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IGF-1
Insulin-Like Growth Factor 1
Matthew Klinka
Background
Primarily produced in the liver
 However is also a paracrine hormone

◦ Present in many cell types in a wide range of
tissue types.

Typically bound to proteins when both
intra or extracellular
◦ 98% of IGF-1 is protein bound
◦ IGFBP-3 most common
http://www.ncbi.nlm.nih.gov/Structure/mmdb/m
mdbsrv.cgi?uid=20049
Production

Production of IGF-1 is linked to dietary
protein intake
◦ Especially casein
◦ Protein free diet can result in IGF-1 deficiency

Made in response to growth hormone
signalling
Function

Anabolic Hormone
◦ IGF-1 triggers growth until adulthood
◦ After adulthood triggers hypertrophy in
skeletal muscle

Regulates kidney function and growth
Receptor

Receptor is IGF1R
◦ “Insulin-like growth factor 1 receptor

Tyrosine Kinase receptor
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Dimeric
Two sets of Alpha & Beta subunits
320 Kda
Member of the Insulin receptor family
Beta subunits contain the catalytic tyrosine
residues
IGF-2 Binding
IGF1R may also bind IGF-2
 Key differences:

◦ IGF-2 functions primarily in fetal development
 During gestation aids neural development
◦ IGF-1 functions in adults
 During gestation deals with physical development
http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.
cgi?uid=68828
Primary Result
IGF1R triggering often results in cell
proliferation or growth
 However still a cell specific response

◦ Ie: may trigger growth in size of an adult’s
skeletal muscle cells, or may trigger growth
and subsequent division of embryonic cells
◦ May even trigger growth (hypertrophy) of
heart muscle cells
Role in reproduction
IGF1R plays a role in the development of
limb buds in an embryo
 IGF1R serves to facilitate lactation in
pregnant and nursing females

◦ Differentiates breast cells into duct and
glandular tissue
◦ Prevents apoptosis of duct and glandular
tissue during pregnancy and nursing
Cancer

Because of it’s anti-apoptotic action,
IGF1R may contribute to some cancers
◦ Prostate
◦ Breast
◦ Cervical

All of the above have been observed to
contain cells with heightened levels of
IGF1R
Craniosynostosis

Premature ossification of sutures in an
infant cranium
◦ Results in oddly shaped skull and in most
cases brain damage if not corrected

Caused by a number of different single
nucleotide polymorphisms in IGF1R
Secondary Receptor

IGF-1 Can also bind insulin receptor
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Also a tyrosine Kinase receptor
Much lower binding affinity than IGF1R
IGF-1 binds at 10% of the rate of insulin
May form a heterodimer with IGF1R
Regulation

In serum may be bound by certain IGFBPs
◦ IGF-1 has a higher affinity for some of these
than it does for its receptor
◦ IGF1R may be targeted with tyrosine kinase
inhibitors
◦ miRNA thought to play a role in regulation as
well
Laron Syndrome
Laron Syndrome
Autosomal recessive
 Results from low levels or low efficacy of
IGF-1

◦ Most cases are due to a lack of GH receptor
◦ Some due to mutation in genes coding for
IGF-1 or IGF1R
Symptoms
Normal GH levels
 Very low IGF-1 levels
 Short stature
 Prominent forehead
 Obesity in the trunk of the body
 Lack of response to GH therapy

◦ Typically used to treat other forms of
dwarfism
Treatment
Synthetic IGF-1
 Must be taken before puberty
 Not effective if there are other mutations
further along the signaling pathway

Cancer, Diabetes, and aging
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Interestingly, people with Laron syndrome
are nearly immune to cancer and
diabetes.
◦ Two theories for cancer protection
 1. IGF-1 has anti-apoptotic function
 Reduced IGF-1 results in more normal apoptosis
 2. Lack of IGF-1 somehow results in more
protection from oxidative DNA damage
Diabetes protection

Laron syndrome sufferers have high
insulin sensitivity despite being obese
◦ Most likely reason is because IGF-1 can bind
insulin receptor
◦ In the absence of a competitor, a smaller
amount of insulin can have great effect
Aging

In mice, mutations reducing IGF-1 levels
resulted in longer lifespans on average
◦ In nematodes IGF-1 deficiency resulted in
doubling of lifespan

Mechanism is not understood
◦ Unknown if this property occurs in humans
 Only ~300 people with Laron Syndrome worldwide
 Difficult to establish a baseline because incidence of
accidental death is relatively common
http://www.biocarta.com/pathfiles/h_ghrelinPathway.asp
http://www.biocarta.com/pathfiles/h_igf1pathway.asp