Clinical Science (2013) 125, 265–280 (Printed in Great Britain) doi: 10.

1042/CS20120663

Insulin-like growth factor-I (IGF-I) and clinical

nutrition
Callum LIVINGSTONE*†

*Peptide Hormones Supraregional Assay Service (SAS), Clinical Biochemistry Department, Royal Surrey County Hospital NHS Foundation Trust,
Guildford, Surrey GU2 7XX, U.K.
†Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 5XH, U.K.

Abstract
IGF-I (insulin-like growth factor-I) is a peptide hormone, produced predominantly by the liver in response to pituitary
GH (growth hormone), which is involved in a wide variety of physiological processes. It acts in an endocrine,
paracrine and autocrine manner to promote growth. The production of IGF-I signals the availability of nutrients
needed for its anabolic actions. Recently, there has been growing interest in its role in health and disease. IGF-I has
long been known to be regulated by nutrition and dysregulated in states of under- and over-nutrition, its serum
concentrations falling in malnutrition and responding promptly to refeeding. This has led to interest in its utility as a
nutritional biomarker. A considerable evidence base supports utility for measurement of IGF-I in nutritional contexts.
Its concentration may be valuable in providing information on nutritional status, prognosis and in monitoring
nutritional support. However, it is insufficiently specific for use as a screening test for under nutrition as its serum
concentration is influenced by many factors other than nutritional status, notably the APR (acute-phase response)
and endocrine conditions. Concentrations should be interpreted along with clinical findings and the results of other
investigations such as CRP (C-reactive protein). More recently, there has been interest in free IGF-I which holds
promise as a nutritional marker. The present review covers nutritional regulation of IGF-I and its dysregulation in
disease, then goes on to review recent studies supporting its utility as a nutritional marker in clinical contexts.
Although not currently recommended by clinical guidelines, it is likely that, in time, measurement of IGF-I will
become a routine part of nutritional assessment in a number of these contexts.

Key words: clinical nutrition, free insulin-like growth factor-I (free IGF-I), insulin-like growth factor-I (IGF-I), malnutrition, obesity

INTRODUCTION of GH. This hypothesis was later modified when it emerged first
that GH had direct growth-promoting effects and secondly that
Experiments in the 1950s on the action of GH (growth hormone) IGF-I, produced locally in most tissues, also acted in an auto-
to enhance sulfate incorporation into epiphyseal cartilage indic- crine and paracrine manner [3]. Since then, there has been a
ated that its action required a circulating factor, initially called debate about the relative importance of hepatic IGF-I and locally
‘sulfation factor’ [1]. In 1972, this was given the term ‘somat- produced IGF-I in the regulation of growth [4]. Following the
omedin C’, reflecting its ability to mediate the action of GH [2]. discovery of the IGFBPs (IGF-binding proteins), it became clear
Finally, in 1978, it was named IGF (insulin-like growth factor)- that the system was considerably more complex than originally
I, having been characterized and found to resemble insulin in thought. Interest in IGF-I as a nutritional marker began in 1973
its structure and metabolic functions. The original somatomedin when its serum concentrations were observed to fall in malnutri-
hypothesis proposed that pituitary GH stimulated hepatic IGF-I tion [5]. The purpose of the present review is to provide readers
production, which brought about the growth-promoting effects with a perspective and update on IGF-I as a nutritional marker.

Abbreviations: ALS, acid-labile subunit; APR, acute-phase response; BMD, bone mineral density; BMI, body mass index; BMR, basal metabolic rate; BV, biological variation; CF, cystic
fibrosis; CHD, coronary heart disease; CRP, C-reactive protein; CVi , coefficient of variation; DEXA, dual-energy X-ray absorptiometry; GH, growth hormone; IF, intestinal failure; IGF,
insulin-like growth factor; IGFBP, IGF-binding protein; IGF-1R, type 1 IGF receptor; IGF-2R, type 2 IGF receptor; IL, interleukin; IR, insulin receptor; KIRA, kinase receptor activation assay;
LBM, lean body mass; LOS, length of stay; NEFA, non-esterified (‘free’) fatty acid; NGR, nutritional growth retardation; NICE, National Institute for Health and Clinical Excellence; PEM,
protein energy malnutrition; PN, parenteral nutrition; RBP, retinol-binding protein; rhGH, recombinant human GH; RI, refeeding index; RS, refeeding syndrome; RTK, receptor tyrosine
kinase; SBS, short bowel syndrome.

Correspondence: Dr Callum Livingstone (email [email protected]).

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Table 1 Nutritional biomarker proteins

CKD, chronic kidney disease; F, female; LD, liver disease; M, male.

Molecular mass
Biomarker (kDa) Half-life Reference range Positive confounders Negative confounders
IGF-I (total) 150 (ternary 10–16 h Age-related Acromegaly APR, LD, GH deficiency,
complex) hypothyroidism, zinc
deficiency
Transferrin 80 10 days 2.15–3.65 g/l (M) Iron deficiency APR, LD
2.50–3.80 g/l (F)
Prealbumin 50 2 days 0.20–0.50 g/l Hypothyroidism, CKD, APR, LD
pregnancy, steroids
RBP 21 12 h 20–40 mg/l CKD APR, vitamin A deficiency, zinc
deficiency, hyperthyroidism

NUTRITIONAL ASSESSMENT to adjusting the nutritional support. Nutritional support can be

