Archives of Physiology and Biochemistry, February 2008; 114(1): 17 22

REVIEW ARTICLE

Similarities and differences between insulin and IGF-I: Structures,

receptors, and signalling pathways

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HAIM WERNER, DORON WEINSTEIN, & ITAY BENTOV

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv
69978, Israel

Abstract
Insulin and the insulin-like growth factors (IGF-I, IGF-II) are pleiotropic hormones that have multiple roles in regulating
vital metabolic and developmental processes. Although most early data suggested that insulin is mainly involved in metabolic
activities (e.g. control of sugar levels) and IGF-I/II control growth and differentiation events (e.g. bone elongation, cell
division), today, it is clear that there is cross-talk between the various ligands and receptors of the IGF family. As a result of
these complex interactions, the spectrum of activities that were classically assigned to insulin or IGF-I/II has greatly
expanded, and the signalling events mediated by the insulin and IGF receptors is the subject of intensive research. This
review provides a comparative analysis of the structures, receptors, and signalling pathways of insulin and IGF-I.

Key words: Insulin, insulin-like growth factor (IGF), insulin receptor, signalling.

Introduction
Accurate control of the processes of cellular growth
and differentiation is a fundamental requisite that
ensures that the organism will properly develop and
function. The wealth of information that has
accumulated over the past several years on the
insulin and insulin-like growth factors (IGFs) provides a unique paradigm of a composite family of
hormones, cell-surface receptors, extra-cellular binding proteins (IGFBPs), and additional accessory
components that, in a remarkably orchestrated
manner, regulate multiple biological processes
(LeRoith et al., 2001; Rosenfeld, 2005; Werner &
LeRoith, 2000). Most clinical and experimental data
collected since the discovery of the IGFs in the mid1950s suggested a division of labour among
insulin, IGF ligands, and receptors. This compartmentalization of functions provided the foundation
for the classical dogma that prevailed for many years
in the field, which attributed a primarily metabolic
role to the insulin receptor (IR) pathway and a
mitogenic/proliferative role to the IGF-I receptor
(IGF-IR) pathway. However, new information generated in recent years has clearly demonstrated that
many of these old concepts, although correct
regarding their basic assumptions, are essentially

oversimplifications of much more complex situations

(Bentov & Werner, 2004; Yakar et al., 2005). As a
result, there is an urgent need to revise deep-rooted
notions and ideas in order to be able to coherently
and rationally describe the metabolic and growth
processes associated with the insulin/IGF family. The
purpose of this review is to analyse in a comparative
manner the physiological and pathological roles of
some of the members of the insulin/IGF family, in
particular, ligands and receptors.
The insulin-like ligands
The insulin-like ligands comprise at least nine
different genes: two non-allelic insulin genes (in
rodents), igf-1, igf-2, relaxin, and four insulin-like
peptides (ins-3 to -6) (Nakae et al., 2001). The
physiological roles of the non-classical ligands are,
obviously, less well characterized than those of
insulin, IGF-I, and IGF-II. The biological spectrum
of ligand activities is dictated by a number of
parameters, including their affinities for the specific
receptors, their sites of synthesis [Are they produced by one single organ, e.g. insulin, or by
multiple tissues, e.g. the IGFs?], their affinities for
the IGFBPs [Do they circulate bound to carrier
proteins, e.g. the IGFs, or unligated, e.g. insulin?]

Correspondence: Haim Werner. Tel: 972-3-640-8542. Fax: 972-3-640-6087. E-mail: hwerner@post.tau.ac.il

Received for publication 6 November 2007. Accepted 8 January 2008.
ISSN 1381-3455 print/ISSN 1744-4160 online 2008 Informa UK Ltd.
DOI: 10.1080/13813450801900694

