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Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have important anabolic functions in normal tissue growth, which in excess may lead to tumorigenesis. In the present study, circulating IGF-I, IGF-II and their binding proteins (IGFBP-3, IGFBP-2 and IGFBP-1) were determined in 92 adult patients with gastrointestinal inflammation (Crohn's disease, colitis ulcerosa, gastritis, duodenitis errosiva, gastrointestinal candidiasis, and rotaviral and adenoviral enteritis). Serum IGF concentrations were measured by radioimmunoassay, while IGFBP profiles and IGFBP proteolytic patterns were characterized by immunoblotting. Concentrations of both IGF-I and IGF-II were significantly (p < 0.001) lower in patients than in healthy subjects. Immunoblotting demonstrated a decreased amount of intact IGFBP-3 (by approximately 60%), whereas IGFBP-2 and IGFBP-1 were increased (approximately 1.7 and 3.5-fold, respectively). No alteration in either fragmentation pattern or relative degree of proteolysis was detected in patients compared to the control group. It may be concluded that the IGF system is seriously imbalanced in patients with gastrointestinal inflammation, regardless of primary cause. These findings may help towards a better understanding of the metabolic outcome of the inflammatory process, and possibly in predicting the efficiency of patient recovery.

Insulin resistance is an adaptive process in insulin-sensitive tissues characterised by reduced insulin receptor (IR) and insulin-receptor substrate (IRS)-1 expression, increased IRS-1 serine phosphorylation and attenuated downstream signalling. We tested whether this molecular phenotype prevails in cancer cells after long-term exposure to insulin. We characterised expression of IR-related molecules, IRS-1 phosphorylation and downstream signalling in a panel of 5 colon cancer cell lines at different insulin exposures: 15 min (100 nM), approximating to acute stimulation; 48 h (100 nM), used to demonstrate adaptive changes; and 12 weeks (20 nM; chronic insulin exposure, CIE), approximating to chronic hyperinsulinaemia. To assess clinical relevance, we determined IC50 values (increased indicating chemo-resistance) in the CIE-treated cells using oxaliplatin, SN38 (irinotecan) and 5-fluorouracil (5-FU). All colon cancer cell lines (HCT 116, HT-29, C32, CaCo2, LoVo) were sensitive to 15 min insulin exposure with increased phosphorylation of Akt, PRAS40 and p70-S6K. At 48 h, there was incomplete or absent features of insulin resistance. In CIE-treated cells, there was reduced IR expression, incomplete IRS-1 adaptation, lack of signalling pathway attenuation and contra-adaptive increases in IRS-1 tyrosine phosphorylation in several cell types. In CIE cells, there were multiple examples of increased IC50 values (2- to 100-fold) following 24-h treatment with oxaliplatin and SN38, but not with 5-FU. We concluded that CIE in colon cancer cells does not completely induce an insulin resistance molecular phenotype but is associated with chemo-resistance. Adaptive changes seen in insulin-sensitive non-neoplastic cells in response to long-term insulin may not extrapolate to neoplastic cells.