1. Insulin-Like Growth Factor 1 Matthew Klinka
IGF-1
Insulin-Like Growth Factor 1
Matthew Klinka

2. 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

4. 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

5. Function Anabolic Hormone Regulates kidney function and growth
IGF-1 triggers growth until adulthood
After adulthood triggers hypertrophy in skeletal muscle
Regulates kidney function and growth

6. Receptor Receptor is IGF1R Tyrosine Kinase receptor
“Insulin-like growth factor 1 receptor
Tyrosine Kinase receptor
Dimeric
Two sets of Alpha & Beta subunits
320 Kda
Member of the Insulin receptor family
Beta subunits contain the catalytic tyrosine residues

7. 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

9. 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

10. 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

11. 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

12. 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

13. Secondary Receptor IGF-1 Can also bind insulin receptor
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

14. 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

15. Laron Syndrome

16. 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

17. 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

18. Treatment Synthetic IGF-1 Must be taken before puberty
Not effective if there are other mutations further along the signaling pathway

19. Cancer, Diabetes, and aging
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

20. 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

21. 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