delivered orally, enterally or parenterally depending on the clin-
Research studies have increasingly linked malnutrition and ical situation, the first two routes being the more physiological.
obesity to the development of disease, but both conditions are PN (parenteral nutrition) is reserved for patients with IF (intest-
still under-diagnosed and under-treated. Malnutrition is partic- inal failure) where the gut is either dysfunctional or inaccessible.
ularly prevalent in hospital patients, in whom it increases the The provision of nutritional support requires careful monitoring
risk of adverse outcomes such as post-operative complications to enable the early detection of complications. NICE (National
or delayed recovery [6]. This increases the LOS (length of stay) Institute for Health and Clinical Excellence) provides guidance
for patients, in turn increasing healthcare costs. Once diagnosed, on the monitoring of patients [13]. This includes anthropometric
however, malnutrition can be treated with nutritional support. and laboratory measurements.
This can buy time for other therapeutic interventions to aid re- Biomarkers of protein energy status can be useful adjuncts to
covery, thereby reducing morbidity and mortality [7]. Early de- nutritional assessment, with their attraction being their objectiv-
tection of malnutrition is therefore vital in order that nutritional ity. As such, they can complement clinical nutritional assess-
support can be commenced. In this context, we should distin- ment, which is in part subjective. This has prompted researchers
guish between nutritional assessment and nutritional screening. to identify novel markers. However, the diagnostic performance
The former is generally considered to indicate a relatively detailed of biomarkers is difficult to assess as there is no universal ‘gold
evaluation, carried out by a professional trained in clinical nutri- standard’ method for nutritional assessment against which they
tion, to help to decide on appropriate therapeutic interventions can be compared. If a novel biomarker is to be of value, its result
[8]. Traditionally, it involves a combination of history taking, should lead to clinical action, potentially improving the outcome
physical examination, anthropometric measurements and labor- for the patient. Biomarkers can be considered as having three po-
atory tests. Nutritional screening, on the other hand, is a quick and tential roles: namely diagnosis of malnutrition and micronutrient
initial means of determining whether potentially malnourished or disorders, monitoring of therapeutic interventions and providing
overweight patients require in-depth nutritional assessment. It is information on prognosis, i.e. predicting outcome. The latter can
usually carried out by a non-expert. Nutritional screening of hos- assist the clinician in deciding whether to intervene therapeutic-
pital patients has been advocated by professional bodies as a ally. Biomarkers currently available are transferrin, pre-albumin
means of facilitating the detection of malnutrition, which may and RBP (retinol-binding protein), all of which may exhibit re-
otherwise be easily overlooked [9]. At present, it is carried out duced serum concentrations in malnutrition (Table 1). Although
using screening tools such as the MUST (malnutrition universal they are sensitive tests for the detection of malnutrition, their dia-
screening tool) [10]. gnostic specificity is too low for use in screening. Their main role
Once the decision has been taken to provide nutritional sup- in clinical practice is in monitoring nutrition support. However,
port, the individual’s nutritional requirements should be met if their clinical utility is debated and current NICE guidelines do
the full benefit is to be realized. Energy requirements can be es- not advocate their measurement [13].
timated based on body weight and age using a method such as
the Schofield equation to determine the BMR (basal metabolic
rate) [11,12]. Likewise, protein requirements can be estimated
from body weight. It should be emphasized that these methods THE IGF AXIS
only provide approximate values. Requirements can be signific-
antly altered in, for example, critical illness and it should be The IGF system consists of the peptide hormones IGF-I and IGF-
remembered that the final arbiters of the success of nutritional II, their cell-surface receptors and IGFBPs. IGF-I and IGF-II are
support are weight restoration and recovery. Patients should there- 7.5 kDa peptides consisting of 70 and 67 amino acid residues
fore be closely monitored for evidence of nutritional repletion, respectively. Both have biological roles during development and
and, if they are not recovering, consideration needs to be given in adulthood and circulate in considerably higher concentrations

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IGF-I and clinical nutrition

Various regulatory mechanisms regulate the release of IGFs

from complexes increasing interaction with receptors [25]. First,
the proportions of the different IGFBPs in serum may be import-
ant. The levels of IGFBP-1 and -2, although constituting a small
proportion of the total IGFBP pool, are thought to have a role in
regulation of free IGF-I. Conditions influencing their levels can
alter free IGF-I concentrations without affecting total IGF-I [20].
Proteases and matrix metalloproteinases can fragment IGFBPs,
thereby reducing their affinity for IGFs and enhancing IGF re-
lease [20]. A variety of catabolic states, namely critical illness,
post-surgery and malignancy, are known to be accompanied by
increased IGFBP-3 proteolysis [26–28]. It is also increased in
maternal serum during pregnancy [29]. This may be an adaptive
Figure 1 The IGF system process in these conditions which enables IGFs to be mobilized
The IGF system consists of IGF-I and -II, six IGFBPs (IGFBP-1–6), IGF-1R
and IGF-2R. Both IGFs bind to all six IGFBPs. For simplicity, all of the IGF- from their vascular store, making them available to extravascu-
BPs are shown as binding IGF-I. IGFBP-3 binds IGFs in serum as ternary lar tissues. However, it may be maladaptive in some situations.
complexes with ALS from liver. Most of the physiological effects of IGFs IGFBP-3 protease activity released by breast cancer cells acts as
are considered to follow their binding to IGF-1R. IGF-2R is identical with
the mannose 6-phosphate (6MP) receptor. It is thought to have a role in a tumour-growth stimulator by increasing local IGF availability
IGF-II clearance. Both IGFs can also bind to and activate the IR and in- [30]. PAPP-A (pregnancy-associated plasma protein A), is a loc-
sulin can bind to IGF-1R as well as IR. The Figure is not drawn to relative
scale. The approximate molecular masses of the components are IGF-I
ally acting IGFBP-4 protease released from cells which is thought
and IGF-II, 7.5 kDa; insulin, 5.8 kDa; ALS, 85 kDa; IGFBP-1, 25 kDa; to increase local bioavailability of IGF-I [31]. This is thought to
IGFBP-2, 31 kDa; IGFBP-3, 43 kDa; IGFBP-4, 24 kDa; IGFBP-5, 29 kDa; be activated by the pro-inflammatory cytokines TNFα (tumour
IGFBP-6, 28 kDa; IR, 300 kDa; IGF-1R, 155 kDa; IGF-2R, 274 kDa. Re-
produced from Growth Hormone & IGF Research, 13/4, Juul Anders,
necrosis factor α), IL (interleukin)-1β and IL-6 [32]. Inhibitors
Serum levels of insulin-like growth factor I and its binding proteins in of IGFBP protease expression include N-acetylcysteine and anti-
health and disease,  c 2003, with permission from Elsevier. oxidants [33]. Release of IGFs from complexes is also regulated
by IGFBP phosphorylation and cell-surface association via the
extracellular matrix [34].
than insulin [14,15]. The IGFs bind to three cell-surface trans-
membrane receptors: IGF-1R (type 1 IGF receptor), IGF-2R (type
2 IGF receptor) and IR (insulin receptor) [16]. Biological actions
of the IGFs are mediated predominantly via binding to IGF-1R PHYSIOLOGICAL EFFECTS OF IGF-I
[17,18]. They activate an RTK (receptor tyrosine kinase) which
initiates an intracellular signalling cascade generating their bio- IGF-I has a wide variety of effects, but, essentially, these can
logical responses [17]. IGF-2R has no signalling activity and be divided into acute metabolic effects and longer-term growth-
is thought to enable degradation of IGF-II, thereby reducing its promoting effects [15]. The acute actions of IGF-I overlap with
availability to receptors [19]. Figure 1 illustrates the components those of insulin on carbohydrate and protein metabolism to pro-
of the IGF system. mote energy storage. They include stimulation of amino acid
The IGFBPs are a family of six proteins which bind the IGFs uptake into skeletal muscle and stimulation of peripheral glucose
in serum. They are synthesized in liver, connective tissue and vari- uptake [35]. Its long-term effects are on cell proliferation, differ-
ous other cell types [20]. Their role is to transport and sequester entiation and anti-apoptosis [36,37]. IGF-I is a potent mitogen
IGFs, thereby regulating their availability to receptors. In addi- increasing DNA synthesis and accelerating cell-cycle progres-
tion, they are thought to have actions independent of IGFs [21,22]. sion. It also enhances protein synthesis and inhibits proteolysis
The individual proteins have binding preferences; IGFBP-2, for throughout the body, having a key role in growth regulation both
example, binding preferentially to IGF-II [23]. The IGFBPs bind embryonically and postnatally [38]. IGF-I is essential for the at-
approximately 99 % of the circulating IGF-I, but a small propor- tainment of normal body size during fetal development, peak
tion (<1 %), which exists as free IGF-I, is thought to be the bio- bone mass during puberty and optimal fecundity during the re-
active component. Circulating IGFs are largely bound in 150 kDa productive period.
ternary complexes consisting of IGF-I or IGF-II, IGFBP-3 and Briefly, the growth-promoting actions of IGF-I on individual
ALS (acid-labile subunit), an 85 kDa protein synthesized in liver tissues are summarized as follows. It is the most important medi-
[24]. Compared with free IGF-I, these complexes have a relat- ator of muscle growth helping to maintain skeletal muscle mass by
ively long half-life (10–16 h) in the circulation, essentially acting stimulating protein synthesis [39,40]. It induces an increase in ex-
as an endocrine store of IGFs. The remaining IGFs are present in pression of oxidative enzymes which promote fatigue resistance
the free form or as binary complexes with IGFBPs [15]. Ternary [41]. In brain, IGF-I is a potent neurotrophic and neuroprotective
complexes are unable to cross capillary endothelia, but binary factor [42]. It is a critical promoter of brain development and
complexes, having access to tissues, may act as a pericellular neuronal survival influencing cognitive function. IGF-I has a role
reservoir. The size of the circulating pool of IGF-I is determined in regulation of β-cell mass and the regulation of insulin secretion
by the amount of circulating IGFBP-3 and ALS. and sensitivity [43]. It is also considered to have a physiological

