The Insulin-Like Growth Factor System,Metabolic Syndrome,and Cardiovascular Disease Risk

Abstract

The metabolic syndrome is a combination of metabolic and clinical features that aggregate in individuals and increase cardiovascular disease (CVD) risk considerably. It is believed, although sometimes controversially, that the underlying basis for this syndrome is insulin resistance (IR) and accompanying compensatory hyperinsulinemia. Insulin and insulin-like growth factors (IGFs) have significant homology and interact with differing affinity with the same receptors. Therefore, their actions can be complementary, and this becomes particularly significant clinico-pathologically when their circulating levels are altered. This review of currently available information attempts to answer the following questions: (1) Is there any evidence for changes in the components of the IGF system in individuals with established CVD or with increased CVD risk as with the metabolic syndrome? (2) What are the underlying mechanisms for interactions, if any, between insulin and the IGF system, in the genesis of CVD? (3) Can knowledge of the pathophysiological changes in the IGF system observed in macrosomic newborn infants and growth hormone (GH)–treated children and adults explain some of the observations in relation to the IGF system and the metabolic syndrome? (4) Can the experimental and clinical evidence adduced from the foregoing be useful in designing novel therapies for the prevention, treatment, and assignment of prognosis in metabolic syndrome–associated disease, particularly ischemic heart disease? To answer these questions, we have performed a literature review using bibliographies from PubMed, Medline, and Google Scholar published within the last 10 years. We suggest that IGF-1 levels are reduced consistently in individuals with the metabolic syndrome and its components and in those with ischemic CVD. Such changes are also seen with GH deficiency in which these changes are partially reversible with GH treatment. Furthermore, changes are seen in levels and interactions of IGF-binding proteins in these disorders, and some of these changes appear to be independent of IGF-binding capability and could potentially impact on risk for the metabolic syndrome and CVD. The promising therapeutic implications of these observations are also discussed.

Introduction

O ne of the modern plagues of humans is obesity. When fat distribution is predominantly abdominal or visceral, it often is associated with a constellation of metabolic features (including glucose intolerance, atherogenic dyslipidemia, and elevated blood pressure) that have now been categorized as the metabolic syndrome. In some populations, close to 50% of adults have the metabolic syndrome. Its significance resides in the fact that it constitutes a major risk factor for atherosclerotic vascular disease, the commonest cause of death in Western countries. It is thought that an important underlying pathogenetic basis for the metabolic syndrome is insulin resistance (IR) and accompanying compensatory hyperinsulinemia. Insulin and the insulin-like growth factor (IGF) system share common structural homology, receptors, and functions, and excessively high insulin levels could manifest effects from prolonged and persistent IGF receptor stimulation. Additionally, ambient high insulin levels could influence circulating levels of IGF and binding proteins. The IGF system is associated with growth, differentiation, and development of tissues, and nonphysiological activation of this system may have implications in atherogenesis and/or oncogenesis. This review explores the putative collaboration between the IGF system and insulin in the development and expression of the metabolic syndrome and especially in the understanding of their disparate roles in the genesis of cardiovascular disease (CVD).

Medline, PubMed, and Google Scholar were searched for articles on the IGF system and metabolic syndrome and CVD published in the past 10 years. The search was limited to humans and the English language, including original investigative reports, clinical trials, meta-analyses, randomized controlled trials, reviews, and case reports. The authors also used a personal database of references on metabolic syndrome collected over the past 20 years. The articles cited have mostly defined metabolic syndrome by either the World Health Organization (WHO) or the revised National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, consisting of combinations of elevated triglycerides, decreased high-density lipoprotein, central obesity (increased waist circumference), impaired fasting glucose (as an index of IR), and high blood pressure.

The IGF System

The IGF system comprises growth hormone (GH), GH receptors, IGF-1 and -2, IGF receptors (IGFR) -1 and -2, IGF-binding proteins (IGFBPs), and IGFBP proteases. This system functions primarily to regulate growth and differentiation of cells and tissues, although recently, it has been implicated in tumorigenesis.¹

GH binds to hepatic GH receptors and acts to promote hepatic IGF synthesis. The latter accesses the peripheral circulation and exerts negative feedback on the somatotropic axis with suppression of further pituitary GH release.² IGFs also are generated in multiple nonhepatic tissues. IGF-1/-2 share about 70% identity and have ≈50% homology to proinsulin. They possess multiple endocrine, paracrine, and autocrine functions.³ Hepatic IGF-1 synthesis is mostly mediated by GH, insulin, and possibly other factors, including nutritional status.⁴ The synthesis of IGF-2 is relatively GH independent and is probably most important in fetal life, where it has a regulatory function.

