S E M I N A R S I N M E D I C I N E O F T H E B ET H I S R A E L D E AC O N E S S M E D I CA L C E N T E R

Seminars in Medicine of the

Beth Israel Deaconess Medical Center

J E F F R E Y S. F L I E R , M . D. , Editor
L I S A H . U N D E R H I L L , Assistant Editor

I NSULIN - LIKE G ROWTH F ACTORS

DEREK LE ROITH, M.D., PH.D.

HE insulin-like growth factors (IGFs) participate in the growth and function of almost
every organ in the body.1 Because of the wide
range of their biologic effects and their therapeutic
potential in a variety of clinical disorders, the IGFs
have become the focus of research by an increasing
number of investigators.2-4 The object of this seminar is to review the clinical aspects of the IGFs, including their potential therapeutic value, and to discuss briefly their structure, synthesis, regulation, and
physiologic role.

BASIC BIOCHEMISTRY AND PHYSIOLOGIC

FUNCTIONS
Structure and Synthesis

The three peptide hormones, or growth factors, in

the IGF family insulin, IGF-I, and IGF-II have
approximately 50 percent of their amino acids in common. Insulin is synthesized in the beta cells of the
pancreas as proinsulin, which is cleaved to form insulin and C peptide. The IGFs, which are synthesized primarily by the liver, retain the C peptide and
have an extended carboxy terminus.1 Insulin circulates at picomolar concentrations and has a half-life
of minutes. The IGFs, on the other hand, circulate
at much higher (nanomolar) concentrations and are
largely bound to one of six IGF-binding proteins
that modulate IGF activity.5 These binding proteins,
like the IGFs, are synthesized primarily in the liver.
IGFs and their binding proteins are also produced
locally by most tissues, where they act in an autocrine or paracrine manner.

From the Diabetes Branch, National Institutes of Health, Rm. 85235A,

Bldg. 10, Bethesda, MD 20892-1770, where reprint requests should be
addressed to Dr. Le Roith.
1997, Massachusetts Medical Society.

Physiologic Role and Mechanism of Action

Insulin acts primarily on the liver, muscle, and adipose tissue,6 whereas the IGFs are important in the
function of almost every organ in the body.1,7 Both
of the IGFs are essential to embryonic development,8
and nanomolar concentrations of both are maintained in the circulation into adult life. After birth,
however, IGF-I appears to have the predominant role
in regulating growth, whereas the physiologic role of
IGF-II is unknown.
Insulin, IGF-I, and IGF-II bind specifically to two
high-affinity membrane-associated receptors that are
tyrosine kinases. Insulin activates the insulin receptor, and both IGFs activate the IGF-I receptor (Fig.
1).9 (A third receptor, the IGF-II-mannose-6-phosphate receptor, binds IGF-II but has no known intracellular signaling actions.) Activation of either the
insulin receptor or the IGF-I receptor evokes similar
initial responses within the cell.10 However, since insulin regulates metabolic functions and the IGFs
regulate growth and differentiated functions, the final pathways these hormones activate within the cell
must be separate and distinct.
Regulation and Differentiation of Function

The interaction of growth hormone with its hepatic receptor stimulates expression of the IGF-I
gene and the release of the IGF-I peptide (Fig. 2, lefthand panel).1 Serum concentrations of IGF-I usually parallel 24-hour mean serum concentrations of
growth hormone, and IGF-I inhibits the secretion of
growth hormone by the pituitary. How the liver regulates the synthesis of IGF-II is unknown.
The circulating IGF-binding proteins limit the access of the IGFs to specific tissues and to the receptors for IGF-I and insulin. Of the six binding proteins, IGF-binding protein 3 binds more than 95
percent of the IGF in serum. The IGFIGF-binding
protein-3 dimer forms a complex with another protein subunit, the acid-labile subunit, and in this ternary complex the IGFs have a serum half-life of many
hours. Once released from the complex, the IGFs
leave the circulation and enter target tissues with the
aid of other IGF-binding proteins. Growth hormone
increases the serum concentrations of both the acidlabile subunit and IGF-binding protein 3.5
Some IGF-binding proteins bind the growth factors with greater affinity than do the IGF receptors,
thereby preventing the activation of intracellular signaling pathways. The affinity of these binding proteins for the IGFs can be reduced by protease cleavage or increased phosphorylation of the binding
protein or by the binding of the protein to the surface
of cells rather than the extracellular matrix. The reduced affinity enhances the biologic activity of the
IGFs by increasing the amount of free growth factor
available to IGF-I receptors.5
The mechanisms of the metabolic effects of insuVo l u m e 3 3 6