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role in maintaining the function of the immune system [44]. Loc- concentrations, the physiological purpose of which is to divert
ally produced IGF-I is responsible for much of the growth in the substrates towards these energy needs [59]. Low IGF-I concen-
body, but it is considered to be unable to replace liver-derived trations favour protein catabolism in skeletal muscle, mobilizing
IGF-I for mediating certain GH actions, namely regulation of amino acids for hepatic gluconeogenesis, a process in which sim-
cortical bone mass, GH secretion and insulin sensitivity [45]. ultaneously occurring low insulin concentrations are permissive.
This process is assisted by the relatively insulin-resistant state
which exists in starvation. Gluconeogenesis maintains glucose
levels needed to supply glycolytic tissues such as brain. The
REGULATION OF IGF-I decrease in circulating IGF-I concentrations also results in en-
hanced GH secretion. However, there is also a state of relative
A wide variety of factors influence serum IGF-I concentrations, GH insensitivity in which the liver does not respond normally
namely age, gender, genetic factors, nutritional status and dis- to the elevated GH, resulting in persistently low IGF-I concen-
ease. IGF-I levels are low at birth and increase to the age of trations [60–62]. This favours lipolysis in adipose tissue making
20 years, thereafter declining gradually [46]. This decline ap- NEFAs [non-esterified (‘free’) fatty acids] available as an energy
pears to be entirely physiological occurring independently of source [63]. GH also enhances hepatic gluconeogenesis by ant-
malnutrition and inflammatory processes [47]. Genetic factors agonizing insulin’s suppressive action and by providing amino
have a significant influence on its expression accounting for up to acids from muscle. Thus GH has an anti-insulin effect increasing
50 % of serum concentrations under physiological circumstances the availability of glucose and NEFAs.
[48,49]. Other hormones influence GH-stimulated hepatic IGF- The mechanism of the decline in serum IGF-I during fasting
I secretion. Thyroxine and androgens enhance IGF-I secretion, has been studied extensively in animal models, but less in humans
whereas oestrogens antagonize IGF-I secretion [50]. The pro- [64]. The relative resistance to GH action on liver in malnutrition
duction of hepatic IGF-I in response to pituitary GH is acutely results in a block in hepatic IGF-I secretion. In severe dietary
regulated by a negative-feedback loop. Factors causing serum restriction, there is reduced expression of hepatic GH recept-
IGF-I concentrations to fall reduce feedback inhibition, resulting ors, whereas protein restriction alone is associated with a post-
in increased GH levels. This increase is directly related to the receptor defect in GH action [65]. The decline also reflects the
reduction in free IGF-I which has led to the belief that it is general decrease in hepatic protein synthesis which accompan-
the free component which regulates pituitary GH secretion ies malnutrition, caused in part by reduced availability of amino
[51,52]. By suppressing GH secretion, hepatic IGF-I indirectly acids. Other factors contributing to the decline are nutritionally
enhances insulin sensitivity. The bioactivity of IGF-I is regulated induced hormonal changes, namely reduced concentrations of in-
at the level of its expression, binding to IGFBPs and by IGF res- sulin, as discussed above, and tri-iodothyronine. During dietary
istance. Factors that regulate IGFBPs, particularly IGFBP-3, have restriction, there is also increased clearance and degradation of
a major influence on free IGF-I concentrations in serum, in turn serum IGF-I mediated by changes in concentrations of circulating
influencing IGF-I signalling [25]. Tissue sensitivity to IGF-I can IGFBPs. IGFBP-1 and -2 levels rise early during malnutrition,
be regulated by tissue-specific expression of receptor numbers or possibly to limit the amount of bioactive IGF-I as a means of
by factors influencing the intracellular signalling pathways [53]. preventing hypoglycaemia. IGFBP-3 levels fall if malnutrition is
prolonged.
Nutritional regulation of IGF-I As noted above, IGF-I was observed to be dysregulated in
Growth is a complex process driven by genes, but dependent on malnutrition shortly following its discovery. The decline in its
many other factors. It is an energy-demanding process which, concentrations was greater in those with PEM (protein energy
in addition, requires plentiful substrate for cellular proliferation. malnutrition) compared with protein malnutrition alone [66,67].
Since IGF-I is responsible for physiological up-regulation of pro- Of the two factors, protein appears to be the more important in
tein synthesis, it is logical that its release should be linked to determining circulating IGF-I concentrations. Where energy re-
sufficient substrate availability, indicating that the individual is striction is moderate and long-term, this does not reduce serum
nutritionally replete. Hepatic IGF-I synthesis also requires portal IGF-I, but concentrations fall significantly in moderately protein-
insulin, the presence of which signals sufficient carbohydrate in- restricted subjects [68]. In terms of the response of IGF-I levels
take [54]. Insulin stimulates IGF-I gene transcription and peptide to nutritional support, it appears that optimal intakes of both pro-
synthesis independently of GH, but also regulates GH receptor tein and energy are required for their restoration [64]. The dietary
density [55,56]. It inhibits synthesis of IGFBP-1 and -2 in the essential amino acid intake is also critical for IGF-I restoration
liver, both of which are thought to have inhibitory actions on following fasting. A diet in which the protein content is low in
IGF-I bioactivity by reducing free IGF-I concentrations. In this essential amino acids (80 % non-essential amino acids) attenu-
way, insulin enhances both IGF-I levels and bioactivity [57,58]. ates the return of IGF-I to normal [69]. Serum IGF-I also appears
Both the IGFs and insulin are therefore part of an energy-sensing to be sensitive to both the amount and type of fat provided in
mechanism linking nutrition and growth. nutritional support. Fish oil and low fat solutions were signific-
During malnutrition, adaptation is necessary so that metabolic antly correlated to serum IGF-I, appearing to promote a more
resources normally used for growth can supply the immediate rapid recovery of its concentrations [70]. Figure 2 illustrates
energy needs of the individual. Starvation, semi-starvation, fast- the main regulatory influences upon production of IGF-I and its
ing and caloric restriction all result in lowering of serum IGF-I action.