The type 1 IGF receptor (IGF-1R) is a transmembrane heterotetramer consisting of two α-subunits and two β-subunits, with about 60% sequence homology with the similarly structured insulin receptor (IR).⁵ IGF-2 and insulin also bind to the IGF-1R, but with considerably lower affinity.⁵ In general, most of the actions of IGFs are mediated via the IGF-1R. Like the IR, the IGF-1R possesses intrinsic tyrosine kinase activity with activation of specific postreceptor binding signal transduction pathways initiated by sequential autophosphorylation of tyrosine residues in proteins such as insulin receptor substrates (IRS) and Shc.¹ The consequences include regulation of cellular migration, differentiation, proliferation, and survival as well as antiapoptotic protection through a network of signaling molecules such as the phosphatidylinositol-3 kinase (PI3K)-serine/threonine protein kinase B (PKB or AKT), target of rapamycin (TOR) system, and the serine/threonine kinase (RAF)–mitogen-activated protein kinase (MAPK) system.¹ The type 2 IGF receptor, also known as the cation-independent mannose-6-phosphate receptor (IGF-2R/M-6-P), is structurally and functionally different from the IGF-1R and, although it binds IGF-2 with much greater affinity than IGF-1, it does not bind insulin.¹ The receptor is a monomeric membrane-spanning glycoprotein, with a large extracellular domain, that binds M-6-P, lysosomal enzymes, and IGF-2.⁶ The IGF-2R has no intracytoplasmic signaling domain. Most of the biological actions of IGF-2 are thought to be mediated via IGF-IR⁷; the IGF-2R probably only functions as a scavenger receptor.

The IGFBPs are a family of six conserved proteins (IGF-BP 1–6), and these proteins act to bind circulating IGF-1 and IGF-2.¹ This process may be modified by posttranslational changes in the IGFBP molecules that include glycosylation, phosphorylation, and proteolysis, and by interaction with the cell surface or components of the extracellular matrix. All IGFBPs inhibit IGF action by sequestering IGFs and prolong their half-life in the plasma. Some, including IGFBP -1, -3, and -5, also potentiate IGF action and may also have IGF-independent action through cell-surface receptors. The IGF/IGFBP complex can be dissociated by proteases, which include serine proteases, cathepsins, and matrix metalloproteinases.⁸ The IGFs are then released locally. In addition, free IGFBPs can be proteolysed with loss of high affinity for IGFs and consequent increase in circulating free IGF levels.

The biological effects of IGF-1 and IGF-2 on target cells are mediated by the cell-surface receptors, IGF-1R, IGF-2R, and IR. IGF-1 binds with high affinity to the IGF-1R and with much lower affinity to the IR. IGF-2 binds with high affinity to the IGF-2R and low affinity to the IGF-1R, but does not bind the IR.¹ Cells also have hybrid receptors composed of an insulin α-β half-receptor linked to an IGF-I α-β half-receptor. The hybrid receptors exhibit hormone-binding properties similar to IGF-I receptors (i.e., low affinity for insulin), and they have the still incompletely characterized potential to mediate cellular responses by both their IGF-I and IR intracellular domains.⁴

The most important IGF in the context of this review is IGF-1, for the reasons stated above. It is almost completely (>99%) bound to IGFBPs, especially IGFBP-3, where it circulates in a large ternary complex that also includes acid-labile subunit (ALS). Circulating IGFBP-3 and ALS probably originate in the liver and may also be regulated by GH.^7,9 The ALS stabilizes the IGF–IGFBP-3 complex, maintains IGF-1 in the circulation, and thereby extends its half-life.¹⁰ As noted above, it is becoming increasingly likely that the IGFBPs 1–6 and their fragments have significant intrinsic biological activity independent of their IGF/IGF-1R interactions.^11