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Insulin

IGF-I

IGF-II

Insulin receptor

Metabolic actions

IGF-I receptor

IGF-II-M-6-PR

Growth and differentiation

Figure 1. Binding of Circulating IGFs to Target Cells.

Three binding sites for the IGFs are expressed on the surface of target cells: the insulin receptor, the IGF-I receptor, and
the IGF-II-mannose-6-phosphate receptor (IGF-II-M-6-PR). Insulin and IGF-I receptors are structurally homologous
both are tyrosine kinases and interact with various intracellular mediators. The IGF-II-M-6-PR differs from the insulin
and IGF-I receptors in structure, and it has no known signaling action. Insulin binds to its own receptor and to the IGF-I
receptor. Both IGFs bind to the insulin receptor. The relative affinities of ligands for the various receptors and binding
proteins are indicated by the width of the arrows in the upper part of the diagram. Adapted with modifications from
Ruderman et al.,9 with the permission of the author and the publisher.

lin and the growth effects of the IGFs differ. Liver

and fat cells express only insulin receptors, whereas
muscle cells express both insulin and IGF-I receptors. Insulin controls hepatic glucose production
and lipolysis by signaling exclusively through insulin
receptors. Similarly, insulin-stimulated uptake of glucose into cells is mediated exclusively by insulin receptors. The actions of insulin and the IGFs are also
differentiated by the IGF-binding proteins, which
do not bind insulin but do direct the IGFs to their
specific receptors.
Tissue IGFs

Locally produced IGFs are important in the activity of several organ systems. Growth hormone, parathyroid hormone, and sex steroids regulate the pro634 

duction of IGF-I in bone, whereas sex steroids are

the main regulators of local production of IGF-I in
the reproductive system. The functions of circulating IGF-I are becoming clearer, but the actions of
locally produced IGFs have yet to be defined.
PATHOLOGIC CONDITIONS ASSOCIATED
WITH ALTERATIONS IN THE IGF SYSTEM
IGF-I

Many variables, such as age, sex, nutritional status,

and growth hormone secretion, affect serum IGF-I
concentrations. The concentrations are low at birth,
increase substantially during childhood and puberty,
and begin to decline in the third decade (Fig. 3).11,12
These changes parallel the secretion of growth hormone. In growth hormone deficiency the serum

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S E M I N A R S I N M E D I C I N E O F T H E B ET H I S R A E L D E AC O N E S S M E D I CA L C E N T E R

Normal GHIGF Axis

GH

GH Deficiency

GH Insensitivity Syndrome

GH

GH
IGF-I

IGF-I

IGF-I

IGF-I

IGF-I

IGF-I

Figure 2. The Circulating Growth HormoneIGF-I Axis in Health and Disease.

In normal subjects (left-hand panel), pituitary growth hormone (GH) interacts through specific growth hormone receptors on hepatocytes to increase transcription of the gene for IGF-I and IGF-binding protein 3 (not shown) and secretion of the mature polypeptide. IGF-I circulates in the blood bound to IGF-binding proteins (not shown) and interacts with specific receptors on target tissues,
such as bone, to stimulate longitudinal growth. IGF-I also acts on the pituitary to inhibit the secretion of growth hormone. In patients with growth hormone deficiency (middle panel), growth hormone secretion is low, causing low secretion of IGF-I with a
resultant decrease in the stimulation of target tissues. In patients with the growth hormone insensitivity syndrome (right-hand panel), mutated growth hormone receptors on the liver are unresponsive to growth hormone. Serum IGF-I concentrations are reduced,
causing decreased growth of responsive tissues. The inhibitory effects of IGF-I on growth hormone secretion are reduced, and
serum growth hormone concentrations are increased.