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IGF-I and clinical nutrition

stage of critical illness appear to have prognostic value. A pro-

spective observational study of 102 critically ill ICU (intensive
care unit) patients observed higher IGF-I levels in the survivors
[83].
These responses probably developed as an adaptation to reg-
ulate utilization of limited resources [53]. During acute illness,
the immediate survival of the organism demands that growth and
energy storage are restricted. In the short term, it is therefore im-
portant that amino acids continue to be mobilized from muscle to
fuel gluconeogenesis. By inhibiting the anabolic effects of IGF-I,
cytokines and glucocorticoids enable energy to be provided for
the immune system [44,53]. Glucocorticoid hormones also pro-
mote protein catabolism by antagonizing the anabolic actions of
IGF-I at the molecular level. Although the basis of these responses
is adaptive, there are pathological consequences. Sustained cy-
tokine action leads to a reduction in skeletal muscle mass which
can prolong mechanical ventilation [84]. Cytokines also induce
sickness behaviour such as malaise, fatigue, reduction in appetite
and change in sleep patterns [85].
The findings of low IGF-I levels in critical illness stimulated
interest in therapeutic use of rhGH (recombinant human GH).
Treatment did result in increased IGF-I concentrations with ni-
Figure 2 Regulatory influences upon IGF-I production and action trogen retention and decreased LOS. However, two large trials in
Circulating IGF-I is synthesized predominantly in liver, but by other tis- 1999 reported increased mortality associated with infection and
sues as well. It exists in the circulation mainly (>99 %) bound in ternary organ dysfunction [86]. Smaller clinical trials have re-examined
complexes consisting of IGF-I, IGFBP-3 and ALS. The small fraction
present as free IGF-I is considered to be the biologically active com- rhGH treatment in prolonged critical illness, demonstrating in-
ponent and can traverse the capillary endothelium, where it binds to creased IGF-I and IGFBP-3 concentrations. In a recent trial of 30
IGF-1R on target tissues bringing about the metabolic and anabolic ac-
multiple trauma patients with prolonged critical illness, pulsatile
tions of IGF-I. IGF-I is principally regulated by pituitary GH which binds
to the growth hormone receptor (GHR) in liver and increases hepatic rhGH delivered intravenously normalized IGF-I concentrations
synthesis of IGF-I under physiological circumstances. A number of pos- [87]. Recombinant GH supplementation may be safer and more
itive and negative regulatory influences on hepatic IGF-I synthesis are
shown. In addition, cytokines are considered to influence IGF-I signalling
efficacious in some critically ill patients, but the subgroup likely
following receptor binding. Locally produced IGF-I can enter the circula- to benefit needs to be defined. A clearer understanding of the GH
tion, but can also act on the cell where it is produced (autocrine action) resistance present in critical illness should lead to the develop-
or on neighbouring cells (paracrine action).
ment of new therapies to restore the anabolic effects of GH and
IGF-I. Current guidelines recommend against therapeutic use of
rhGH in critical illness [88].
Dysregulation of IGF-I in disease Dysregulation of the IGF axis is implicated in the adverse
Critically ill patients with sepsis, injury and burns are in neg- effects of aging [89]. The decline in IGF-I concentrations which
ative nitrogen balance, a state which occurs independently of occurs with age is associated with reduced muscle mass and
total body protein status and irrespective of whether the patient strength, reduced protein synthesis and increased cellular apop-
is receiving adequate nutritional support [71]. These patients tosis [90]. As well as a decline in concentrations, there appears to
also exhibit a state of GH resistance in which there is a reduc- be an impairment of intracellular signalling which contributes to
tion in both circulating and locally produced IGF-I, analogous age-related loss of muscle and bone mass [91]. During aging, in-
to that observed in malnutrition [72–75]. The mechanism of the dividuals can develop visceral adiposity, a pro-inflammatory state
decrease is incompletely understood, but pro-inflammatory cy- associated with impairment of IGF-I action. These changes are
tokines such as IL-1 and IL-6 act to inhibit IGF-I expression in accompanied by a decline in the concentrations of other anabolic
liver and skeletal muscle [76,77]. In some conditions, reduced hormones, namely DHEAS (dehydroepiandrosterone sulfate) and
IGF-I concentrations are in part due to decreased IGFBP-3 con- testosterone. In contrast, there is a relative abundance of catabolic
centrations resulting from increased proteolysis [78]. Whatever hormones such as thyroid hormones and cortisol. This cata-
the mechanism, IGF-I concentrations tend to be inversely related bolic milieu is associated with frailty, cognitive decline and mor-
to those of APR (acute-phase response) markers such as CRP (C- tality in the elderly [92]. The changes in IGF-I appear to influence
reactive protein) [79]. Studies have also provided evidence that survival. A prospective study in elderly men observed that higher
cytokines induce IGF resistance without influencing expression circulating IGF-I bioactivity was better associated with overall
of IGF-1R [80,81]. They appear to block post-receptor intracellu- survival. Those in the lowest quartile had 1.8-fold increased mor-
lar signalling. This may contribute to the inability of nutrient sup- tality risk compared with the highest quartile [93]. It has been
plementation to promote gain of LBM (lean body mass) in acutely recognized for many years that the decline in the IGF-I axis
ill patients [82]. IGF-I concentrations measured in the post-acute which occurs with aging may be linked to cognitive deficits and

