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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

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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


Igf 1

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


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


Igf 1

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


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 syndrome

Laron Syndrome


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


Igf 1

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


Igf 1

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


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