insulin‐like growth factor (igf)‐i, igf‐ii and igf‐binding protein (igfbp)‐3 levels in...

ORIGINAL ARTICLE

Insulin-like growth factor (IGF)-I, IGF-II and IGF-binding protein (IGFBP)-3 levels in Arab subjects withcoronary heart disease

A. O. AKANJI1, C. G. SURESH3, R. AL-RADWAN4 & H. R. FATANIA2

Departments of Pathology1 and Biochemistry4, Kuwait University Faculty of Medicine2, Cardiology

Unit, Mubarak Al-Kabir Hospital, and 3Central Blood Bank, Kuwait

AbstractObjective. Insulin-like growth factors (IGF-I, IGF-II) and their binding protein (IGFBP-3) may berisk markers for coronary heart disease (CHD). This study aimed to assess the levels anddeterminants of the serum levels of IGF-I, IGF-II and IGFBP-3 in Arab patients with establishedCHD. Material and methods. Two groups of subjects were matched for age, gender, BMI andwaist–hip ratio (WHR): (i) CHD (n5105), median age 51.0 (range 40.0–60.0) years; (ii) controls(n597) aged 49.0 (range 37.0–60.0) years. We measured fasting serum levels of glucose andlipoproteins (total cholesterol, triglycerides, LDL, HDL, apo B), insulin, HOMA-IR, IGF-I, IGF-IIand IGFBP-3 and compared the results between groups. The effects of body mass and the metabolicsyndrome (MS) on IGF levels were also examined, and linear correlations were sought between thevarious parameters. Results. The levels of IGF-I, IGF-II and IGFBP-3 were significantly lower (allpv0.01) for the CHD group than for the control group. These differences were not influenced byBMI or with the presence of MS. In CHD, there were no significant correlations between levels ofIGF-I and IGF-II and age, BMI, WHR, lipoprotein concentrations and insulin sensitivity, althoughIGFBP-3 had weakly significant relationships with some of the lipoproteins. Conclusions. Levels ofIGF-I, IGF-II and IGFBP3 are reduced in male Arab patients with CHD, and did not appearinfluenced by traditional CHD risk factors such as age, BMI, insulin sensitivity and presence of MS.Perturbations in the IGF/IGFBP-3 axis may be potential additional targets for pharmacologicalmanipulation in CHD.

Key Words: Arabs, coronary heart disease, IGF-I, IGF-II, IGFBP-3, insulin resistance

Introduction

Insulin-like growth factors I and II (IGF-I, IGF-II) are secreted by the liver and serve

unique functions during post-natal and pubertal development and also in adult life [1].

Correspondence: Abayomi Akanji, Clinical Chemistry Unit, Department of Pathology, Faculty of Medicine, Kuwait University,

P.O. Box 24923 Safat, 13110 Kuwait. Tel: +965 498 6231. Fax: +965 533 8905. E-mail: [email protected]

(Received 28 August 2006; accepted 14 December 2006)

Scand J Clin Lab Invest 2007; 67: 553–559

ISSN 0036-5513 print/ISSN 1502-7686 online # 2007 Taylor & Francis

DOI: 10.1080/00365510601173153

Scan

d J

Clin

Lab

Inv

est D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 11

/11/

14Fo

r pe

rson

al u

se o

nly.

IGF-I and IGF-II circulate in blood as complexes with IGF-binding proteins (IGFBPs 1–

6), especially IGFBP-3, which serve as reservoirs from which IGFs can be dissociated into

free forms and which stabilize circulating plasma levels [1,2].

It has previously been reported that abnormalities in the IGF/IGFBP axis may increase

the risk of cardiovascular disease (CVD). In some studies, IGF-I deficiency has been

associated with premature atherosclerosis and increased risk of cardiovascular mortality [3–

6], while in others the increased CVD risk is associated with elevated IGF levels [7,8].

There may also be racial differences. In a study of a multiracial USA sample it was reported

that the relationship of IGF-I to atherogenic lipids differs in some respects between white

and black men [9].

