Insulin-Like Growth Factors

Insulin-like growth factors (IGFs) are multifunctional hormones that regulate cellular proliferation, differentiation, and metabolism. These proteins resemble insulin in structure and function; hence, the metabolic actions of IGFs mimic those of insulin. IGFs are transported in the circulation bound to insulin-like growth factor-binding proteins (IGFBPs), which regulate the bioavailability and function of IGFs.

There are at least two distinct IGFs—IGF-I and IGF-II, the former being the major form produced in many adult tissues and the latter being the major form produced in the fetus. The liver is the predominant source of IGFs as well as the predominant site [Page 408]of IGFs degradation. There are six types of IGFBPs. The most important of these chemicals in clinical practice are IGF-I and IGFBP-3. The major portion of IGF-I (75 percent) is bound to IGFBP-3, while 20 percent is bound to other high-affinity IGFBPs (mainly IGFBP-1 and IGFBP-2), and 5 percent is free-floating in the circulation.

IGF-I is a potent mitogen (stimulus for cell growth) and a strong stimulus for cell differentiation (functional maturation). It has a particularly profound effect on bone and cartilage, stimulating osteoblasts (bone cells) replication, and collagen and bone matrix synthesis. IGF-I is the mediator for growth hormone (GH) action, and its level in the circulation is regulated by GH, which is one of the pituitary hormones.

Nutritional status and growth situations influence IGF-I levels. When ample supplies of diverse nutrients are available, the high serum amino acid levels stimulate GH and insulin secretion and the high serum glucose levels stimulate insulin secretion. The high levels of GH and insulin stimulate IGF-I production, and these conditions are appropriate for growth. If the diet is high in calories but low in amino acids, this will result in high insulin but low GH and IGF-I levels. Insulin also stimulates IGF-I production, and per se, GH cannot stimulate IGF-I production in the absence of insulin. Starvation, on the other hand, effectively inhibits IGF-I secretion, even when GH levels are high.

There is evidence suggesting a potential role for IGF-I in the development of obesity. Obesity is associated with growth hormone undersecretion; therefore, it may be expected that total IGF-I concentrations would be lower in obese subjects compared with nonobese subjects. Obesity is also associated with hyperinsulinemia (elevated insulin levels), which may increase IGF-I. Insulin also regulates IGFBP-1 and IGFBP-2 levels through inhibition of their hepatic (liver) synthesis. Finally, it has been recently suggested that IGFBP-2, the principal binding protein for IGF-I in preadipocytes (fat cell precursors), may play a role in the development of obesity.