Pro- and mature IGF-II during diet-induced weight loss in obese subjects

Background: In normal subjects up to 10% of circulating insulin-like growth factor II (IGF-II) consists of pro-IGF-II. However, its regulation and biological impact remains unknown. In obese subjects, serum free and total IGF-II are increased, and we therefore investigated the impact of obesity and diet on serum pro-IGF-II. Design: Non-diabetic, obese subjects (n = 34) with a body mass index (BMI) of 38.9 +/- 0.5 kg/m(2) were subjected to 8 weeks with very low calorie diet (800 kcal/day) followed by 12 weeks with a weight-stabilizing diet. Fasting serum was collected before the study, and after 8 and 20 weeks. Pro-IGF-II was determined after acid-gel chromatography using a novel, highly specific in-house assay, free and total IGFs were measured after ultrafiltration and acid-ethanol extraction, respectively, and IGF-binding proteins (IGFBPs) were measured with specific immunoassays. Results: Diet reduced BMI and fasting levels of insulin and glucose (P < 0.001). Serum pro-IGF-II was markedly reduced in obese subjects as compared with matched normal-weight controls (means and 95% confidence intervals: 93 mu g/l (82-104 mu g/l) versus 1.71. mu g/l (152-192 mu g/l), respectively; P < 0.001), and levels remained unchanged after the weight loss. In contrast, during the study period total and free IGF-II decreased (P < 0.05), whereas total IGF-I, IGFBP-1 and IGFBP-2 increased (P < 0.001). Serum free IGF-I remained unaltered. Cross-sectional and longitudinal correlation analyses showed that pro-IGF-II was closer and more consistently associated with IGF-I than IGF-II. Conclusion: This study demonstrates that pro-IGF-II is reduced in obesity, in contrast to mature IGF-II. This indicates a hitherto unrecognized link between nutrition and pro-IGF-II. In addition, our data indicate that pro-IGF-II is regulated independently of mature IGF-II.