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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

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igf 1

IGF-1

Insulin-Like Growth Factor 1

Matthew Klinka

background
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
production
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
Function
  • Anabolic Hormone
    • IGF-1 triggers growth until adulthood
    • After adulthood triggers hypertrophy in skeletal muscle
  • Regulates kidney function and growth
receptor
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
igf 2 binding
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
primary result
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
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
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
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
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
regulation
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 syndrome1
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
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
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
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
diabetes protection
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
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
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