INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEINS AS GLUCOREGULATORS

Circulating insulin-like growth factors (IGFs) represent an important pool of potential hypoglycemic activity, which is largely inhibited by their sequestration in a heterotrimeric complex comprising growth factor, IGF-binding protein-3 (IGFBP-8), and acid-labile subunit (ALS). Less than 1% of total IGFs circulate in the free form, yet even this amount might contribute significantly to circulating insulin-like activity. The ternary binding protein complex appears to inhibit insulin-like activity of bound IGFs by preventing their egress from the circulation. Although the integrity of this complex might be affected by limited proteolysis of IGFBP-3 in pregnancy and catabolic conditions, the evidence that this increases IGF bioavailability, and thus hypoglycemic potential, is as yet unclear. However, in patients with IGF-II-secreting tumors, hypoglycemia may result from a failure of the ternary complex to adequately sequester the IGFs, Improvement in complex formation, by treatment with corticosteroids or growth hormone, alleviates the hypoglycemia, even if (as seen with growth hormone treatment) IGF-II hypersecretion persists. In these patients, blood glucose levels are inversely correlated with IGFBP-2 levels, suggesting that this protein might play a part in transporting IGFs to their target tissues, Conversely, ALS levels correlate positively with blood glucose, emphasizing the importance of the ternary complex in preventing hypoglycemia. Unlike the other IGF binding proteins, IGFBP-1 is acutely regulated in the circulation, in a manner consistent with its acting as a glucose counterregulator. It might act in this way by inhibiting the activity of free IGFs in the circulation. Its acute rise following hypoglycemia, and suppression after glucose ingestion, are consistent with such a role. Following IGF-I administration in humans, adaptive changes in IGFPB-3, ALS, and IGFBP-1 are seen, which might affect subsequent responses to IGFs. Understanding the mechanisms and consequences of these changes will be important in optimizing the therapeutic applications of IGF-I. Copyright (C) 1995 by W.B. Saunders Company.