The most common cause of adult mortality in Arabs resident in the Arabian Gulf Region

is coronary heart disease (CHD) [10]. We have reported on aspects of CHD risk associated

with blood lipids in this population [11,12], but to our knowledge there have been no

reports on the possible role of the IGF-I/IGFBP axis in Arabs. This cross-sectional case-

control study therefore aimed to investigate levels of IGF-I, IGF-II and IGFBP-3 in

relation to lipid profiles, body mass, insulin sensitivity and presence or absence of the

metabolic syndrome (MS) in Arab patients with CHD and healthy control subjects. We

hypothesized that there would be changes in the IGF/IGFBP axis with CHD and that these

changes would be influenced by presence or absence of the metabolic syndrome.

Subjects

We recruited two age-matched, gender (all male)-matched, BMI-matched and waist–hip

ratio (WHR)-matched groups of subjects into the study after receiving informed voluntary

consent as follows: (a) 97 apparently healthy control (HC) subjects, median age 49.0

(range 37.0–60.0) years, recruited from the Central Blood Bank, Kuwait; (b) 105 patients,

median age 51.0 (range 40.0–60.0) years, with CHD. These subjects had been diagnosed

with proven acute myocardial infarction (from clinical features, characteristic ECG

patterns and increased serum troponin levels) at the Coronary Care Unit of the Mubarak

Al-Kabeer Hospital, Kuwait. Significant coronary artery stenosis was confirmed in all cases

by coronary angiography performed approximately 4–6 weeks after the acute event, at

which time patients were stable, and their fasting blood samples were collected.

None of the subjects smoked on a regular basis and none was diabetic or hypertensive;

additionally, none was or had been on any form of hypoglycaemic or hypolipidaemic

medication.

In each group, the patients were further subdivided as follows: (i) normal weight (BMI

(25 kg/m2) and overweight (BMI w25 kg/m2) and (ii) with or without the metabolic

syndrome (MS). MS was diagnosed from waist circumference and fasting levels of glucose,

triglyceride and HDL in accordance with the NCEP ATPIII [13] and IDF [14] criteria.

Subjects with diabetes and hypertension or receiving treatment were excluded from the

study.

We obtained ethical approval for the study from our Institutional Research Ethics

Committee.

Methods

A detailed clinical assessment was made of each subject. Anthropometric measurements of

height, weight and waist and hip circumferences were taken and the body mass index

554 A. O. Akanji et al.

Scan

d J

Clin

Lab

Inv

est D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 11

/11/

14Fo

r pe

rson

al u

se o

nly.

(BMI) and WHRs were calculated. Each subject also gave a fasting blood sample from

which serum was extracted for glucose and lipid (total cholesterol (TC), triglycerides (TG),

high-density lipoprotein cholesterol (HDL-C) analyses on a Beckman-Coulter LX-20

Autoanalyzer. Low-density lipoprotein cholesterol (LDL-C) levels were derived using the

Friedewald formula [15]. Serum levels of Apo B were determined using the Beckman

IMMAGER Analyzer. Fasting serum insulin was measured using an enzymatic ‘one-step’

sandwich kit immunoassay (DSL, Tx., USA). IGF-I, IGF-II and IGFBP-3 assays were also

done using ELISA (DSL, Tx., USA). These assays were done on batched specimens stored

frozen without any prior thawing at 270˚C for no longer than 3 months. The intra- and

inter-assay CVs for assays for insulin, IGF-I, IGF-II and IGFBP-3 were always v5.0 %.

The index of insulin sensitivity used was the HOMA-IR [16].

Data analysis

The results are expressed as median(s) and range(s) as appropriate, and the differences

between the two groups (HC and CHD) in relation to anthropometric and demographic

indices, fasting lipid and lipoprotein levels and concentrations of IGF-I, IGF-II and

IGFBP-3 were assessed by non-parametric Mann-Whitney U-test. Differences within each

group in relation to BMI and presence/absence of MS were similarly assessed. We explored

correlations between IGF-I, IGF-II and IGFBP-3 and each of these biochemical and

anthropometric parameters using Spearman’s rank correlation coefficients. These tests

were computed using the SPSS software. A p-value v0.05 was considered significant.

Results

Table I gives the demographic and anthropometric parameters and levels of lipids,

lipoproteins and IGF-I, IGF-II and IGFBP-3 in the two groups. As expected, the HC

group had lower values for TC, TG, LDL and apo B (all pv0.02). Although BMI, WHR

Table I. Demographic and anthropometric parameters and levels of lipoproteins, IGF-I, IGF-II and IGFBP-3 in

the two groups of subjects (results are expressed as medians (ranges)).