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18

H. Werner et al.

and, finally, the signalling events elicited following

activation of the receptor.
The original somatomedin hypothesis, formulated in the late 1950s, following the identification of
somatomedin by Salmon and Daughaday (1957),
proposed that growth hormone (GH) governs somatic growth by stimulating hepatic production of
IGF-I. This hypothesis was modified in the 1980s to
incorporate the discovery that IGF-I was, in fact,
produced by most body tissues (in addition to the
liver) and, consequently, may exert both endocrine
and autocrine/paracrine types of activities. This
revised version of the hypothesis also embraced the
notion that IGF actions were modulated by the
IGFBPs, which control the fraction of free,
bioavailable IGF-I. In 1999 the publication of the
phenotype of animals with a liver-specific IGF-I gene
disruption, by Yakar et al. (LeRoith et al., 2001;
Yakar et al., 1999), led to a further revision of the
somatomedin hypothesis. Specifically, the observation that a drastic reduction in serum IGF-I levels
did not result in a growth deficit indicated that locally
produced IGF-I, rather than hepatic IGF-I, is the
critical determinant of growth and development.
Alternatively, the contemporary interpretation of the
somatomedin hypothesis is compatible with the
possibility that levels of free IGF-I are sufficient to
maintain their growth-promoting activities despite a
large reduction in total IGF-I levels.
The structural and functional similarities between
insulin and IGF-I suggest that both molecules are
derived from a common ancestral precursor that
probably participated in food intake and regulation of
cellular growth (Alarcon et al., 1998; Rinderknecht &
Humbel, 1978). A divergence of functions most
likely occurred before the appearance of the first
vertebrates, with insulin mostly active in the regulation of metabolism and IGF-I in growth processes.
However, in view of their common evolutionary
origins and semi-conserved architecture, there is a
certain degree of cross-talk between insulin, IGF-I,
and their receptors (Werner et al., 1991). Accordingly, insulin exhibits a number of IGF-I-like
activities, including growth stimulation, whereas
IGF-I, on the other hand, exerts several metabolic
effects. In addition, the fact that IGF-I, but not
insulin, is carried in the circulation and extracellular
fluid by IGFBPs further contributes to the divergent
actions of the ligands.
An additional parameter that contributes to the
divergent biological activities of the insulin-like
peptides is the developmental stage. Ontogenetic
analyses in rodents have revealed low IGF-I levels
and high IGF-II levels during the prenatal period,
whereas postnatal stages are characterized by an
increase in circulating IGF-I and the disappearance
of IGF-II. These observations might have led to an
erroneous generalized interpretation of the roles of
IGF-II and IGF-I as foetal and pubertal growth
factors, respectively. In humans, however, this

expression pattern does not exist and both ligands

are produced from the prenatal to the postnatal
periods. In fact, in normal healthy adults circulating
IGF-II levels are higher than IGF-I levels (Bentov &
Werner, 2004).
The insulin-like receptors
The classical insulin-like receptors comprise the IR,
IGF-IR, and IGF-IIR family (Ebina et al., 1985;
Ullrich et al., 1985; Ullrich et al., 1986). An
additional receptor molecule is the insulin receptorrelated receptor (IRR), although the specific ligand
involved in IRR binding and activation has not yet
been identified (Klammt et al., 2005; Shier & Watt,
1989). IR, IGF-IR, and IRR are members of the
ligand-activated receptor kinase superfamily. Upon
ligand activation, the receptors undergo a conformational change that leads to ATP binding and
autophosphorylation of the tyrosine kinase domain.
This event, in turn, enhances the kinase activity of
the receptors and confers upon them the ability to
phosphorylate a series of cytoplasmic substrates,
collectively referred to as downstream signal transduction mediators. Most available evidence is
consistent with the view that both IGF-I and IGFII activate the ubiquitously expressed IGF-IR with
relatively similar affinities (see below).
The IGF-IR, like the IR, is synthesized as a single
polypeptide chain that is processed to yield a
glycopeptide of Mr 180 kDa (Jacobs et al., 1983;
Werner et al., 1991). Precursor chains include at
their N-terminal domain a signal peptide rich in
polar residues, which is involved in the transfer of
the nascent protein into the endoplasmic reticulum.
Partially processed proreceptors form disulfidelinked dimers that are subsequently glycosylated
and proteolytically cleaved at a basic tetrapeptide
sequence (Arg-Lys-Arg-Arg) to yield mature a and
b subunits. The mature heterotetramers have a b
a a b conformation. Structurally, the a subunits
of the mature receptors reside entirely extracellularly and include a cysteine-rich region and several
potential N-linked glycosylation sites (Asn-X-Ser/
Thr motifs). The cysteine-rich domain of the IGFIR is important for high-affinity IGF-I binding,
unlike the IR in which regions N- and C-terminal to
this domain are critical for insulin binding (Kjeldsen
et al., 1991). Interestingly, the b subunit features a
unique hydrophobic sequence that constitutes the
transmembrane domain. The juxtamembrane domain contains an Asn-Pro-X-Tyr motif that is
important for receptor internalization and biological
functioning of both IR and IGF-IR. Finally, the
cytoplasmic portions of the b subunits contain a
tyrosine kinase enzymatic domain. Inside this
catalytic region, there is a glycine-rich conserved
element (Gly-X-Gly-X-X-Gly) that participates in
the transfer of the phosphate moiety of ATP to
specific substrates.

