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Insulin-like growth factor 1 (IGF-1) is a polypeptide protein hormone similar in molecular structure to insulin. It plays an important role in childhood growth and continues to have anabolic effects in adults. Production and circulation IGF-1 is produced primarily by the liver as an endocrine hormone as well as target tissues in a pracrine/autocrine fashion. Production is stimulated by growth hormone and can be retarded by undernutrition, growth hormone insensitivity, lack of growth hormone receptors, or failures of the downstream signalling pathway post GH receptor including SHP2 and STAT5b. Approximately 98% of IGF-1 is always bound to one of 6 binding proteins (IGF-BP). IGFBP-3, the most abundant protein, accounts for 80% of all IGF binding. IGF-1 binds to IGFBP-3 in a 1:1 molar ratio. Action Its primary action is mediated by binding to specific IGF receptors present on many cell types in many tissues. The signal is transduced by intracellular events. IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and multiplication and a potent inhibitor of programmed cell death. Almost every cell in the human body is affected by IGF-1, especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin, and lungs. In addition to the insulin-like effects, IGF-1 can also regulate cell growth and development, especially in nerve cells, as well as cellular DNA synthesis. IGF-2 and Insulin; related growth factors IGF-1 is closely related to a second protein called "IGF-2". IGF-2 also binds the IGF-1 Receptor. However, IGF-2 alone binds a receptor called the "IGF II Receptor" (also called the Mannose-6 phosphate receptor), which is apparently a non-signaling receptor. As the name "insulin-like growth factor 1" implies, IGF-1 is structurally related to insulin, and is even capable of binding the insulin receptor, albeit at lower affinity than insulin. Receptors IGF-1 binds to at least two cell surface receptors: the IGF-1 Receptor (IGFR), and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor - it binds IGF-1 at significantly higher affinity than it binds the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase - meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the Insulin receptor at approximately 0.1x the potency of insulin. Part of this signaling may be via IGF1R/Insulin Receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the Insulin receptor, and hypoglycemia). IGF-1 is produced throughout life. The highest rates of IGF-1 production occur during the pubertal growth spurt. The lowest levels occur in infancy and old age. Use as a diagnostic test IGF-1 levels can be measured in the blood in 10-1000 ng/ml amounts. As levels do not fluctuate greatly throughout the day for an individual person, IGF-1 is used by physicians as a screening test for growth hormone deficiency and excess. Interpretation of IGF-1 levels is complicated by the wide normal ranges, and variations by age, sex, and pubertal stage. Clinically significant conditions and changes may be masked by the wide normal ranges. Sequential management over time is often useful for the management of several types of pituitary disease, undernutrition, and growth problems. Diseases of deficiency and resistance Rare diseases characterized by inability to make or respond to IGF-1 produce a distinctive type of growth failure termed Laron dwarfism which does not respond well to growth hormone treatment. Factors influencing the levels of IGF-1 in the circulation Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include an individuals genetic make-up, the time of day, their age, sex, exercise status, stress levels, genetics, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake (Scarth 2006). The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals - see also endocrine disruptor. IGF-1 as a therapeutic agent IGF-1 has been manufactured recombinantly on a large scale using both yeast and E. coli. Several companies have evaluated IGF-1 in clinical trials for several indications including growth failure, type 1 diabetes, type 2 diabetes, Amyotrophic Lateral Sclerosis (ALS aka Lou Gherig's Disease), severe burn injury and Myotonic Muscular Dystrophy (MMD). Results of clinical trials evaluating the efficacy of IGF-1 in type 1 diabetes and type 2 diabetes showed great promise in reducing HbA1c levels as well as daily insulin consumption. However, the sponsor, Genentech, discontinued the program due to an exacerbation of diabetic retinopathy in patients coupled with a shift in corporate focus towards oncology. However, in the last few years, two additional companies Tercica and Insmed compiled enough clinical trial data to seek FDA approval in the United States. In August, 2005, the FDA approved Tercica's IGF-1 drug, Increlex, as replacement therapy for severe primary IGF-1 deficiency based on clinical trial data from 71 patients. In December 2005, the FDA also approved IPLEX, Insmed's IGF-1/ IGFBP-3 complex. By delivering the drug in a complex they can get the same efficacy as far as growth rates but obtain fewer side effects with less severe hypoglycemia. The drug is injected once a day versus the twice a day version that Tercica sells. This makes sense since in the human body 97 to 99 percent of IGF-1 is always bound to one of 6 IGF binding proteins. IGFBP-3, is the most abundant binding protein, accounting for approximately 80% of all IGF binding. Terminology IGF-1 has been known as "sulfation factor" (1957 Salmon and Daughaday) and its effects were termed "nonsuppressible insulin-like activity" (NSILA) in the 1970s. It was also known as "somatomedin C" in the 1980s. | |||||||
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