Female subjects
Male subjects
1000

800

IGF-I (ng/ml)

IGF-I concentration is very low (Fig. 2, middle panel), and with excess growth hormone secretion the
serum IGF-I concentration is high. Measurements
of serum IGF-I are useful in the diagnosis and management of acromegaly, although the correlation between the clinical features of acromegaly and serum
concentrations of IGF-I is not close.11
Growth hormone deficiency and retarded growth
may result from impaired release of growth hormone
from the pituitary due to diseases of the hypothalamus or pituitary gland. Alternatively, mutations in
the gene for the growth-hormone receptor can cause
insensitivity to growth hormone and growth retardation with low serum IGF-I concentrations (e.g.,
Laron dwarfism13) (Fig. 2, right-hand panel).
Nutritional status affects serum IGF-I concentrations. Fasting results in complete resistance to growth
hormone, and the restriction of protein or calories (or
both) causes lesser degrees of resistance to growth
hormone.14 These conditions are associated with impaired signaling of the growth hormone receptor,
which reduces the synthesis of IGF-I by the liver.
Thus, since growth hormone and IGF-I are anabolic
hormones, malnutrition leads to a state of catabolism.
In other catabolic states, such as severe trauma and
sepsis, the serum IGF-I concentration is low and there
is resistance to growth hormone.
In both insulin-dependent and non-insulin-dependent diabetes mellitus, the growth hormoneIGF-I
axis is abnormal. Many patients with insulin-dependent diabetes have some hepatic resistance to growth
hormone, with elevated serum growth hormone

600

400

200

5

68

9 11 12 15 16 24 25 39 40 54

Age (years)
Figure 3. Mean Serum IGF-I Concentrations in Normal Subjects
from Birth to Adulthood.
The numbers of subjects in each group ranged from 40 to 195.
Adapted from August,12 with the permission of the publisher.

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Tumor

Glucose
uptake

Pituitary

Big IGF-II

Muscle

Glucose
uptake
GH
Fat

IGF BP-3
IGF-I

Liver

Pancreas

Insulin
Glucose production

Figure 4. The Role of IGF-II in Tumor Hypoglycemia.

Some tumors secrete large amounts of a prohormone form of IGF-II (big IGF-II). Big IGF-II directly
stimulates the uptake of glucose by the tumor and by insulin-responsive tissues such as muscle and
fat. Hepatic glucose production and insulin secretion are decreased by hypoglycemia and by the direct
inhibitory effects of big IGF-II on the pancreatic beta cells. In addition, big IGF-II inhibits the secretion
of pituitary growth hormone (GH), which in turn decreases the synthesis and secretion of IGF-I and
IGF-binding protein 3 (IGF BP-3); decreased concentrations of IGF BP-3 enhance the effects of circulating IGF-II.

concentrations and decreased serum IGF-I concentrations, probably as a result of insufficient insulin action on the liver.15 During puberty, these
changes may decrease linear growth, and the increase in the secretion of growth hormone may
worsen the hyperglycemia by counteracting the action of insulin in peripheral (muscle and fat) tissues.
If insulin therapy is inadequate, the unopposed
action of glucagon allows increased hepatic glucose production. In poorly controlled non-insulindependent diabetes, the hypersecretion of growth
hormone may also counteract insulin in the peripheral tissues, thus allowing glucagon to act unopposed. In either type of diabetes, administration of
IGF-I may improve the hyperglycemia and reduce
insulin resistance by lowering serum concentrations
of growth hormone and glucagon. Furthermore, in
non-insulin-dependent diabetes, IGF-I can inhibit
the secretion of insulin and prevent hyperinsulinemia,
636 

thereby allowing the increased expression of insulin

receptors (see below).
IGF-II

Some tumors secrete IGF-II, which may affect the

growth of tumor cells.16 Most of these tumors also
overexpress IGF-I receptors and various IGF-binding proteins.17 Some mesenchymal (nonislet-cell)
tumors produce and release an excessive amount of
a prohormone form of IGF-II (often termed big
IGF-II)18 (Fig. 4). The increased serum IGF-II concentration inhibits the secretion of insulin and growth
hormone, and the reduction in serum growth hormone decreases the circulating levels of the ternary
complex of IGF-I, IGF-binding protein 3, and the
acid-labile subunit. Big IGF-II interacts poorly with
the IGF-binding protein complex, and the resulting
increase in unbound IGF-II causes hypoglycemia by
inhibiting hepatic glucose uptake and enhancing the