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Similarities and differences between insulin and IGF-I

Molecular cloning of the IGF-IIR revealed that a
single cell-surface receptor is able to bind both
mannose 6-phosphate (M6P)-containing moieties
and IGF-II molecules (Morgan et al., 1987). The
IGF-II/M6P-R is a monomeric receptor with a large
extracellular domain composed of 15 repeat sequences and a small region homologous to the
collagen-binding domain of fibronectin. The IGFII/M6P-R targets IGF-II for lysosomal degradation
and thus reduces the bioavailability of circulating
IGF-II. Diminished levels of IGF-II lead to depressed activation of the IGF-IR. In accordance with
these findings, the IGF-II/M6P-R has been defined
as a tumour suppressor gene product (Leboulleux
et al., 2001). Consistent with this definition,
several neoplasms feature a mutated or deleted
IGF-II/M6P-R.
Genomic and structural comparisons between
IR and IGF-IR
There is a striking similarity in the genomic
organization of the IR and IGF-IR (Table I) (Abbott
et al., 1992; Seino et al., 1989). Twelve exons (out of
21) of the IGF-IR gene are identical in size with the
homologous exons of the IR. Furthermore, with the
exception of the first and last exons, differences in
size between the remaining homologous exons do not
exceed 15 nucleotides. As expected from their
conserved gene arrangements, the primary structures
of the IR and IGF-IR proteins also share a high
degree of similarity. For example, the length of the IR
precursor is 1370 amino acids (including a 27-amino
acid signal peptide), compared with 1367 amino
acids (including a 30-amino acid leader peptide) for
the IGF-IR. The highest similarity (84%) between
both molecules is found in the tyrosine kinase
domain of the b subunit (Table II). Relatively high
resemblance (64% 67%) is also found between the
extracellular a subunit regions flanking the cysteinerich domains. The cysteine-rich domains themselves
exhibit 48% homology, despite conservation in the
Table I. Structural comparison of insulin and IGF-I receptors.

Precursor size
Signal peptide size
Predicted Mr of
precursor
Predicted Mr of
a-subunit
Predicted Mr of
b-subunit
Location of Arg-LysArg-Arg sequence
(cleavage site)
a-subunit size
b-subunit size
Transmembrane
domain

Insulin receptor

IGF-I receptor

1370 amino acids

27 amino acids
152,000

1367 amino acids

30 amino acids
151,869

82,400

80,423

69,700

70,866

At position 720

At position 707

719 amino acids

620 amino acids
Residues 915
(or 918) 940

706 amino acids

627 amino acids
Residues 906 929

IGF-IR of 24 out of 26 cysteines that are present in

the IR. In addition, 15 out of 16 putative N-linked
glycosylation sites (Asn-X-Thr/Ser) in the extracellular region of the IGF-IR are located at almost
identical positions in the IR. The lowest amino acid
identity (27%) is found in exon 14 of the IGF-IR,
which contains sequences encoding the membranespanning domain. Taken together, the impressive
similarity in overall structure between these two
genes is consistent with the notion that both receptor
genes share a common evolutionary origin.
However, despite a remarkable similarity between
the receptors, each ligand exhibits high-affinity
binding to its cognate receptor (Bayne et al., 1989;
Rechler et al., 1980; Tollefsen & Thompson, 1988).
Scatchard analysis of IGF-I and IGF-II binding to
the IGF-IR generates a linear plot, suggesting a
single class of receptors with an affinity of *10710
M. Insulin binds to the IGF-IR with lower affinity
(1078 M). On the other hand, IR yields curvilinear
plots that typically suggest the presence of high
(*10710 M) and low affinity binding sites. IGF-II
binds the IR with an affinity 10- to 50-fold lower than
that of insulin, and IGF-I with an affinity 100- to
500-fold lower. Interestingly, IGF-II can also signal
via IR-A, a particular isoform of the IR that is
generated by alternative splicing of the IR gene
(Denley et al., 2006; Frasca et al., 1999; Morrione
et al., 1997). In addition to their divergent affinities,
differences between IR and IGF-IR activities were
postulated to result from the different sets of downstream targets that are activated by each receptor (see
below). Furthermore, the pattern of expression of
each receptor may explain the preferential effects of
each ligand in particular organs and at specified
developmental stages. Thus, high levels of IR are
found in liver and adipose tissue, whereas IGF-IRs
are essentially absent in liver and present at low levels
in adipose tissue (Dupont & LeRoith, 2001).
Insulin-like growth factor binding proteins
The substantial majority of IGF peptides in the
circulation are not found in a free form, but rather in
a ternary complex that includes, in addition to the
IGF ligand, a liver-derived glycoprotein (the acidlabile subunit, ALS) and a high-affinity binding
protein, the IGF-binding protein 3 (IGFBP3). Six
IGFBPs (IGFBP1-6) and a number of IGFBPrelated proteins have been characterized to date

Table II. Homology between insulin and IGF-I receptors.