–17

Because the IGFs are significantly bound in circulation, it is of interest to evaluate whether free circulating levels, especially of IGF-1, could have important physiological implications. However, the problems with free IGF-I are several. First, it is difficult to measure.^18
–20 Investigators have used various techniques, such as acidification to cause dissociation from binding proteins and equilibrium dialysis strategies, but there has never been adequate confidence that any of these methods provide a true measure of the free hormone. Additionally, IGF-binding proteins may variably serve to inhibit IGF-I binding to cell-surface receptors or, alternatively, deliver IGF-I to receptors in a way that promotes rather than inhibits the action of the hormone. Measures of free IGF-I could in no way provide insight into this aspect of IGF-I activity.¹⁸ Also, IGFs have the capacity to associate with cell surfaces, and this may provide a local concentration of IGF-I that has a major influence on the action of the hormone. Again, the cell-associated pool of IGF-I would not be assessed in measurements of the free hormone. As a result of these challenges to measuring free IGF-I levels and then interpreting their significance relevant to IGF hormone action, it has generally been accepted to work with total serum/plasma IGF-I measurements.^18

–22 This undoubtedly provides only part of the story on IGF hormone activity, but it is not currently considered that free IGF-I levels provide better insight.^18

–22

The Metabolic Syndrome

The metabolic syndrome has been defined as a combination of features that predispose to enhanced CVD risk, morbidity, and mortality.²³ There have been questions about the worldwide applicability of specific cutoff points for many of the components of metabolic syndrome and its clinical significance. To address these issues specifically, a workshop was convened in 2004 to review the discrepancies in relation to definition of the syndrome and the implications for clinical outcomes, associated risks, metabolic components, pathogenesis, clinical diagnostic criteria, and therapeutic options.²⁴

The NCEP ATP III identified six components of the metabolic syndrome²³: Abdominal obesity (or increased waist circumference), atherogenic dyslipidemia [hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) concentrations], raised blood pressure, IR with glucose intolerance, proinflammatory state [elevated C-reactive protein CRP)] and a prothrombotic state [with increased plasminogen activator inhibitor-1 (PAI-1), fibrinogen]. CVD is the primary clinical outcome of metabolic syndrome. Most people with metabolic syndrome also have IR, with its increased risk for type 2 diabetes. Other clinical disorders associated with metabolic syndrome are polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some forms of cancer.

At least three organizations (NCEP ATP III, WHO, and American Association of Clinical Endocrinologists [AACE]) have recommended clinical criteria for the diagnosis of the metabolic syndrome.^23,25
–27 These criteria are similar in many aspects, especially in relation to underlying IR, but they also reveal fundamental differences in positioning of the predominant causes of the syndrome. All essentially agree that, pathogenetically, metabolic syndrome likely arises from a combination of obesity and disorders of adipose tissue, IR (and hyperinsulinemia), and other independent factors (such as adipocytokines) that are still being evaluated. Another consensus meeting, in harmonizing the various viewpoints, highlighted the need for further long-term prospective studies to provide a more solid evidence base for the respective contributions of each of these variables, including the compensatory hyperinsulinemia, to enhanced CVD risk.²⁸ These abnormalities indeed constitute targets for therapy with the long-term objective of reducing aggregate risk of diabetes and CVD. Such therapeutic modalities include: (1) Lifestyle changes with appropriate diet and increased physical activity for weight reduction; (2) use of metformin and insulin sensitizers for IR; (3) use of other drugs, such as statins and fibrates, to correct the atherogenic dyslipidemia and aspirin as antiplatelet therapy for the prothrombotic state.

Association of IGF-1 Levels with CVD

From the foregoing, there is ample experimental and physiological evidence to the effect that insulin can mediate some of the effects of IGF-1 and vice versa, acting via shared receptors. It is also believed that at least some of the CVD risk that is attributable to the metabolic syndrome has a pathogenetic basis in IR and accompanying compensatory hyperinsulinemia.^28

–31 Thus, it is tempting to speculate that IGF-1 might also participate in the phenotypic expression of these disorders, especially because insulin, at high levels, might stimulate the IGF-1R and hybrid receptors with consequent exaggeration in IGF-1 activity, particularly in relation to mitogenicity and oncogenesis.³² As the initial stages of atherogenesis involve endothelial and vascular smooth muscle cell (VSMC) proliferation, it is possible that exposure of susceptible individuals to high circulating levels of insulin could contribute to CVD through effects on vascular cells, and possibly additionally acting via IGF-1 receptors.

