Article: Insulin-like growth factor 1

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 by the liver and target tissues. Production is stimulated by growth hormone and retarded by undernutrition. A large fraction of circulating IGF-1 is complexed with IGF binding proteins.

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. The effect is the promotion of cell growth and multiplication.

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.

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, IGF-1 is used by physicians as a screening test for growth hormone deficiency and excess.

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.

IGF-1 as a therapeutic agent

IGF-1 has been synthesized and used in therapeutic trials for several conditions including growth failure and diabetes. Results of clinical trials sponsored by Genentech in the 1990s were not considered promising enough to pursue.

However, in the last few years, Tercica compiled enough clinical trial evidence to seek FDA approval in the United States. In August, 2005, the FDA approved Increlex as replacement therapy for severe IGF-1 deficiency based on clinical trial data from 71 patients. Data reported at the 2004 Annual Meeting of the Endocrine Society and the 2005 meeting of the Lawson Wilkins Society demonstrated a statistically significant increase in growth rate over an eight-year period in response to Increlex therapy. Compared to pre-treatment growth patterns, on average, children gained an additional inch per year for each year of therapy over the course of eight years. In addition, an analysis of safety in the study concluded that treatment for up to several years was safe enough to meet approval standards. The most common adverse events were hypoglycemia, lipohypertrophy, tonsillar hypertrophy, and coarsening of facial features.

IGF-1 has been implicated as a possible neuroprotective agent in fighting the adverse effects of amyotrophic lateral sclerosis (ALS).

Insmed has received FDA approval of IGF-1 attached in a complex to binding protein 3. 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 bound to binding protein 3.

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.