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Extra info for Biology of IGF-1: Its Interaction with Insulin in Health and Malignant States (Novartis Foundation Symposia)
There are interesting di¡erences. In the normal tissue there is a limited cleavage. In the tumours you get other proteases such as cathepsins and the tumour starts to acidify, and there is a di¡erent pattern of cleavage. The consequences of this still need to be worked IGF PHYSIOLOGY 27 out in terms of di¡erent fragments. As soon as you acidify you release the IGF from the binding proteins anyway, so there is a di¡erent interpretation of the clipping again. LeRoith: If I understand correctly from the data you presented on disease states, it is because of this inhibitor in interstitial tissue that you have intact binding protein and IGF-1 in the disease state.
The IGFBPs are structurally closely related to each other, although they are each distinct gene products and they all have very distinct functional properties (Firth & Baxter 2002). In terms of physiology there is still very limited understanding of the exact role of each of the IGFBPs. In humans IGFBP-3 clearly acts as the main circulating carrier protein, but it is also expressed extensively in many tissues and obviously has many additional local functions. One of these proteins, IGFBP-1, is more restricted in its sites of expression; IGFBP-1 present in the circulation is predominantly derived from the liver where its expression is under the dynamic control of insulin which suppresses its production.
At the same time the incidence of malignancy goes up. What do we know about in vivo levels of free IGF-1? If indeed IGF-1 plays a role, there should be an increase or at least a stabilization of free IGF-1 with age. Holly: I don’t believe in free IGF. Roger Ekins put forward the free hormone hypothesis, breaking down complex systems into two compartments, a free fraction of hormone which is active and a bound fraction which is inactive (Ekins 1992). But over the last decade many of us have shown that with IGF and binding proteins in many cell systems, the bound is more active than the free.