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Table 2 Pathophysiological influences on total serum IGF-I utility for measurement of IGF-I in nutritional contexts. As a
concentrations marker of nutritional status, IGF-I is more sensitive and specific
Key: ↑, increase; ↓, decrease; U, unchanged. than prealbumin, transferrin and RBP [59,119]. Its shorter serum
Factor Effect on serum IGF-I Reference(s) half-life, indicative of high turnover, renders it more sensitive
Genes U/↑/↓ [48,49] to changes in nutritional status, an attribute which increases its
Age ↑ until 20 years ↓ until [96] value in monitoring compared with previous markers [120]. The
50 years findings of studies on IGF-I in under-nutrition and obesity are
Pregnancy ↑ as pregnancy [97] discussed below.
progresses
Malnutrition ↓ [98,99] Anorexia nervosa
Obesity U/↑/↓ [100–107] As in other situations where there is malnutrition, GH levels are
Zinc deficiency ↓ [108] high in patients with anorexia nervosa, following the reduction in
Chronic wasting conditions ↓ [109] negative feedback on GH secretion [121]. Likewise, suppressed
Catabolic conditions ↓ [76] IGF-I reflects the GH resistance present as part of the adapt-
Severe liver disease ↓ [110] ive response to malnutrition [122]. Since increases in GH and
Chronic kidney disease ↓/U [111,112] IGF-I during puberty are essential for increased bone formation,
Hypothyroidism ↓ [50,113]
these changes do have pathological consequences. In patients
GH deficiency ↓ [114]
with anorexia nervosa, low BMD (bone mineral density) can oc-
cur [123]. In addition to changes in the IGF axis, patients with
Acromegaly ↑ [114]
anorexia nervosa often have multiple other endocrine abnormal-
ities, including amenorrhoea, hypothyroidism and hypercortisol-
ism [124]. These are not hallmarks of anorexia nervosa itself,
but occur secondarily to malnutrition as they are also observed
Alzheimer’s disease [42]. Loss of IGF-I also has pathological
in starvation states accompanying other conditions such as cata-
effects on the immune system [53].
bolic states and liver disease. They return to normal upon weight
There is a paradox in the actions of IGF-I in that some are po-
restoration [125].
tentially harmful. Whereas the growth factor and anti-apoptotic
During recovery, IGF-I has an active role in regenerative pro-
effects of IGF-I are beneficial in physiological proportions, per-
cesses. Since its serum concentrations respond to nutritional sup-
sistently elevated IGF-I bioactivity and hyperinsulinaemia ap-
port, it has been investigated as an indicator of nutritional status in
pear to be detrimental, increasing the risk of age-related diseases
these patients [99]. Total serum IGF-I concentrations are closely
[94]. There is epidemiological evidence to suggest that excess
related to BMI, body fat and body muscle mass, reflecting the
IGF-I has a role in the development of some cancers, Type 2
severity of nutritional depletion [98]. During nutritional rehab-
diabetes and atherosclerosis. Patients with IGF-I concentrations
ilitation, IGF-I increased in parallel with the BMI S.D. score, a
in the upper quartile of normal have an increased incidence of
measure of leanness. The authors of this study concluded that
cancers, whereas low serum IGF-I concentrations are associated
IGF-I can be considered an indicator of nutritional status which
with diminished tumour growth and metastasis [95]. IGF-I also
is sensitive to short-term weight changes. The increase in serum
promotes tumour growth and metastasis in pre-existent cancers.
IGF-I which occurs with weight gain predicts increases in mark-
Pathophysiological factors influencing total serum IGF-I concen-
ers of bone formation and BMD [126,127].
trations are summarized in Table 2.
Following recovery, a possible use for IGF in the context of
anorexia nervosa is in prediction of relapse. This is an import-
ant issue as patients who appear clinically recovered still have a
CLINICAL UTILITY OF IGF-I IN NUTRITIONAL high rate of relapse. In this situation, body weight alone may be
CONTEXTS misleading as a parameter of energy balance because it reflects ex-
tracellular fluid as well as body cell mass. Weight measurements
Currently, the principal utility of serum total IGF-I measurements alone may therefore underestimate the risk of relapse. Monitor-
is in the assessment and monitoring of GH status in deficiency ing of IGF-I may help avoid this problem. Investigation of this
and acromegaly, which have been reviewed elsewhere [114]. At would require the IGF-I concentration to be studied prospectively
present, NICE guidance does not recommend measurement of to assess whether its decline precedes that of significant loss of
IGF-I in the context of clinical nutrition [13]. However, there LBM, as assessed by an imaging technique such as DEXA (dual-
is abundant evidence from studies supporting its measurement. energy X-ray absorptiometry) scanning. Monitoring of IGF-I as
The serum IGF-I concentration has long been recognized to re- a marker of repletion during artificial nutrition support may also
flect nutritional status, declining during starvation and responding potentially help to avoid overfeeding of patients and the adverse
to refeeding [59,115–117]. During nutritional support, concen- consequences thereof.
trations have been observed to rise incrementally in relation to
weight gain, correlating with anthropometric indices such as BMI Paediatrics
(body mass index) and the levels of other biomarkers [59,116– Many diseases can present with growth failure in childhood.
118]. These findings led researchers to consider possible clinical These include coeliac disease, renal disease, HIV infection and