Indeed, our working hypothesis is that IR (and associated compensatory hyperinsulinemia) as seen with metabolic syndrome probably enhances the mitogenic and oncogenic effects of insulin acting via receptors shared with IGF-1. The high insulin levels could also probably cause a downregulation of IGF-1 production by the liver and other tissues, as another compensatory homeostatic mechanism, effected most likely through a differential modulation of production of the IGFBPs. This might be responsible for the low IGF-1 levels seen in association with states of IR. In some support for this hypothesis, it has furthermore been reported that IGFBP-1 and possibly IGFBP-3 are downregulated by insulin.³³

In examining these possibilities, it is important to first evaluate any available information in the scientific literature on relationships between the IGF system and diagnosed CVD, on the basis of a wide range of human and experimental studies excellently reviewed by Conti et al.³² The putative relationships with increased CVD risk, as indicated by the presence of metabolic syndrome, can then be explored, especially with the additional support given by observations derived from long-term, prospective human studies.

IGF-1, Diabetes, and CVD: Clinical and Epidemiological Aspects

There is a strong and independent inverse relation between circulating total and free IGF-1 concentrations and markers of IR such as obesity (waist-to-hip ratio [WHR] and body mass index [BMI])³⁴ and risk of future development of diabetes.³⁵ Indeed, in relation to diabetes, a CVD risk equivalent, IGF-1 has been reported, more effectively than insulin, to stimulate muscle glucose transport in type 2 diabetic patients.³⁶ Co-treatment with recombinant human IGF-1 (rhIGF-1) in these patients can significantly reduce glucose levels and insulin requirement³⁷ while improving glucose tolerance, hyperinsulinemia, and hypertriglyceridemia.^38,39 Even in nondiabetic subjects, rhIGF-1 enhances insulin sensitivity, suppresses lipolysis, clears postprandial lipemia, and increases oxidative and nonoxidative glucose metabolism.^40,41 The higher prevalence of IR and metabolic syndrome in older compared with younger individuals may be attributable, at least in part, to the decline of serum and tissue IGF-1 concentrations with advancing age.⁴⁰ Reduced IGF-1 levels are independently associated with glucose intolerance, diabetes, abdominal obesity,^34,42 and atherogenic dyslipidemia.^43,44 Overall, these data suggest an important and independent role of IGF-1 in protecting against the development of CVD.

There also is compelling evidence that IGF-1 deficiency may contribute to the genesis of atherosclerotic disease.^31,32 In prospective and case–control studies, low circulating IGF-1 is seen in clinical and angiographically documented coronary artery disease,^45
–47 and free IGF-1 levels correlate inversely with carotid intima media thickness (IMT).⁴⁸ Furthermore, it has been reported that admission serum IGF-1 levels were reduced in patients with acute myocardial infarction, and could indicate prognosis, independently of infarct size.⁴⁹

IGF-1, Diabetes, and CVD: Pathogenetic Aspects

The relation between serum IGF-1 levels and protection against heart disease remains significant, even after adjustment for a variety of confounding variables including BMI, smoking, cholesterol levels, menopause, alcohol intake, physical activity, sex, age, social class, previous diabetes, family history of ischemic heart disease, self-evaluated health, use of antihypertensive agents, and circulating IGFBP-3 levels (which lower IGF-1 bioavailability).^46,47,50 Indeed, many of the traditional CVD risk factors, including oxidized low-density lipoprotein (LDL),⁵¹ IR,^34,42,44 diabetes,³⁵ obesity,^34,43 WHR,³⁴ reduced coronary flow reserve,⁵² smoking,⁵³ sedentary life,⁵⁴ and psychological distress,⁵⁵ which act via effects on endothelial dysfunction and apoptosis and impaired endothelial-dependent vascular reactivity, have been associated with low serum IGF-1 levels and reduced IGF-1 and IGF-1R mRNA and protein expression in VSMCs.⁵¹ Low IGF-1 may thus represent an additional independent CVD risk factor, and it is tempting to speculate that increasing IGF-1 levels could be beneficial in modulating CVD risk.

