Paradoxical elevations in serum IGF-II and IGF binding protein-2 in acromegaly: insights into the regulation of these peptides

Objective: Circulating insulin-like growth factor (IGF)-II and IGF binding protein-2 (IGFBP-2) are frequently altered, often in parallel, in numerous pathologies including neoplastic disease but little is known about their no rmal regulation. This study compared serum IGF-II and IGFBP-2 distributions between acromegalics and a large normal adult population to explore possib le determinants. Patients: Sixty acromegalic patients undergoing screening colonoscopy (age range 25-81 years); normative data from 306 healthy adults (age range 20-89 years). Measurements: Serum IGF-I, IGF-II, IGFBP-2 and IGFBP-3 were measured in hea lthy adults and acromegalics. Mean growth hormone (GH) levels were obtained for acromegalic patients. Differences were compared using t-tests (unadjus ted) and multiple regression models (adjusted for age and gender). Correlat ions were expressed as Pearson's coefficient (r). Results: For acromegalic patients, GH was significantly correlated with IGF -I (r = 0.50; P < 0.001) and IGFBP-3 (r = 0.29; P = 0.03) but not IGF-II or IGFBP-2. Contrary to expectations, mean IGF-II and IGFBP-2 levels were sig nificantly raised in the acromegalics compared with normals [adjusted mean difference (95% CI) = 226 (181, 271) mug/l and 305 (200, 410) mug/l, respec tively]. Ten acromegalic patients had colorectal neoplasia but their presen ce did not contribute to the elevations in serum IGF-II and IGFBP-2. The (I GF-I + IGF-II)/IGFBP-3 molar ratios were remarkably constant in both health y adults and acromegalics, but the relationships of the ligands individuall y with IGFBP-3 were not linear: as IGFBP-3 increased, IGF-I also increased whereas IGF-II initially increased but then decreased. IGFBP-2 did not corr elate with IGF-II, but molar concentration significantly correlated with th e IGF-II/IGFBP-3 molar ratio (r = 0.40; P = 0.001). Conclusions: Serum IGF-II and IGFBP-2 levels were paradoxically elevated in acromegalics, independent of the presence of colorectal neoplasia. The (IG F-I + IGF-II)/IGFBP-3 molar ratio appears to be pivotal in determining IGF- II values, which, in turn, expressed as a ratio of IGFBP-3, is related to I GFBP-2. These observations offer new insights into the regulation of these peptides.