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IGF-1

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

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IGF-1

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  1. 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

  3. http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=20049http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=20049

  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 • IGF-1 triggers growth until adulthood • After adulthood triggers hypertrophy in skeletal muscle • Regulates kidney function and growth

  6. Receptor • Receptor is IGF1R • “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

  8. http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=68828http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=68828

  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

  22. http://www.biocarta.com/pathfiles/h_ghrelinPathway.asp

  23. http://www.biocarta.com/pathfiles/h_igf1pathway.asp

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