CHD patients n5105 Healthy control subjects n597 p*

Age (years) 51.0 (40.0–60.0) 49.0 (37.0–60.0) ns

BMI (kg/m2) 28.0 (20.6–39.9) 29.8 (19.8–38.6) ns

WHR 0.94 (0.86–1.05) 0.93 (0.87–1.08) ns

Glucose 4.8 (1.8–6.1) 4.8 (3.5–6.1) ns

TC (mmol/L) 5.2 (3.3–7.8) 4.7 (2.4–6.4) 0.02

TG (mmol/L) 1.39 (0.53–4.68) 1.10 (0.40–4.90) 0.04

HDL(mmol/L) 0.86 (0.48–1.41) 0.85 (0.52–1.17) ns

LDL (mmol/L) 3.67 (1.16–6.57) 2.78 (1.09–4.59) v0.001

ApoB (g/L) 1.20 (0.62–1.88) 1.04 (0.62–1.51) 0.01

Insulin (mU/L) 4.67 (0.01–22.34) 3.25 (0.20–15.45) 0.05

HOMA-IR 0.97 (0.01–4.77) 0.69 (0.01–4.19) 0.05

IGF-I (nmol/L) 11.9 (2.4–44.2) 19.8 (10.4–60.5) v0.001

IGF-II (nmol/L) 151.3 (84.1–346.1) 159.7 (103.6–347.2) 0.03

IGFBP-3 (nmol/L) 134.1 (61.3–268.3) 180.5 (106.7–340.2) v0.001

n5Number of subjects (all male). p*– for differences between the two groups of subjects. Abbreviations:

CHD5coronary heart disease; BMI5body mass index, WHR5waist-hip ratio; TC5total cholesterol; Apo

B5apolipoprotein B; HOMA-IR5index of insulin sensitivity.

IGFs in coronary heart disease in Arabs 555

Scan

d J

Clin

Lab

Inv

est D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 11

/11/

14Fo

r pe

rson

al u

se o

nly.

and HDL levels were similar for the two groups, those with CHD had greater insulin

resistance with higher values for fasting insulin and HOMA-IR (pv0.05). IGF-I, IGF-II

and IGFBP-3 levels were lower in the CHD group (all pv0.03). The difference was most

marked for IGF-I, with a 40% reduction in median values.

In the patients with CHD, we also assessed the role of obesity and the MS in determining

the levels of IGF and IGFBP-3. The demographic and anthropometric parameters and

levels of lipids, lipoproteins and IGF-I, IGF-II and IGFBP-3, as well as insulin and

HOMA-IR, were therefore compared in the CHD patients considered on the basis of high

(w25) or normal ((25) BMI. As expected, the results (Table II) indicate that the

overweight (BMI w25) had significantly higher TG and apo B levels and lower HDL

levels, and were more insulin resistant (with significantly higher fasting insulin and HOMA-

IR values). However, there were no differences in IGF-I, IGF-II and IGFBP-3 levels on the

basis of normal or high BMI, although those with BMI w25 tended to have lower values

(not significantly) for these parameters. A similar pattern of observations (not given in the

Table) was seen in the healthy control subjects.

The demographic, anthropometric and biochemical parameters in the CHD patients

considered on the basis of presence or absence of the MS are given in Table III. Again, as

expected, those patients with MS had higher WHR, TG and apo B and lower HDL

(pv0.04) levels and greater insulin resistance (fasting insulin and HOMA-IR values) than

those without MS. However, as with the BMI observations, the presence or absence of MS

did not influence levels of IGF-I, IGF-II and IGFBP-3, although, again, those with MS

tended to have lower values (not significantly) for these parameters. A similar pattern was

seen in the HC group.

In the CHD group, there were no significant linear correlations between levels of either

IGF-I or IGF-II and age, BMI, WHR, lipids (including apoB), insulin and HOMA-IR.

Nor were there cross-correlations between IGF-I, IGF-II and IGFBP-3. However, levels of

Table II. Demographic and anthropometric parameters and levels of lipoproteins, IGF-I, IGF-II and IGFBP-3

and insulin resistance indices in the CHD patients considered on the basis of BMI (results are expressed as

medians (ranges)).

