaques of nonparticipants differed in some way from those who did participate, and this difference could not be captured by the heterogeneity in plaque echolucency that was present (e.g. if there was a threshold effect at very advanced disease). Finally, the data are cross-sectional, so it is possible that we have observed effects on the IGF system that are secondary to plaque morphology (i.e. reverse causality), rather than causal effects of IGF-I and IGFBP-3 on plaque stability. The majority of IGF (>80%) is synthesized in the liver and is under endocrine control, with large interindividual variations related to diet and lifestyle (54, 55). Thus, although we cannot exclude secondary phenomena, our findings warrant further prospective investigation. Results from cross-sectional analyses may differ depending upon when in the life course the measures are taken. Circulating IGFs in early adulthood may be more important for the etiology and development of plaques, whereas in elderly subjects, such as in the present study, any associations with plaque stability might become apparent.

An advantage of our study was that it was population based, including a mixture of participants with and without clinically manifest disease. Apart from the positive association of IGF-II with bifurcation IMT, associations of IGF-I and IGFBP-3 with plaque stability were similar in those with and without clinically identified (and, therefore, possibly more advanced) IHD.

We conclude that circulating levels of IGF-I and IGFBP-3, but not IGF-II or IGFBP-2, may play a role in plaque instability and vulnerability to rupture. The clinical implications are that IGF-I and IGFBP-3 may be possible serum/plasma biomarkers of atherosclerotic plaque instability and propensity to rupture or potential therapeutic targets in plaque stabilization. The public health implications are that dietary or environmental manipulation of the endocrine regulation of these peptides (54, 55) may promote plaque stability. However, to our knowledge this is the first study to examine the circulating IGF system in relation to measures of plaque stability, and these findings require verification, particularly in prospective studies.


   Acknowledgments
 
We thank the cohort members who participated in the follow-up study. We also thank all the research workers in the original survey in 1937–1939. We thank Professor John Pemberton for information concerning the conduct of the original survey, Professor Peter Morgan, director of the Rowett Research Institute, for the use of the archive, and Walter Duncan, honorary archivist to the Rowett. We also thank Susie Potts for her secretarial and administrative support to the study, and Jane Carter and Paul Savage for performing the IGF analyses.


   Footnotes
 
The study was funded by a Wellcome Trust research training fellowship in clinical epidemiology for R.M.M. (GR063779FR), the British Heart Foundation (Grant PG/02/125), the World Cancer Research Fund (Grant 2001/31), and United Kingdom Survivors.

Disclosure Statement: The authors have nothing to disclose.

First Published Online January 22, 2008

Abbreviations: BMI, Body mass index; CI, confidence interval; GSM, gray scale median; HOMA, homeostasis model assessment; IGFBP, IGF binding protein; IHD, ischemic heart disease; IMT, intima-media thickness; OR, odds ratio; PAPP-A, pregnancy associated plasma protein-A.

Received October 15, 2007.

Accepted January 10, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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S. Pellitero, J. L Reverter, M. L. Granada, E. Pizarro, M C. Pastor, D. Tassies, J. C. Reverter, I. Salinas, and A. Sanmarti
Association of the IGF1/pregnancy-associated plasma protein-A system and adipocytokine levels with the presence and the morphology of carotid plaques in type 2 diabetes mellitus patients with stable glycaemic control
Eur. J. Endocrinol., June 1, 2009; 160(6): 925 - 932.
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