Receptor domain
b-subunit tyrosine kinase domain
a-subunit regions flanking the
cysteine-rich domain
a-subunit cysteine-rich domain
b-subunit transmembrane domain

Homology (%)
84
64 67
48
27

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H. Werner et al.

(Holly & Perks, 2006). IGFBP3, the predominant

IGFBP in serum, is the largest and, therefore, the
only one that cannot traverse the capillary membrane. The ternary complex among IGF-I, IGFBP3,
and ALS modulates IGF-I action by protecting the
growth factor from proteolysis and prolonging its half
live in the circulation (Baxter, 2000). In addition,
some IGFBPs exert their biological effects in an IGFindependent manner (Grill & Cohick, 2000). In
general, the IGFBPs inhibit IGFs metabolic and
proliferative actions, although some IGFBPs may
display IGF-potentiating effects as well. IGFBP3, in
particular, is recognized as an inhibitor of proliferation, driving the cell to apoptosis. Several potential
mechanisms were postulated to explain IGFBP-3
inhibition of IGF action, including sequestration of
IGF-I from the receptor and binding competition
with the IGF-IR. As alluded to above, the fact that
the biological actions of insulin are not affected by
circulating or extracellular IGF-BPs is one of the key
aspects that demarcate the spectrum of actions of
insulin compared with those of IGF-I.

In addition, and in agreement with its well-documented cell survival role, the initial proliferative
switch in oncogene-induced transformation was
correlated with focal activation of IGF-II (Christofori
et al., 1994). Transfection with an anti-sense
oligonucleotide to the IGF-II mRNA interfered with
tumour cell proliferation in vitro, and transgenic mice
homozygous for a disruption of the IGF-II gene
developed tumours with reduced malignancy. Combined, these results suggest that, in addition to the
oncoprotein, IGF-II signalling is necessary to elicit
hyperproliferation.
Finally, it was demonstrated that IGF-IR protects
cells from apoptotic death in multiple cultured cells
as well as in vivo (Resnicoff et al., 1995; Sell et al.,
1995). A highly significant positive correlation was
found between cell survival and the number of cellsurface IGF-IRs. Furthermore, elevated levels of
cell-surface IGF-IR allowed cells to switch from a
nonmitogenic to a mitogenic mode, whereas
above a certain threshold value, cells acquired the
ability to grow in soft agar (Rubini et al., 1997).

Biological actions of IGF-I and IGF-II

Signalling pathways: similarities and

differences

At the cellular level, IGF-I stimulates a mitogenic

response and inhibits cell death in a wide variety of
cell types, including primary cultures and cancer cell
lines (Macaulay, 1992). Quiescent cells in G0 can be
induced to enter G1 by competence factors (e.g.
PDGF, bFGF). Once the cell enters into G1, subphysiological doses of IGF-I will allow it to evade
arrest in G1 and to progress through the cell cycle
(Lu & Campisi, 1992). Thus, IGF-I functions as a
progression factor (Moschos & Mantzoros, 2002).
IGF-I can also induce differentiation and this activity
can be blocked by specific anti-sense oligonucleotides (Florini & Ewton, 1990). IGF-I exhibits a
variety of cellular functions, including regulation of
hormone synthesis and secretion, chemoattractant
migration, immune cell recognition, and neuromodulation (Bentov & Werner, 2006). Metabolic effects
of IGF-I include elevation of glucose uptake and
hypoglycemia, without lowering free fatty acid levels.
In addition, IGF-I was shown to improve renal
function by increasing renal blood flow and the
glomerular filtration rate (Guler et al., 1987).
IGF-II is a bifunctional ligand that can stimulate
both IR and IGF-IR signalling, although with
different potencies (Nakae et al., 2001). Recent
studies have identified IGF-II as a key regulator of
pluripotent human embryonic stem cells (Bendall
et al., 2007). Specifically, IGF-II, but not IGF-I, was
shown to play a direct, supportive role in embryonic
stem cells. IGF-II and IGF-IR transcripts were
shown to be expressed in both human and mouse
blastocysts, and IGF-IR-mediated signalling was
required for survival of the mouse inner cell mass.
These studies demonstrate a direct role of the IGFII/IGF-IR axis on embryonic stem cell physiology.