CHD patients

BMI w25 kg/m2 (n579) BMI (25 kg/m2 (n526) p*

Age 51.5 (40.0–60.0) 48.5 (40.0–57.0) 0.22

BMI (kg/m2) 29.2 (25.1–39.9) 23.9 (20.6–24.7) v0.001

WHR 0.95 (0.87–1.05) 0.91 (0.86–0.98) 0.05

Glucose (mM) 4.9 (2.0–6.1) 4.3 (1.8–5.5) 0.05

TC (mM) 5.2 (3.3–7.8) 5.0 (3.5–6.5) 0.18

TG (mM) 1.47 (0.53–4.68) 1.14 (0.64–2.80) 0.04

HDL (mM) 0.81 (0.48–1.41) 0.89 (0.60–1.24) 0.04

LDL (mM) 3.69 (1.16–6.57) 3.60 (2.17–4.84) 0.17

ApoB (g/L) 1.22 (0.75–1.88) 1.10 (0.62–1.38) 0.05

Insulin (IU/L) 4.76 (0.01–22.34) 0.01 (0.01–12.50) 0.04

HOMA-IR 1.02 (0.01–4.77) 0.02 (0.01–3.06) 0.03

IGF-I (nM)) 10.5 (2.4–44.2) 14.1 (3.1–22.2) 0.44

IGF-II (nM) 150.3 (84.1–214.5) 155.2 (118.5–346.1) 0.59

IGFBP-3 (nM) 137.2 (61.3–268.3) 143.00 (109.8–171.8) 0.60





Scan

d J

Clin

Lab

Inv

est D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 11

/11/

14Fo

r pe

rson

al u

se o

nly.

IGFBP-3 had weak but significant correlations only with TC (rs 0.35, pv0.01), TG (rs

0.34, pv0.01) and HDL (rs 0.28, pv0.04). In the healthy control subjects, there were

significant correlations of IGF-I with TC (rs 20.36, pv0.03), IGF-II with age (rs 20.58,

pv0.001) and IGFBP-3 (rs 0.40, pv0.01) and IGFBP-3 with IGF-II (rs 0.40, pv0.01),

but not with any of the insulin sensitivity or anthropometric parameters.

Discussion

The IGF/IGFBP axis could influence atherogenesis via its postulated role in stimulation of

vascular smooth muscle cell proliferation and migration and development of macrophages

into foam cells [3,5,7], and possibly also via effects on blood lipid levels and insulin

sensitivity [17]. This latter postulation is rational, as both insulin and IGF-I can act as

ligands for the insulin and IGF-I receptor [1,2]. Insulin resistance and MS are now

recognized as important risk factors for atherogenesis [13,14], but the role, if any, for IGFs

in the process, remains speculative.

In this study, we have shown that levels of IGF-I, IGF-II and IGFBP-3 are lower in

individuals with CHD, compared to a healthy age-matched and gender-matched control

group, and did not appear significantly influenced by body mass and presence or absence of

the metabolic syndrome (MS). The subjects we studied were exclusively males, age-

matched and were not diabetic, hypertensive, smokers or on lipid-lowering or other

medications and so were relatively homogeneous. Univariate regression analyses in the

patients with CHD indicated that the levels of IGF-I and IGF-II did not correlate

significantly with age, BMI, WHR, lipid and lipoprotein concentrations and indices of

insulin sensitivity. IGFBP-3 had rather weakly significant correlations with some of the

lipoproteins in the patients with CHD. A similar pattern was seen in the healthy control

subjects. It is therefore likely that these traditional CHD risk factors do not influence the

potential role of IGFs in atherogenesis.

Table III. Demographic and anthropometric parameters and levels of lipoproteins, IGF-I, IGF-II and IGFBP-3

and insulin resistance indices in the CHD patients considered on the basis of presence or absence of the metabolic

syndrome. (Results are expressed as medians (ranges)).