The subsequent paragraphs in this section and other later sections will attempt to explore the suggested mechanisms for this putative antiatherogenic effect of IGF-1, in which, indeed, the recent literature is replete with evidence. Initially, some inconclusive data had earlier suggested that IGF-1 may be atherogenic because of its effect in inducing VSMC proliferation in vitro. ^56

–59 Subsequently however, it was demonstrated that the effect of IGF-1 on VSMC was to compensate for local apoptosis, and that, overall, IGF-1 is not proatherogenic in native arteries but antiatherogenic. Indeed, IGF-1 directly counteracts endothelial dysfunction by interacting with high-affinity endothelial binding sites, leading to enhanced nitric oxide (NO) production.⁴¹ This, in turn, promotes insulin sensitivity,⁴² accelerates opening of membrane potassium channels,⁶⁰ and attenuates postprandial lipemia,⁴⁴ apart from other antiapoptotic⁶¹ and antiinflammatory⁶² properties. In addition, IGF-1 induces vasodilatation,^63

–66 thereby influencing the regulation of vascular tone and arterial blood pressure and preserving coronary flow reserve.^63,64 IGF-1, therefore, acting through intracellular tyrosine kinase signaling cascades, may augment enhanced NO release with beneficial effects on vasodilatation, platelet function, and glucose uptake.^67,68 Some of these actions have been described with acute insulin infusions as well,^69

–72 but not in relation to chronic hyperinsulinemia in vivo. These effects of IGF-1 and its putative inverse relationship with the chronic hyperinsulinemia of the metabolic syndrome could therefore link the IGF system to metabolic syndrome and susceptibility to clinical ischemic events.

The IGF System and Metabolic Syndrome

In the foregoing discussion, the putative relationships between the IGF system and established CVD, including potential pathogenetic mechanisms, have been described. In the subsequent sections, evidence from the literature is searched to establish whether the IGF system is operative in enhancing or reducing CVD risk in individuals already at high risk, i.e., those with metabolic syndrome. Again the suggested link is the homology between insulin and especially IGF-1 and affinity of both, to some degree, to the same receptors. The further significance of the exposure of these receptors (IR, IGF-1R, and hybrid receptors) to very high insulin levels, as seen with the IR of the metabolic syndrome, will be considered. Clinical and experimental evidence adduced from adults with metabolic syndrome as well as children and adults with growth disorders and treated with GH is reviewed, as well as the reported links between obesity, metabolic syndrome, and cancer and potential underlying mechanisms.

IGF and Metabolic Syndrome in Adults

There is a wealth of clinical and experimental evidence that associates changes in blood levels of IGF-1 and IGFBP3 with the presence of the metabolic syndrome and/or its components in adults. IGF-1 deficiency has been associated with an increased risk of CVD and atherosclerosis,⁷³ hyperlipidemia (hypercholesterolemia or mixed dyslipidemia),⁷⁴ coronary heart disease (CHD) in Arabs,⁷⁵ and fatty liver.⁷⁶ Furthermore, CRP levels correlate negatively with total IGF-1,⁷⁷ suggesting a link between low IGF-1 and the proinflammatory component of metabolic syndrome.

Data from a large number of subjects in the Framingham study also indicated that the serum IGF-1 level correlated negatively with IR and was lower in the individuals with metabolic syndrome.⁷⁸ Other inverse associations of IGF-1 were with age, BMI, presence of diabetes,^78,79 and IR.^80

–83 There was however a positive correlation with HDL levels.^83,84 In addition, each metabolic syndrome component (increased waist circumference [WC], higher triglycerides (TG), lower HDL-C, higher blood pressure, higher fasting glucose, and diabetes) was associated with lower levels of IGF-BP3 and the ratio IGF-I/IGFBP3 and higher levels of insulin, in a graded manner in nondiabetic and diabetic subjects.^84,85 An Argentinian study also reported on a potential role for polymorphisms in the IGF-1R gene in individual susceptibility to the development of IR and hypertension.⁸⁶ It was even suggested that each unit increase in IGF-I was associated with 90% metabolic syndrome risk reduction.⁸³

The interrelationships between IGFs and the other hormones involved in energy homeostasis and/or body weight regulation, such as ghrelin, leptin, and vitamin D, have also been explored in recent studies, particularly in relation to the development of metabolic syndrome. Ghrelin levels are lower with metabolic syndrome and correlate positively with IGF-1,^87,88 and both findings are common in type 2 diabetes with IR and leptin resistance.⁸⁷ With respect to vitamin D, reports on a British cohort of individuals followed up for 45 years, indicated that metabolic syndrome prevalence was lowest when levels of both 25(OH) vitamin D and IGF-1 were high.⁸⁹ The converse is probably also true.