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cystic fibrosis [128]. Malnutrition is the common factor under- SBS who merit more aggressive therapeutic intervention [139].
lying growth failure in patients with these conditions, but catch- Utility has been suggested in children with IF undergoing intest-
up growth can usually be achieved with appropriate nutritional inal transplantation. Transplantation can potentially free these
intervention. Serum IGF-I concentrations, along with those of patients from long-term PN, but it is often difficult to achieve
IGFBP-3, are regulated by nutritional intake, with their regu- satisfactory growth post-transplant. Low pre-transplant concen-
latory patterns being similar to those observed in adults. It has trations of IGF-I predicted negative linear growth velocity [140].
therefore been suggested that their measurement may indicate Pre-transplant IGF-I concentrations may therefore be useful in
adequacy of nutrient intake [129]. When used in the assessment identifying those patients requiring more intensive nutritional
of growth in malnourished children, the IGF-I concentration cor- support post-transplant. rhGH is another treatment that may re-
relates strongly with height S.D. score, suggesting that it is a duce the amount of PN required in patients with SBS. When this
useful indicator of growth and nutritional status [130]. was recently trialled in PN-dependent children, they remained
Serum IGF-I has been extensively studied as a marker of on PN, but significantly more nutrition could be delivered en-
LBM in children with medical disorders. In CF (cystic fibrosis), terally [141]. This paralleled an increase in their energy balance
it correlated with LBM, as evaluated by DEXA scanning, inde- over a 12-month period during which serum IGF-I concentra-
pendently of weight [131]. The significance of this is that reduced tions increased significantly. There may therefore be a place for
LBM can impair respiratory function, worsening the clinical out- monitoring IGF-I in the context of rhGH treatment.
come in these patients. IGF-I could therefore be used to identify
patients at risk of deteriorating respiratory function. In a separ- RS (refeeding syndrome)
ate study of children with CF, decreased IGF-I was observed to RS, the hallmark of which is hypophosphataemia, can occur as a
reflect growth retardation [132]. It was also used as a marker of complication following the commencement of nutrition support
LBM in a recent study of children starting antiretroviral ther- in malnourished patients [142,143]. Although there are recom-
apy for HIV infection [133]. During treatment, improved muscle mendations on how to recognize patients at risk of RS [13],
mass, but not linear growth, was associated with IGF-I concen- prediction is difficult in practice. Many at-risk patients do not
trations returning to normal. In children with congenital heart suffer refeeding complications. Conversely, some patients who
disease, the presence of cyanosis was the most important factor develop complications are not identified as being at-risk. In prac-
influencing serum IGF-I. Concentrations were significantly lower tice, NSTs (nutrition support teams) adopt a cautious approach
in cyanotic compared with acyanotic patients [134]. The authors of initially underfeeding most patients. Although this minimizes
suggested that chronic hypoxia has a significant role in the patho- complications, it has the consequence that many patients are un-
genesis of malnutrition, reflected by serum IGF-I concentrations. derfed unnecessarily. The availability of reliable objective mark-
In addition, the loss of the growth-promoting effect of IGF-I in ers or RS risk would enable these patients’ nutritional needs to
these patients may be directly responsible for the decrease in left be met at an earlier stage, thereby promoting their recovery. A re-
ventricular mass. cently published study on patients receiving PN examined three
Prolonged suboptimal energy intake can result in NGR (nutri- parameters as potential predictors of RS, namely serum IGF-I
tional growth retardation), a condition which is easily overlooked. measured before commencement of PN, the leptin concentration
It can be detected by monitoring body weight over time. In con- and an RI (‘refeeding index’) derived from the other two values
trast with children with PEM, these patients do not appear wasted [144]. Although the RI predicted a fall in the serum phosphate
and IGF-I concentrations, in common with RBP, prealbumin and concentration more sensitively and specifically than the other two
transferrin, do not distinguish them from patients with constitu- parameters, IGF-I was a better predictor of mortality. Such pro-
tional short stature. This is because these patients have adapted gnostic value is useful as it indicates to the clinician the need for
to reduced nutritional intake to conserve energy. They have a cautious caloric delivery. Aside from IGF-I, there is potential for
reduced BMR due to reduced Na + /K + -ATPase activity [135], other markers of the IGF system, or composite indices thereof,
reduced protein synthesis, which accounts for 10–15 % of the to assist in prediction of refeeding risk. The reported effects of
BMR, and a reduction in body temperature [136]. The essential under-nutrition and obesity on the levels of IGF axis components
needs of metabolism are still met, but with less energy available other than IGF-I are shown in Table 3. Proposed clinical utility
for growth. of IGF-I measurement in endocrine and nutritional contexts is
summarized in Table 4.
SBS (short bowel syndrome)
IGF-I measurement has been used in the context of research stud- Obesity
ies to monitor PN where changes in its concentrations have been Studies on the effects of obesity on the IGF system have ob-
observed to correlate with changes in protein metabolism [137]. served changes, but these are less consistent than in malnutri-
It has also been studied in children with SBS receiving PN. Levels tion. There is considerable overlap in serum IGF-I concentrations
improved in line with nitrogen balance, suggesting that it may be between obese and lean subjects. When assessed in large popu-
of value, along with other measurements, in assessing protein nu- lation groups, total concentrations follow an inverted U-shaped
tritional status of these children [138]. Not all children with SBS distribution curve, maximal at a BMI of 30–35 kg/m2 , although
respond equally to standard nutritional support, and it is import- the changes are relatively small [152]. Obesity is associated with
ant to identify those who may respond poorly. There is evidence hyposecretion of GH, the mechanistic basis of which is incom-
supporting IGF-I measurement as an index of IF in children with pletely understood [153]. Its reversibility upon weight reduction

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Table 3 Effect of malnutrition and obesity on serum concentrations of other proteins of the IGF axis
Key: ↑, increase; ↓, decrease; U, unchanged.

Protein Malnutrition Reference(s) Obesity Reference(s)

IGF-II ↓ [116,122] ↑ [105–107,115,145,146]
Free IGF-I ↓ [57,147] U/↑/↓ [66,68,92–94]
Free IGF-II ↓ [146] ↑ [146]
IGFBP-1 ↑ [147] ↓ [148,149]
IGFBP-2 ↑ [122] ↓ [58,150]
IGFBP-3 ↓ [130,132] ↑ [151]

Table 4 Proposed clinical utility for measurement of serum has been suggested that dysregulation of the IGF system plays a
IGF-I major role in this link [158]. Research in this area will continue to
seek the underlying mechanisms, but it remains to be established
Feature Reference
whether measurement of IGF-I is of clinical value in predicting
Endocrinology
or monitoring mortality risk.
Diagnosis and monitoring of acromegaly [114]
Diagnosis of GH deficiency [114] The metabolic syndrome
Monitoring of recombinant GH treatment [141] Numerous studies have observed an inverse relationship between
Clinical nutrition IGF-I and CRP concentrations in subjects with the metabolic syn-
Indicator of short-term change in nutritional status [98] drome [159–161]. The number of metabolic syndrome features
Assessment of nutritional status of premature [129] increase with declining IGF-I and increasing CRP. A population-
infants based study on elderly subjects observed that this inverse as-
Monitoring of PN and nitrogen balance [138] sociation between IGF-I and inflammatory markers persisted in
Index of IF in children with SBS [139] individuals with hsCRP (highly sensitive CRP) below 3.0 mg/l,
Prediction of intestinal transplant patients [140] i.e. within the population reference range [162]. The population-
requiring intensive nutritional intervention
based CARDIA (Coronary Artery Risk Development in Young
post-transplant
Adults) male hormone study investigating healthy young black
Prediction of refeeding risk and mortality [144]
males and white males observed a correlation between the two
Prediction of survival in critical illness [83]
variables which was confined to black male smokers [163]. The
causal nature of the association was unclear, but the elevated
CRP is indicative of chronic subclinical inflammation which,
along with insulin resistance, is implicated in atherogenesis. Both
suggests that it is an adaptive change to excess energy provision
factors are related to CHD (coronary heart disease) risk which
favouring energy storage.
may have implications for preventative strategies. There are ex-
Various studies have investigated the effect of therapeutic in-
tensive data from studies to demonstrate that IGF-I is a metabolic
terventions on IGF-I concentrations in obesity. These have fairly
biomarker associated with health outcomes [164]. A study of
consistently observed a reduction in concentrations in response
846 healthy young men provided outcomes and IGF-I data [165].
to various approaches, namely caloric restriction [107], physical
IGF-I was positively associated with improved aerobic fitness
activity [154], combinations of dietary restriction and exercise
and muscular endurance in these subjects. IGF-I may have utility
training [155], and gastric banding [156]. In the case of dietary
in assessing cardiovascular risk associated with metabolic syn-
restriction, the duration and extent of the calorie restriction ap-
drome, but it is not clear at present what value it would provide
pear to be important. In obese subjects subjected to short-term
over existing approaches.
calorie restriction, serum IGF-I fell less readily than in subjects of
normal weight, particularly where protein intake was sufficient.
During 3 weeks on a low-energy diet (445 kcal; 1 kcal = 4.184
kJ), but with adequate protein (50 g), total serum IGF-I did not FREE IGF-I
change in obese subjects [157]. This and other studies suggest
that, in obesity, the maintenance of serum IGF-I concentrations is Total serum IGF-I suffers from the drawback that its concentra-
less dependent upon energy intake, providing that protein intake tion does not necessarily reflect IGF-I bioactivity. Consequently,
is adequate. Presumably this is because these subjects are able to interest has increased in measurement of free IGF-I as a biolo-
utilize energy stores to maintain hepatic protein synthesis. gically and potentially more clinically relevant parameter. Since
Although the research findings in obesity are interesting, 1994, assays have been available for free IGF-I enabling it to
measurement of IGF-I in this context does not currently appear be studied in clinical context [166]. It is usually estimated by
to be of value in guiding clinical management. There is an in- measurement of IGF-I immunoreactivity following extraction of
creasing interest in the link between obesity and cancer, and it IGFBPs, which is a technically simple method. When measured

