The induction of a specific protease for insulin-like growth factor binding protein-3 in the circulation during severe illness

Abstract

The insulin-like growth factors (IGF-I and IGF-II) are almost completely bound in the circulation to specific binding proteins (IGFBPs). These IGFBPs appear to play a pivotal role in maintaining circulating levels and modulating the delivery of the IGFs to the tissues. A large proportion of the circulating IGFs are bound with high affinity to one of the binding proteins. IGFBP-3. The mechanism by which these IGFs are transferred from the circulatory pool to the tissue receptors is at present unclear. Recent studies in late pregnancy have demonstrated the presence of specific proteases which may modify the IGFBPs such that their affinities for the IGFs are reduced. In this paper, we have demonstrated the presence of a heat-sensitive cation-dependent proteolytic enzyme specific for IGFBP-3 in the serum of five severely ill patients. The activity of this protease was found to vary in these patients, becoming more apparent during fasting than when studied after commencement of parenteral nutrition, indicating that one of the influencing factors in the activity of this protease is the nutritional intake of the patient. Age- and sex-matched healthy adults were also studied in a similar protocol, but no proteolytic modification of any of the IGFBPs was found in any of the samples examined. As the levels of both IGF-I and IGF-II were found to be low in the patients, the presence of a circulatory protease suggests that this may be an adaptive response to increase the bioavailability of the IGFs and possibly to improve the nitrogen retention and counter the catabolic state in severe illness.

Differential interactions between IGFBP-3 and transforming growth factor-beta (TGF-β) in normal vs cancerous breast epithelial cells

“…The basal levels of IGF-I and -II produced by both the MCF-10A and the Hs578T cells, as measured by radioimmunoassays previously described (Taylor et al, 1990;Davies et al, 1991) were found to be lower than the detection limits of the assays and hence negligible in relation to the doses required for IGF responses in these cells (i.e. 51 ng ml 71 ; data not shown).…”

IGF-I, IGF-I-binding proteins and GH-binding protein in malnourished elderly patients with inflammation receiving refeeding therapy

“…The partial proteolysis of IGFBP-3 is detectable in normal serum (30), but has been reported to increase considerably in the postoperative phase (21)(22)(23) and during critical illness (24,25). In critically ill patients who had recently undergone surgery, Davies et al (25) reported this proteolytic activity to be strongly regulated by parenteral nutrition. However, in fasted healthy controls (age-and sex-matched), no IGFBP-3 proteolysis was observed, suggesting that other specific factors related to surgery are involved.…”

“…Plasma GH levels may also be low, as reported in cases of prolonged critical illness, thereby contributing to low plasma IGF-I levels (20). Partial proteolysis of IGFBP-3 has been reported to increase during the postoperative phase (21)(22)(23) and in critical illness (24,25), but the mechanisms regulating this process are poorly understood. Changes in the IGF system have not been thoroughly studied in ill, elderly subjects, in whom this system may be affected by both malnutrition and aging.…”

Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer

“…An increased IGFBP-3 protease activity has been described in certain pathological conditions like diabetes (Bereket et al, 1995), severe illness (Davies et al, 1991), but also in patients suffering from advanced malignancies, including breast cancer (Frost et al, 1996). If this also occurs for patients with early breast cancer, it could make total IGF-I an unreliable predictor of bioavailable IGF-I in these patients.…”