These relationships between IGF-1 and metabolic syndrome (and components) are not consistently seen in all studies in all populations. For instance, in older Italians aged >65 years, no independent relationship could be established between IGF-1 and metabolic syndrome.^90,91 Similarly, studies in healthy elderly nondiabetic Lebanese men and Moroccans established no significant relationship of either adiponectin or leptin (as proxies for metabolic syndrome) with GH or IGF-1 values.^92,93 Another study in Arab men with CHD in whom low levels of IGF-1 and IGFBP were found failed to establish any correlations between IGF-1 and indices of IR and/or components of metabolic syndrome.⁷⁵

It is also likely that the IGFBPs have effects on metabolic syndrome and CVD risk that are independent of the IGFs. It is known that IGFBP-1 is downregulated by insulin and could serve as a potential indicator of metabolic syndrome and CVD risk.³³ Furthermore, low fasting IGFBP-1 and -3 and increased WC predicted diabetes in women and men.^33,81,94 Levels of IGFBP-2 were low in metabolic syndrome and associated positively with hyperglycemia and IR and negatively with TG and LDL.⁹⁵ Serum IGFBP-1 levels correlated inversely with BMI, insulin, IR, and IGF-I and positively with age⁹⁶ and increased with higher energy and carbohydrate (CHO) intake. Indeed, the combination of insulin, BMI, and CHO intake together explained up to 39% of variability in IGFBP-1 levels in men.⁹⁶ Other studies have suggested that IGFBPs have robust relationships with circulating CRP levels and might thereby play a direct role in the mediation of the inflammatory processes seen in the initiation of atherosclerosis.^97,98

Of further interest is the finding that the associations between IGFBPs (especially IGFBP-1) and metabolic syndrome and CVD risk were influenced by gender.^78,99,100 In a cross-sectional study on the relationship between IGFBP-1 and cardiovascular risk factors in a healthy population of men and women, it was reported that the fasting IGFBP-1 level was lower in men than in women and was positively correlated to age in men but not in women. Furthermore, the low circulating level of IGFBP-1 was associated with features of metabolic syndrome in a pattern that was dissimilar between men and women.⁹⁹ Another molecular genetic study in a Finnish population also showed that IGFBP-5 has a gender-specific association with adiponectin, which may modulate the development of metabolic syndrome.¹⁰⁰ Therefore, it is important that any evaluation of links between the IGF system, metabolic syndrome, and CVD risk should be done with this gender bias in perspective, because it could contribute to the widely recognized gender differences in prevalence of metabolic syndrome and CVD risk.

Observations on Newborn and Prepubertal Children with Growth Disorders

In normal children, circulating levels of IGF-1 and the IGFBPs change throughout development and with specific disease and in some cases are gender dependent. Presently, the clearest clinical utility of circulating IGF-1 assays in children is in cases of GH deficiency or insensitivity or with GH treatment.¹⁰¹ Studies on some of these children have provided some illumination into the relationships between body mass and the IGF system; these have included investigations of neonates who were born large for gestational age (LGA) and prepubertal children, who, for various reasons, were treated with GH.

Prepubertal children (aged 6–7 years) born LGA to healthy mothers tend to have higher levels of fasting insulin and IR but lower IGFBP-3 than appropriate for gestational age (AGA) children.¹⁰² Also small for gestational age (SGA) children, aged 2–6 years, gained more total and abdominal fat and raised their insulin and IGF-I more than did AGA children.¹⁰³ Other studies have shown that aortic IMT (aIMT) was higher, and serum IGF-1 lower, in macrosomic newborns, and correlated positively with IGF-1 and IGFBP-3 levels.¹⁰⁴ Humans with IGF-I mutations are born SGA and exhibit very poor subsequent growth with development of metabolic syndrome and mental retardation. Although these children tend to have relatively normal growth factor levels, as a group, their IGFBP-3 levels remain relatively low in relation to their IGF-I levels.^105,106 Other studies on SGA children without IGF-1 mutations reported that IGFBP-1 levels were similar to AGA controls when they were lean, but significantly lower in short SGA adults with normal fat mass. Indeed, IGFBP-1 correlated significantly with insulin, systolic blood pressure, and blood lipids in these subjects.^105,107 These changes could influence atherogenesis later in life.¹⁰⁴