With metabolic syndrome

(n532)

Without metabolic syndrome

(n573) p*

Age (years) 54.5 (40.0–60.0) 49.0 (40.0–60.0) 0.08

BMI (Kg/M2) 28.2 (23.9–34.7) 28.0 (20.6–39.9) 0.89

WHR 0.99 (0.86–1.22) 0.94 (0.87–1.05) 0.05

Glucose (mM) 5.2 (1.8–6.1) 4.6 (2.0–5.9) 0.04

TC (mM) 5.5 (3.3–7.2) 5.2 (3.5–7.8) 0.52

TG (mM) 1.86 (0.65–5.07) 1.17 (0.53–4.68) 0.03

HDL (mM) 0.78 (0.48–1.19) 0.86 (0.54–1.41) 0.04

LDL (mM) 3.92 (1.16–5.11) 3.71 (2.17–6.57) 0.09

ApoB (g/L) 1.20 (0.75–1.88) 1.12 (0.62–1.81) 0.05

Insulin (mU/L) 6.86 (1.45–22.34) 4.76 (0.01–15.20) 0.04

HOMA-IR 1.55 (0.01–4.77) 0.95 (0.01–3.43) 0.02

IGF-I (nM) 11.1 (3.7–44.2) 12.3 (2.4–37.1) 0.85

IGF-II (nM) 139.6 (84.1–196.1) 152.6 (96.1–346.1) 0.14

IGFBP-3 (nM) 123.8 (73.5–250.1) 144.6 (61.3–268.3) 0.56





Scan

d J

Clin

Lab

Inv

est D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 11

/11/

14Fo

r pe

rson

al u

se o

nly.

The results from our study concur with those of most other studies that low IGF-I

levels are seen in CHD [3–6,17–19]. Some other studies have shown that the IGF-I level

is elevated in CHD [7,8]. It has been reported that IGFBP-3 levels are increased in CHD

[3–7], contrary to our findings here. The suggestion was that increased IGFBP-3 should

reduce availability of IGF-I [20]. This contention would be rational if free IGF-I levels

were the parameters measured. A Swiss study [7] reported that despite increased values

for total IGF-I and IGFBP-3 in CHD, free IGF-I levels were similar for CHD and

controls and there was no significant association between free IGF-I levels and CHD.

The issue therefore remains controversial, but an explanation for the discrepant

observations might be the time interval after the acute coronary event that the blood

specimen is taken [5,17–19]. It might therefore be necessary to standardize the timing of

specimen collection after acute events in CHD in comparing results between studies.

What appears generally accepted, however, is that the changes in IGFs and binding

proteins seen in CHD appear not to be significantly influenced by most of the traditional

risk factors such as lipids and lipoproteins, insulin sensitivity, smoking and glucose

intolerance [17–20].

This study, although cross-sectional, is probably the first to specifically investigate any

link between MS and IGFs. A limitation is the relatively small subject numbers, but this

was due to very stringent exclusion criteria in an attempt to achieve good sample

homogeneity. Indeed, we studied only male subjects. Including females in the study might

confound the results because of the described effects of menopausal hormonal changes on

IGF levels [21]. It is also likely that excluding diabetic and hypertensive subjects narrowed

the range of HOMA-IR values and reduced the severity of metabolic syndrome in the CHD

patients. However, including those subjects, all of whom were on long-term medications

with known metabolic implications, would again have confounded the interpretation of

results. Nonetheless, the results obtained are of some interest, especially as this is probably

the first such study in the Arabian Gulf population with a recognized high prevalence of

CHD.

Conclusions

The study suggests that levels of IGF-I, IGF-II and IGFBP-3 are reduced in male Arab

patients with CHD, and do not appear to be influenced by traditional CHD risk factors

such as age, body mass and presence of the metabolic syndrome. It is suggested that

perturbations in the IGF/IGFBP-3 interactions could constitute additional targets for

pharmacological manipulation in the prevention and treatment of CHD.

Acknowledgements

We acknowledge the technical help of Dr S. George and Mr. P. K. Shihab. The study was

supported by a Kuwait University Research Administration Grant no. MG 01/03.

References

[1] Holly J. Physiology of the IGF system. Novartis Foundation Symp 2004;262:19–35.

[2] Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev

2002;23:824–54.

[3] Frystyk J, Ledet T, Moller N, Flyvbjerg A, Orskov H. Cardiovascular disease and insulin-like growth factor I.

Circulation 2002;106:893–5.