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in malnourished patients, free IGF-I concentrations have been relationship with a number of metabolic syndrome features in-
observed to fall in common with total IGF-I [147,167]. It has cluding fasting blood glucose levels and insulin resistance [173].
been reported to be more sensitive than total IGF-I as a marker Measurement of IGF-I bioactivity may therefore have a place
of short-term nutritional status [57]. In a study on healthy fit in cardiovascular risk assessment in those with features of the
young men exposed to 8 days of energy deficit, the authors re- metabolic syndrome.
ported that concentrations of all ternary complex components Although it is an attractive research tool, many questions sur-
followed the loss in body mass more closely than transferrin or round free IGF-I as measured by KIRA. To date, it has only been
RBP [148]. Free IGF-I measured by immunoradiometric assay in applied to serum IGF-I which is predominantly liver-derived. It
this study was more closely associated with changes in LBM than does not therefore take into account the IGF-I produced and act-
the other IGF system parameters. The authors concluded that free ing locally at the tissue level. A disadvantage of the method, as it
IGF-I along with other parameters of the system had utility in stands, is that it would be too demanding for clinical laboratories.
assessing the severity of an energy deficit and changes in body Simple and inexpensive methods are preferred for clinical pur-
composition. In studies on obese subjects, free IGF-1 concen- poses. Clinical guidelines are unlikely to advocate measurement
trations have been reported as normal [105], high [106,145,146] of free IGF-I until more information is available.
or low [115], although most suggest high concentrations. An in-
crease in free IGF-I may be explained by decreases in levels of
IGFBP-1 and -2 which have been described in obesity as a con-
sequence of chronic hyperinsulinaemia [168,169]. However, this FACTORS INFLUENCING IGF-I
elevation of free IGF-I may be confined to non-diabetic subjects INTERPRETATION
because obese Type 2 diabetic subjects had free IGF-I concentra-
tions which were not significantly elevated compared with lean Confounding factors
controls. Subjects with Type 1 diabetes had a marked reduction It is worthwhile considering the characteristics of the ideal nu-
(>50 %) in free IGF-I [106]. tritional biomarker which would be unaffected by limitations
Different assay methods for free IGF-I yield different results. (Box 1). Although there is no ideal biomarker currently avail-
Consequently, there has been a debate over how best to meas- able, this list should be kept in mind when considering the merits
ure it. Although results obtained by immunoreactivity are valid of novel markers. IGF-I meets the first four criteria but, in com-
in many cases, they may not closely reflect IGF-I bioactivity in mon with other biomarker proteins in current use, suffers from
all conditions [57]. In addition, immunoreactivity does not take the limitation that factors other than nutritional status influence
into account the effects of IGFBPs or their proteases on the in- its serum concentration [174]. The influence of these factors may
teraction of IGF-I with receptor. A novel KIRA (kinase receptor not be possible to separate from that of malnutrition. These are
activation assay) has been described which measures the ability discussed below.
of serum to activate IGF-1R autophosphorylation [170]. It can As discussed above, hepatic IGF-I expression is reduced in
be argued that KIRA provides the most relevant measurement acute illness due to the influence of cytokines. This causes serum
available as it measures IGF-I available to its receptor and so IGF-I, in common with the concentrations of other biomark-
accounts for the effects of IGFBPs and proteases. Age-specific ers, to fall during the APR regardless of the nutritional state
normal values for IGF-I bioactivity as measured by KIRA have [71,72,175,176]. Inevitably, this is most problematic in hospital-
been reported which show it to decline with age as for total IGF-I ized patients who are acutely ill. The serum IGF-I concentration
[171]. In order to assess the nutritional information provided by correlates strongly with negative nitrogen balance in these pa-
bioactivity, a study was carried out comparing RTK activation to tients [177]. In subjects with malignancy who have an active sys-
total IGF-I in patients with anorexia nervosa [147]. Both para- temic inflammatory response, IGF-I is limited as a marker of nu-
meters were significantly reduced and closely related, suggesting tritional status [174]. Where there is acute inflammation, methods
that total IGF-I may be considered a surrogate marker for IGF-I detecting changes in body composition, performance or physical
bioactivity in these patients at least. In a study on malnutrition activity may be better options for evaluating nutritional support.
in patients receiving continuous ambulatory peritoneal dialysis,
IGF-I bioactivity measured by KIRA was associated with changes
in nutrient intake [172]. The findings suggested that IGF-I bio- Box 1 Features of the ideal protein-energy marker
activity, rather than total IGF-I, is involved in acute responses 1. Short biological half-life
to nutritional interventions. IGF-I bioactivity may therefore be a 2. Exists primarily within an accessible body fluid
more sensitive index than total IGF-I to acute nutritional inter-
3. Limited homoeostatic regulation
ventions in these patients. It remains to be established whether
these findings apply to other malnourished states. 4. Prognostic value for outcome
IGF-I bioactivity may also yield prognostic information about 5. Uninfluenced by vitamin or mineral status
survival. Elderly individuals with the highest activity were repor- 6. Constant rate of catabolism
ted to survive longer than those with lower activity. High bioactive
7. Uninfluenced by pathology other than malnutrition
IGF-I appears to be associated with lower CHD risk and cardi-
ovascular mortality [93]. A more recent study by the same group 8. Measurement is simple, cheap and available locally
observed that IGF-I bioactivity followed an inverted U-shaped