As mentioned above, ligand binding to the extracellular domains of IR or IGF-IR leads to autophosphorylation of the receptors on tyrosine residues.
These phosphotyrosines are docking sites for SH2
domain-containing substrates, including the insulin
receptor substrate (IRS)1-4, Shc, and others. These
substrates, in turn, undergo phosphorylation, leading
to activation of the PI3K-Akt/PKB and Ras-RafMAPK pathways. Interestingly, the vast majority of
the components of these pathways are shared by both
receptors, raising the question how IR and IGF-IR
succeed in engaging in basically different biological
activities (Dupont & LeRoith, 2001; LeRoith et al.,
1995). A number of potential mechanisms were
postulated to explain this paradox, including a
different tissue distribution of IR and IGF-IR
(Werner et al., 1991), different internalization kinetics and sub-cellular distribution of the hormonereceptor complex (Zapf et al., 1994), as well as
different hormone-receptor affinities (Mastick et al.,
1998) (Table III). In addition, various substrates and

Table III. Potential mechanisms responsible for IR and IGF-IR

differential activation.
Differences in cellular expression of IR and IGF-IR
(predominant IR expression in liver and adipose tissue).
Differences in internalization and subcellular distribution of the
ligand-receptor complex following receptor activation on the
cell surface.
Differences in ligand-receptor affinities.
Differences in substrate specificities and signalling potentials.
Preferential activation of specific substrates by insulin or IGF-I.
Preferential binding of IGF-BPs to IGFs but not to insulin.

Similarities and differences between insulin and IGF-I

signalling mediators that are preferentially activated
by insulin or IGF-I have been identified. For
example, the adapter protein Grb10 associates
mainly with IR but not with IGF-IR (Laviola et al.,
1997). Similarly, the IR, but not the IGF-IR,
interacts with pp120 (Najjar et al., 1997). Differential
activation of these and other substrates may partially
explain the receptor specificity.

21

essential information remains to be elucidated,

including the factors responsible for the specific
activities of the insulin and IGF signalling pathways,
and the distinct roles each pathway plays in cancer.
Understanding the basis of these events at the
molecular, cellular and organism levels will be of
significant basic and clinical relevance.
Acknowledgement

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Lessons from animal models

The essential role played by the IGF system in
growth and development was demonstrated by the
growth deficits observed in mice in which various
components of the IGF system were disrupted by
homologous recombination (Baker et al., 1993).
Targeted disruption of the IGF-II gene resulted in
mice weighing 60% of their normal littermates at
the time of birth (DeChiara et al., 1990). However,
the reduction in growth rate was restricted to the
embryonic period and the animals developed into
essentially normal and proportionate fertile dwarfs.
The phenotype of null mutants for the IGF-I gene is
more complex and depends on the genetic background of the animals. Thus, some of these mice
died shortly after birth, whereas others survived and
reached adulthood (Liu et al., 1993). Surviving IGFI-null mice manifested, among other abnormalities, a
delay in the ossification process, underdeveloped
muscles and lungs, and infertility. Mice heterozygous
for a disrupted IGF-I gene exhibited no major
growth retardation (10 20% less than wild-type
littermates), whereas null homozygotes weighed
*40% less than wild types (Powell-Braxton et al.,
1993). Furthermore, null homozygotes had very high
perinatal mortality rates and a number of phenotypic
aberrations.
Homozygous IGF-IR knockout mice exhibited the
most severe developmental retardation. These animals, which invariably died at birth, weighed only
45% of normal controls and displayed hypoplasia,
abnormal skin formation, delayed bone development, and anomalous central nervous system morphology (Liu et al., 1993). Ablation of the IR gene
resulted in mice displaying no major developmental
delay at the time of birth (*90% of normal
littermates). These animals, however, died during
the first several days of postnatal life as a result of
diabetic ketoacidosis (Accili et al., 1996).
Summary
Over the past two decades new information has
accumulated about the physiological and pathological functions of the insulin/IGF system. These novel
data were generated using genetic tools (transgenic
and knockout animal models) as well as classical
biochemical, molecular, and endocrinological methods. In addition, valuable information was acquired
from the clinics. As outlined in this review, much

Work in the laboratory of H.W. is supported in part

by a grant from the Insulin Dependent Diabetes
Trust, United Kingdom.

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