Scan

d J

Clin

Lab

Inv

est D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 11

/11/

14Fo

r pe

rson

al u

se o

nly.

[4] Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T. Low serum insulin-like growth factor I is

associated with increased risk of ischemic heart disease. A population-based case-control study. Circulation

2002;106:939–44.

[5] Kaplan RC, Strickler HD, Rohan TE, Muzumdar R, Brown DL. Insulin-like growth factors and coronary

heart disease. Cardiol Rev 2005;13:35–9.

[6] Janssen JA, Lamberts SWJ. The role of IGF-I in the development of cardiovascular disease in type 2 diabetes

mellitus: is prevention possible? Eur J Endocrinol 2002;146:467–77.

[7] Fischer F, Schulte H, Mohan S, Tataru M-C, Kohler E, Assmann G, et al. Associations of insulin-like

growth factors, insulin-like growth factor binding proteins and acid-labile subunit with coronary heart

disease. Clin Endocrinol 2004;61:595–602.

[8] Ruotolo G, Bavenholm P, Brismar K, Efendic S, Ericsson CG, de Faire U, et al. Serum insulin-like growth

factor-I level is independently associated with coronary artery disease progression in young male survivors of

myocardial infarction: beneficial effects of bezafibrate treatment. J Am Coll Cardiol 2000;35:647–54.

[9] Colangelo LA, Liu K, Gapstur SM. Insulin-like growth factor-1, insulin-like growth factor binding protein-3

and cardiovascular disease risk factors in young black men and white men. The CARDIA male hormone

study. Am J Epidemiol 2004;160:750–7.

[10] Alwan AA. Cardiovascular diseases in the eastern Mediterranean region. World Hlth Stat Q

1993;46:97–100.

[11] Akanji AO, Al-Sulaiman A, Prabha K, Safar F, Al-Zaid K, Mojiminiyi OA. Profile of hyperlipidaemic

patients in Kuwait: frequency of cardiovascular disease risk factors at presentation and initial response to

treatment. J Kuwait Med Assoc 1997;29:25–33.

[12] Akanji AO. Apo (a) isoforms do not predict coronary heart disease risk in a Gulf Arab population. Ann Clin

Biochem 2000;37:360–6.

[13] Anonymous . Executive Summary of the Third Report of the National Cholesterol Education Program

(NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult

Treatment Panel III). J Am Med Assoc 2001;285:2486–97.

[14] Alberti KGMM, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group. The metabolic

syndrome – a new worldwide definition. Lancet 2005;366:1059–62.

[15] Friedewald WT, Levy RI, Frederickson DS. Estimation of the concentration of low-density lipoprotein

cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502.

[16] Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function. Best Pract Res

Clin Endocrinol Metab 2003;17:302–22.

[17] Conti E, Andreotti F, Sciahbasi A, Riccardi P, Marra G, Menini E, et al. Markedly reduced insulin-like

growth factor-1 in the acute phase of myocardial infarction. J Am Coll Cardiol 2001;38:26–32.

[18] Friberg L, Werner S, Eggertsen G, Ahnve G. Growth hormone and insulin-like growth factor-1 in acute

myocardial infarction. Eur Heart J 2000;21:1547–54.

[19] Spallarosa P, Brunelli C, Minuto F, Caruso D, Battistini M, Caponnetto S, et al. Insulin-like growth factor-1

and angiographically documented coronary artery disease. Am J Cardiol 1996;77:200–2.

[20] Conti E, Carrozza C, Capoluongo E, Volpe M, Crea F, Zuppi C, et al. Insulin-like growth factor-1 as a

vascular protective factor. Circulation 2004;110:2260–5.

[21] Heald A, Kaushal K, Anderson S, Redpath M, Durrington PN, Selby PL, et al. Effects of hormone

replacement therapy on insulin-like growth factor (IGF)-I, IGF-II and IGF binding protein (IGFBP)-1 to

IGFBP-4: implications for cardiovascular risk. Gynecol Endocrinol 2005;20:176–82.


Scan

d J

Clin

Lab

Inv

est D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 11

/11/

14Fo

r pe

rson

al u

se o

nly.

insulin‐like growth factor (igf)‐i, igf‐ii and igf‐binding protein (igfbp)‐3 levels in...

Documents