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In this situation, systemic inflammation is inversely correlated also measured liver function tests and thyroid function tests in an
with survival. Systemic inflammation is best assessed by meas- effort to exclude confounding factors [178].
urement of CRP. Rather than considering IGF-I as a nutritional
marker, it can be considered primarily a marker of short-term Variation
changes in hepatic protein synthesis on which both nutritional BV (biological variation) of analyte concentrations encompasses
status and the APR have an impact. From this perspective, the intra-individual and inter-individual variation. Data on BV en-
APR is not a confounding factor in IGF-I interpretation, but a able derivation of reference ranges and data of use in interpreting
principal determinant of concentrations. Effectively, IGF-I, like serial results. As is the case for other hormones, normal values for
albumin, can be considered a negative acute-phase marker and IGF-I vary significantly between individuals. Reported values
may have value as such. for inter-individual variation of IGF-I range from 27.0 to 45.4 %
The IGF-I concentration is also lowered in disease of the liver, [179]. This largely reflects the genetic factors influencing the
its main site of synthesis [110], and can be normal or lowered in physiological set-point across the population. Consequently,
renal disease due to changes in IGFBP concentrations [111,112] the population reference ranges for IGF-I are relatively wide com-
(see also Table 2). IGF-I concentrations have been reported to pared with intra-individual variation [88]. Another consequence
be low in patients with untreated severe hypothyroidism, reflect- of the large inter-individual variation is that it may be unclear
ing the regulatory influence of thyroxine on IGF-I [113]. These what should be considered the target value indicative of recovery
increased significantly following thyroxine replacement. It may in an individual. A value towards the lower end of the reference
therefore be advisable to assess thyroid function when interpret- range, for example, may be normal for one individual, but not for
ing IGF-I concentrations. In patients with NGR due to chronic another. Given that intra-individual variation is relatively small
energy deficit, adaptations enable homoeostasis to be maintained around the physiological set-point, a pre-morbid value for the
and so IGF-I concentrations tend not to be deranged as in overt individual, if available, could be used as the target. In the absence
malnutrition [135]. Until more sensitive biochemical tests are of a pre-morbid value, an alternative approach may be to observe
available, the detection of NGR requires careful serial weight the fold response over the baseline concentration, as it has been
monitoring. suggested that relative changes in IGF-I may be more useful than
IGF-I also has limitations as a marker of malnutrition in absolute values [98]. In monitoring nutritional rehabilitation of
obese subjects. A common scenario encountered in hospitals chronically malnourished patients, a 2.6-fold increase in serum
is an obese patient who has lost weight due to chronic illness IGF-I concentrations was observed compared with much smaller
or post-operatively. In this situation, it is important that nutri- increases in transferrin [66]. This change correlated with changes
tional needs are fully met in order to hasten recovery, e.g. by in nitrogen balance. It may therefore be useful to know that the
promoting wound healing. Under-provision of nutrition support concentration is improving from baseline.
will favour catabolism. In this context, it should be borne in When interpreting apparent changes in consecutive results,
mind that serum IGF-I concentrations do not fall readily in en- the clinician needs to know whether these are of sufficient mag-
ergy restriction where protein intake has been maintained [157]. nitude to represent a real change or are small enough to be ac-
Pregnancy can also be considered a confounding factor as IGF-I counted for by sources of variation. This principle is of relevance
concentrations rise as pregnancy progresses, particularly in the to IGF-I as its concentrations are likely to be interpreted in serial
third trimester. However, this does not necessarily preclude it as samples. Data on intra-individual variation have clinical utility
a nutritional biomarker in this situation. In malnourished preg- in assessing the significance of differences between consecutive
nant women, IGF-I concentrations correlate with the degree of results obtained from an individual [180]. It can be described
negative nitrogen balance, suggesting that it may be of use as a by the CVi (coefficient of variation) (S.D./mean expressed as a
biomarker of under-nutrition in pregnancy [97]. percentage) derived from measurements at intervals. In a recent
As with older biomarkers, the many confounding factors in- small study on healthy subjects, the CVi for IGF-I was reported to
fluencing IGF-I concentrations in hospital patients result in too be low at 9.4 % [179]. From these data, the authors calculated that
low a specificity for it to be suitable as a screening test. Biochem- a change of 8.4 nmol/l between two samples had a 95 % chance
ical tests appear unlikely to replace nutritional screening tools in of being significant. A study on pre-pubertal children reported a
the foreseeable future. Clearly when used in monitoring, IGF-I CVi of 13.9 % [181]. This higher value may reflect the sensitiv-
concentrations should be interpreted in a clinical context, tak- ity of the IGF-I concentration to short-term change in LBM in
ing the disease state into account. This includes seeking features growing children [58].
suggesting recovery and anabolism, namely weight restoration, The problem with carrying out such studies on normal volun-
recovery of appetite, reduction in oedema, mobilization and gen- teers is that variation, particularly for hormone concentrations,
eral clinical recovery. Biochemically, there may be fall in CRP may be higher in subjects who are unwell [182]. Changes in con-
concentrations and a rise in concentrations of albumin and other centrations of the analyte sufficient to represent real changes un-
biomarkers. In view of the limitations discussed, IGF-I may find der physiological circumstances may not represent real changes in
greater use in out-patients or in hospitalized patients who are patients who are clinically unwell. Ideally, intra-individual vari-
relatively well, particularly when used serially to assess the ad- ation of IGF-I should therefore be studied in subjects with the
equacy of the regimen. There may be value in concurrent meas- relevant clinical condition. There is a need for studies to assess
urement of inflammatory markers, such as CRP, in an effort to intra-individual variation for IGF-I in malnourished and hospital-
exclude inflammatory disease. Authors of research studies have ized patients. As a biomarker, IGF-I has the advantage that there

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IGF-I and clinical nutrition

is minimal circadian alteration in its levels throughout the day. A end, be considered in the context of other clinical findings and
specimen taken at any time of day is therefore a valid measure the results of other laboratory investigations.
of its status [62]. It should be noted that, although analytical im-
precision is a source of variation, its contribution in practice is ACKNOWLEDGEMENTS
sufficiently small to be ignored, provided that assay performance I thank Anh Duong and Nigel Barnes for assistance with graphics.
is satisfactory. IGF-I concentrations are also influenced by the
assay used [183]. It is therefore preferable to use assay-specific
reference data in any given situation. During research on IGF-
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Received 18 December 2012/5 March 2013; accepted 12 March 2013

Published on the Internet 22 May 2013, doi: 10.1042/CS20120663

280 
C The Authors Journal compilation 
C 2013 Biochemical Society