Effects of Circulating GH and GH Replacement Therapy

GH generally exerts antiinsulin actions, whereas IGF-1 has insulin-like properties. Paradoxically, GH-deficient adults and those with acromegaly tend to be insulin resistant.¹⁰⁸ The metabolic abnormalities in adult patients with severe IR are improved by treatment with rhIGF-1, which, when used in combination with insulin therapy, also improves metabolic control in types 1 and 2 diabetes.¹⁰⁹ The components of metabolic syndrome are common in patients with GH deficiency; however, a study that used factor analysis reinforced the contention that GH and IGF-1 do not have identical relationships with metabolic syndrome and its components.¹¹⁰

Other reports in SGA children and adults with GH deficiency (GHD) with or without obesity^111

–114 have suggested that the beneficial effects of GH treatment on insulin sensitivity, glucose tolerance, anthropometric parameters, and levels of IGF-1 and IGFBP-3 in young SGA adults were lost within 6 years after discontinuing such treatment. As previously stated, obese adults with GHD tended to have more components of the metabolic syndrome.¹¹⁰ In these individuals, the peak GH and/or IGF-1 levels were the major determinants of WC, whereas age and IGF-1 were the major determinants of metabolic syndrome.¹¹² In confirmation of reports in macrosomic newborns,¹⁰⁴ common carotid IMT was higher in patients with GHD. GH treatment in these individuals significantly reduced the prevalence of IMT and metabolic syndrome^113,114 with improved insulin sensitivity and visceral adiposity, especially in those with low IGF-1 levels. These effects were reversed shortly after GH cessation.¹¹¹ In another study in similar patients, however, the frequency of metabolic syndrome components (except HDL-C levels) did not improve with 2–5 years of GH treatment.¹¹⁴

The overall impression is that GHD is a potentially atherogenic state, likely related, at least in part, to its association with low IGF-1 levels. This enhanced risk is diminished with appropriate GH treatment, but promptly returns when that treatment is discontinued.

The IGF System, Metabolic Syndrome, and Cancer

There is increasing interest in the link between obesity, the IGF system, and cancer, possibly mediated by the hyperinsulinemia and IR that are associated with the metabolic syndrome.¹¹⁵ As previously stated, IR can alter serum levels of insulin and IGF-1, both of which are important mediators of cell proliferation, differentiation, and inhibitors of apoptosis,¹¹⁶ and could thereby cause unregulated tissue growth.^{117

–122} Exciting as these observations are, they are beyond the scope of the current review. They however raise the hope that increasing research into the IGF system and its relationship with obesity and the metabolic syndrome could provide further useful insight into possibilities for the prevention, treatment and assessment of prognosis in at least some human cancers.^{115,118,123,124}

Additional Brief Mechanistic Insights

In this section, additional mechanistic issues in relation to the associations between iterations in the IGF system (including IGFBPs) and development of the metabolic syndrome (and its components) with future atherogenic risk are reviewed briefly. There is evidence suggesting that modest elevations in blood IGF-1 levels may protect against development of glucose intolerance in insulin-resistant subjects through effects on β-cell function and enhanced insulin sensitivity.¹²⁵ These actions are most likely independent and not due to changes in secretion of adipocytokines,¹²⁶ thyroid hormones, and cortisol nor are they a physiological adaptive response to obesity, starvation, or exercise.^127,128 Information obtained from studies on obese subjects with obstructive sleep apnea syndrome who have reduced spontaneous and stimulated GH secretion and IGF-1 levels in association with impaired peripheral GH sensitivity also suggest that these changes may be due to the effects of hypoxia and sleep fragmentation, causing GH/IGF-1 axis activity disruption.¹²⁹