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disposal of glucose into muscle. Surgical removal

of the tumor or radiotherapy reduces the excess
IGF-II, thereby ameliorating the hypoglycemia.19-22
IGF-I AS A THERAPEUTIC AGENT

Part of the allure of IGF-I as a therapeutic agent is

the wide range of its biologic effects and its actions
on many different tissues. IGF-I mediates many if
not most of the anabolic effects of circulating growth
hormone. It stimulates bone formation, protein synthesis, glucose uptake in muscle, and neuronal survival and myelin synthesis. IGF-I also reverses negative
nitrogen balance during underfeeding and inhibits
protein degradation in muscle. For these reasons,
IGF-I has been proposed as a therapy for osteoporosis, various catabolic states, diabetes, obesity, neuromuscular disorders, growth hormone resistance, and
insulin resistance. The broad spectrum of its biologic
actions offers much promise for IGF-I therapy for
many conditions, but it also increases the likelihood
that IGF-I will have side effects or unwanted actions.

per kilogram twice daily for 24 months, the response

was similar, with the increase in height velocity being greater during the first year of therapy.26 Less
than 30 percent of patients receiving recombinant
IGF-I had low titers of nonneutralizing antibodies
to IGF-I.25
These clinical studies demonstrated that the circulating endocrine form of IGF-I stimulates bone
growth and alters body composition by favoring
protein accretion and loss of fat mass. Growth hormone insensitivity is the first clinical syndrome for
which IGF-I therapy has been approved; IGF-I is the
only effective treatment for this disorder.
In some patients with growth hormone deficiency
due to deletions in the growth hormone gene, antibodies to growth hormone may develop during
treatment with recombinant growth hormone. When
treated with IGF-I, these patients respond with increased height velocity, similar to that in the patients
with growth hormone insensitivity.26
Insulin Resistance and Diabetes Mellitus

Growth Hormone Insensitivity Syndrome

Patients with growth hormone deficiency have reduced serum concentrations of growth hormone
and IGF-I (Fig. 4). In prepubertal patients this causes short stature, a condition that responds to treatment with recombinant human growth hormone.
Growth hormone deficiency in adults changes body
composition (increasing fat mass and reducing lean
body mass), elevates serum cholesterol levels, reduces physical performance and bone density, and diminishes quality of life. All of these conditions respond to
growth hormone therapy.23 A far less common cause
of short stature is insensitivity to growth hormone.13
This syndrome, originally called Laron dwarfism, consists of dwarfism, acromicria, obesity, small genitalia
and gonads, and a high-pitched voice. There are low
serum concentrations of IGF-I and IGF-binding protein 3 and increased serum concentrations of growth
hormone. Inactivating mutations in the growth hormone receptor cause insensitivity to exogenous
growth hormone.
The growth hormone insensitivity syndrome is
ideal for testing the therapeutic potential of recombinant IGF-I. In the initial study by Laron et al. of
five children with the syndrome, a starting dose of
150 mg of IGF-I per kilogram of body weight per
day, given subcutaneously, increased height velocity
threefold, from 3.0 cm per year to 10.8 cm per year,
and decreased body fat, as reflected by decreased
subscapular skin-fold thickness, without causing hypoglycemia.24 In a multicenter study of 27 patients
treated with 40 to 120 mg of IGF-I per kilogram
twice daily, height velocity increased by more than
2 cm during the first year of therapy and was maintained at 6.4 cm in the second year.25 In another
study of five patients given 80 to 120 mg of IGF-I

