THE IGF SYSTEM IN METABOLISM REGULATION

Insulin-like growth factors (IGF-I and IGF-II) are produced in most ti ssues, particularly liver. Via endocrine and paracrine or autocrine me chanisms, they play an essential role in cell proliferation and differ entiation and complement the metabolic effects of insulin. Similaritie s between the effects of insulin and IGF in vitro are largely due to c ross-reaction, owing to their structural homology as well as that of t heir receptors. At physiological concentrations, insulin is not mitoge nic. Compared with insulin, IGFs have negligible metabolic effects on hepatocytes or adipocytes. However, the presence of the IGF-I receptor in muscle accounts for IGF physiological effects in vivo on glucose u ptake and glycogen synthesis. Moreover, recombinant IGF-I administered subcutaneously to healthy subjects or patients with Type 2 diabetes c auses a drop in plasma levels of triglycerides and VLDL as well as cho lesterol and LDL but not HDL, and also increases insulin sensitivity. All these responses reflect IGF-I inhibition of insulin and GH secreti on, In biological media, IGF-I and IGF-II are reversibly associated wi th specific high-affinity (10(9)-10(11)M(-1)) binding proteins (IGFBP- 1 to -6) differing in expression according to tissue of origin and pla ying a variety of roles in IGF transport and half-lives, delivery of I GFs to their target cells and modulation of IGF interactions with thei r receptors. In the blood, where IGF concentrations are 1,000 times th ose of insulin, IGFBP-3 (the major form) binds at least 80 % of IGFs a s 140-kDa complexes which do not cross the capillary endothelium and t herefore prevent the insulin-like action of IGFs. Nevertheless, these circulating IGF reserves may be mobilized in response to metabolic nee ds via limited proteolysis of IGFBP-3 by serine proteases. in the case of IGFBP-1, whose hepatic synthesis is negatively regulated by insuli n, plasma concentrations are subject to extensive nycthemeral variatio n, rising with fasting and dropping after feeding, which may be involv ed in controlling the access of free IGF-I to its cellular receptors a nd hence IGF-I-regulated glucose and amino acid uptake. Therapeutic ap plications of recombinant human IGF-I, currently under trial in the tr eatment of growth retardation resulting from GH receptor abnormalities , hypercatabolic states and would repair, may also be envisaged for ca ses of insulin resistance, particularly type 2 diabetes.