Insulin-Like Growth Factor 1 Matthew Klinka 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/mmdbsrv.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 Regulates kidney function and growth IGF-1 triggers growth until adulthood After adulthood triggers hypertrophy in skeletal muscle Regulates kidney function and growth

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

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 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 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