Severe Insulin Resistance

Insulin resistance is a component of many common and several uncommon clinical syndromes. The
degree of insulin resistance varies from relatively
mild in obesity to more severe in the polycystic ovary
syndrome or non-insulin-dependent diabetes mellitus, but it reaches dramatic proportions in several
congenital and acquired syndromes.27 Patients with
mutations in the insulin-receptor gene or in genes
related to the signal-transduction pathways have different phenotypes, including lipoatrophy, partial lipodystrophy, the type A syndrome of insulin resistance with mutations of the insulin-receptor gene,
pseudoacromegaloidism, leprechaunism, and the
RabsonMendenhall syndrome. In many of these
patients the hyperglycemia is extremely difficult to
treat, because insulin, by definition, is not effective.
IGF-I has been proposed as a therapy for severe
insulin resistance because its biologic actions resemble those of insulin and it may therefore bypass the
defect or defects that block the action of insulin. Intravenous administration of recombinant IGF-I was
found to decrease blood glucose and serum insulin
concentrations in two patients with the type A syndrome of insulin resistance28 and in one child with
the RabsonMendenhall syndrome.29 In a study of
six patients with different phenotypes of severe insulin resistance, administration of IGF-I for four weeks
at a dose of 100 mg per kilogram twice daily decreased fasting and mean 24-hour serum insulin
concentrations by 60 to 80 percent, improved glucose tolerance in patients with impaired tolerance or
overt diabetes, and decreased fasting serum triglyceride concentrations.30 In another study, IGF-I reduced blood glucose and serum insulin concentra-

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tions in nine patients with severe insulin resistance.31

How IGF-I works in insulin resistance remains uncertain, but the response to IGF-I in patients with
mutations in the insulin-receptor gene or postreceptor defects supports the notion that IGF-I acts
through mechanisms similar to but distinct from those
of insulin itself possibly exclusively through the
IGF-I receptor.
Insulin-Dependent Diabetes Mellitus

Patients with poorly controlled insulin-dependent

diabetes, including those entering puberty, often
have high serum growth hormone and low IGF-I
concentrations and some degree of insulin resistance.15 The increased secretion of growth hormone
reflects the loss of IGF-Imediated feedback inhibition, and because growth hormone has anti-insulin
actions, it may worsen the insulin resistance. IGF-I
has been proposed as an adjunct to insulin therapy
in adolescents with poorly controlled diabetes because it decreases the secretion of growth hormone,
increases sensitivity to insulin, and decreases insulin
requirements. When administered as an overnight
infusion or subcutaneous injection every evening for
one month, IGF-I permitted daily insulin doses to
be decreased, reduced growth hormone secretion,
and lessened fluctuations in blood glucose.32,33 These
beneficial effects occur at doses of IGF-I (40 mg
per kilogram once daily) that produce serum IGF-I
concentrations in the normal range for adolescents.32
Non-Insulin-Dependent Diabetes Mellitus

Insulin resistance is common in patients with

non-insulin-dependent diabetes. It is caused by several as yet undefined post-receptor defects in insulin
action.34 Insulin secretion increases to overcome the
defect, but this decreases the expression of insulin
receptors on target tissues and worsens the insulin
resistance. Hypertriglyceridemia is a secondary metabolic abnormality in these patients. IGF-I has been
proposed as a therapy because it may stimulate the
use of glucose by peripheral tissues and reduce resistance to and secretion of insulin through its effects on pancreatic beta cells.
In a five-day study in patients with non-insulindependent diabetes, IGF-I, at a dose of 120 mg per
kilogram twice daily, reduced fasting blood glucose
concentrations by approximately 30 percent and serum insulin and C peptide concentrations by more
than 50 percent, while substantially reducing fasting
serum triglyceride concentrations.35 Serum concentrations of glucose and insulin returned to base-line
levels within 48 to 72 hours after IGF-I was discontinued. In another study, of 12 patients with noninsulin-dependent diabetes, IGF-I decreased fasting
and mean 24-hour blood glucose concentrations,
24-hour mean serum insulin concentrations, and fast638 