The contribution from IGFBPs could also potentially be significant because they contain both IGF high- and low-affinity binders, and, as earlier discussed, exert mitogenic and metabolic actions through a complex interplay between IGF/insulin and its IGF/insulin-independent mechanisms.¹³⁰ Insulin interacts with the GH-IGF system by a reciprocal regulation of IGFBPs, whereas GH, on the other hand, regulates insulin sensitivity in part via bioactive IGF-I. Euglycemic hyperinsulinemic clamp studies¹³¹ have indicated that insulin decreases levels of IGF-I, IGFBP-1, and IGFBP-4 and increases IGFBP-2. This is in keeping with our earlier stated hypothesis with the further suggestion that these phenomena may be exaggerated with hyperinsulinemia. Indeed, these observations were essentially reproduced during an oral glucose tolerance test (OGTT) in subjects with varying degrees of glucose tolerance. GH and IGFBP-1 levels were markedly suppressed during the procedure. Subjects with impaired glucose tolerance (IGT) had pronounced IR and rather low GH, IGFBP-1, and IGFBP-2 levels; also, IGFBP-2 appeared to be an independent predictor of insulin sensitivity and IGF-I bioactivity. Insulin therefore likely decreases IGF-I bioactivity acutely through differential modulation of IGFBPs. This may be one mechanism for the insulin–IGF system cross talk in the genesis of IR and metabolic syndrome,^33,131 and is in keeping with our earlier stated hypothesis.

In further support of this independent role for IGFBPs is the observation from the large National Health and Nutrition Examination Survey III (NHANES III) study that individuals in the lowest quartile of the IGF-I/IGFBP-3 ratio were two- to three-fold more likely to have metabolic syndrome and be insulin resistant. Furthermore, the IGF-I/IGFBP-3 ratio decreased significantly as the number of metabolic syndrome components increased.¹³²

Briefly, other important mechanistic insights have come from observations that:

• Insulin and IGF-1 signaling are involved in the control of aging and longevity in animal models,¹³³ and the prevalence of metabolic syndrome increases with age.

• Metabolic syndrome is associated with activation of the renin–angiotensin–aldosterone system with increase in levels of angiotensin II and aldosterone—changes that may contribute to altered insulin/IGF-1 signaling and reactive oxygen species (ROS) generation and consequent endothelial dysfunction.¹³⁴

• The acute neuroendocrine response to critical illness involves substantial increase in blood levels of IGF-1 and GH-dependent IGFBPs, and a lethal outcome of critical illness is predicted by a high serum IGFBP-1 level. Therefore, the IGF system may also have an adaptive role.¹³⁵

• Polymorphisms in the IGF-2 and IGFBP-1 gene loci have been associated with interindividual differences in insulin sensitivity, accumulation of visceral fat, and development of features of metabolic syndrome.¹³⁶

• The IGF system possibly interacts at some levels with adipocytokines especially adiponectin (ApN) and its related gene apM1 in the development of metabolic syndrome. Indeed, the expression of the apM1 gene was found to be positively regulated by insulin and IGF-1.¹³⁷

These observations are yet unproven but could contribute likely clues in unraveling the discrepancies currently described in the links between the IGF system, metabolic syndrome, and CVD risk.

Conclusion

This review has explored the available scientific data (associations and prospective case–control data in human and experimental animal models) on the putative links between the IGF system, IR, development of the metabolic syndrome, and CVD risk. It is known that IGF-1 and insulin share homology and act via shared receptors with different affinities to mediate a wide range of metabolic and growth-promoting functions. Such activity is likely to be exaggerated with the hyperinsulinemia that is seen with IR with important implications for both atherogenesis and oncogenesis. The effects of the IGFs, especially IGF-1, are also significantly modulated by changes in blood levels of the IGFBPs that are capable of metabolic and growth-promoting functions that are independent of their capacity to bind IGFs. The insulin-resistant states are associated with low IGF-1 levels, and this has been hypothesized to be consequent on the modulating effects of the compensatory hyperinsulinemia on circulating IGFBP levels, possibly as a homeostatic response. Although further work is needed to define specifically the pathogenetic mechanisms involved, these different interactions are potentially subject to pharmacological manipulation in the treatment of, and protection from, disorders associated with the metabolic syndrome and enhanced CVD risk.

Footnotes

Acknowledgments

A.O.A. is grateful to Kuwait University Faculty of Medicine for granting him a sabbatical year leave (2010–2011) and to the Department of Medicine, Warren Alpert Medical School, Brown University, Providence, RI, for hosting him during the 2010–2011 academic year.

Author Disclosure Statement

The authors declare no conflict of interest.

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