ing serum triglyceride concentrations.36 In seven of

the eight patients who completed the six-week study,
IGF-I increased insulin sensitivity threefold, as measured by an intravenous glucose-tolerance test with
frequent sampling performed 14 hours after the last
dose of IGF-I.
Initial enthusiasm about the beneficial effects of
IGF-I in improving glycemic control and insulin
sensitivity was blunted by an unacceptable incidence
of side effects at the high doses used in these studies.37 More recent studies suggest that a well-tolerated and efficacious dose can be defined.38
Several explanations have been postulated for the
increased insulin sensitivity during IGF-I therapy.
When IGF-I inhibits the secretion and lowers serum
and tissue concentrations of insulin, peripheral tissues may up-regulate their insulin receptors and become more responsive to insulin. In addition, IGF-I
inhibits the secretion of glucagon normally a
powerful stimulus to hepatic glucose production.38
Thus, IGF-I may prove to be a useful adjunct to
therapy in patients with non-insulin-dependent diabetes during periods of insulin resistance.
Side Effects of Short-Term IGF-I Administration

A single intravenous dose of IGF-I can cause dramatic cardiovascular responses, including asystole
and hypotension. Some of these effects may be due
to acute hypophosphatemia induced by IGF-I, because they were prevented by the simultaneous administration of phosphate.39 Given the seriousness of
these responses, however, the Food and Drug Administration has limited the dose and rate of infusion of intravenous IGF-I but continues to allow
subcutaneous injections of up to 120 mg per kilogram twice a day.
Side Effects of Multiple Subcutaneous Doses of IGF-I

High-dose IGF-I given subcutaneously for more

than 10 days can cause temporomandibular discomfort, facial and hand edema, weight gain, and dyspnea.2 It also causes sinus tachycardia, thought to be
due to reflex sympathetic activation in response to
lowered peripheral vascular resistance. Increased intracranial pressure, gynecomastia, acromegaloid features, and avascular necrosis of the head of the femur
have occurred, as has Bells palsy; all diminish after
therapy ends.40 The fact that IGF-I is an endothelialcell growth factor necessitates careful surveillance of
microvessels in patients treated with IGF-I.41 Hypoglycemia during IGF-I therapy is a cause for serious
concern, but it can be avoided with judicious use of
the hormone and careful monitoring of blood glucose concentrations. Whether long-term use of IGF-I
can cause features of acromegaly or hypertrophy of
tissues such as the arterial walls or the uterine endometrium, or even potentiate the proliferation of
tumor cells, remains to be determined.

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S E M I N A R S I N M E D I C I N E O F T H E B ET H I S R A E L D E AC O N E S S M E D I CA L C E N T E R

CONCLUSIONS

The broad range of the biologic actions of IGF-I

makes it an attractive therapy for several diseases.
However, our understanding of the IGFIGF-binding protein system in normal physiology remains
incomplete. The availability of recombinant human
IGF-I may clarify this system and provide a useful
tool to probe the pathophysiology of several diseases
in the quest for new or better therapies.
DISCUSSION

DR. GEORGE KING: Can you comment on the

fact that according to some reports, patients with acromegaly, who produce a lot of IGF-I, have a higher
incidence of tumors?
DR. DEREK LE ROITH: It is not absolutely clear
that these patients have a higher incidence of tumors, and because they also overproduce growth
hormone, which may have its own effects in addition
to those of IGF-I, it may be hard to attribute any
higher tumor incidence solely to IGF-I.
DR. JEFFREY S. FLIER: Can you expand on the
possible role of IGFs in enhancing mitogenesis, especially of vascular smooth-muscle cells?
DR. LE ROITH: IGFs have been implicated with
other mitogens as causative agents in vascular complications of some disorders, such as diabetes. The
evidence that IGFs may be directly involved is far
from convincing, and what data are available suggest
they have more of a potentiating role.
DR. FLIER: Since IGF-I has many actions, can you
expand on the other possible conditions that may
respond beneficially to recombinant human IGF-I?
DR. LE ROITH: Patients with one of several conditions are presently being studied, including those
with neuromuscular conditions such as amyotrophic
lateral sclerosis, myotonic dystrophy, and multiple
sclerosis. In addition, IGF-I therapy is being evaluated in patients with acute catabolic states, osteoporosis, healing wounds, and renal failure. In some cases,
the preliminary results are promising.
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