Nonlinear relationship of insulin-like growth factor (IGF)-I and IGF-I/IGF-binding protein-3 ratio with indices of adiposity and plasma insulin concentrations (Sweden) Annekatrin Lukanova 1,2, *, Stefan So¨derberg 2 , Pa¨r Stattin 3 , Richard Palmqvist 4 , Eva Lundin 5 , Carine Biessy 1 , Sabina Rinaldi 1 , Elio Riboli 1 , Go¨ran Hallmans 2 & Rudolf Kaaks 1 1 InternationalAgencyforResearchonCancer,Lyon,France; 2 UniversityofUmea ˚,DepartmentofPublicHealthand ClinicalMedicine/NutritionalResearch,Umea ˚,Sweden; 3 UniversityofUmea ˚,DepartmentofUrologyandAndrology andtheMedicalBiobank,NorthernSwedenUniversityHospital,Umea ˚,Sweden; 4 UniversityofUmea ˚,Departmentof Pathology, Umea ˚, Sweden; 5 University of Umea ˚, Department of Medical Biosciences/Pathology, and Department of Public Health and Clinical Medicine/Nutritional Research, Umea ˚, Sweden Received 15 June 2001; accepted in revised form 15 January 2002 Key words: body mass index, IGF-binding protein-3, IGF-I, insulin, leptin. Abstract Objective: In this study we test the hypothesis of a nonlinear relationship of IGF-I with indices of body fat such as body mass index (BMI), insulin, and leptin. Methods: The controls used in three case–control cancer studies nested in the Northern Sweden Health and Disease Cohort, were combined for this analysis. Measurements of plasma IGF-I, IGFBP-3, insulin, and leptin were available for 445 men and 391 women. Results: In both men and women we found the highest mean IGF-I levels in subjects with BMI between 24 and 26. IGF-I concentrations decreased toward BMI £ 20 and BMI > 30 in men; however, the results for women did not reach statistical significance. The molar ratio of IGF-I/IGFBP-3 showed a similar profile to that of IGF-I, although much less pronounced. The observed peak mean IGF-I levels in the second quintiles of insulin and leptin in men supported these findings. No significant variation of mean IGF-I levels across quintiles of insulin and leptin were observed in women. Conclusions: The results of this study provide evidence that IGF-I plasma concentrations vary substantially over a wide range of body weight and that the relationship is nonlinear. Introduction Elevated plasma levels of insulin-like growth factor-I (IGF-I) have been implicated in the development of cancers of the breast, colon, and prostate, which are common in affluent Western societies [1–6]. Insulin-like growth factor binding proteins (IGFBP) -1, -2, and -3 play an important role in regulating the free fraction of IGF-I and have also been studied in relation to cancer risk. Nutritional status, and particularly energy balance, are regulators of blood concentrations of IGF-I and its binding proteins -1, -2, and -3 [7]. It has thus been hypothesized that the effects on cancer risk of overnu- trition, low levels of physical activity, and sedentariness, typical for the Western lifestyle, might be mediated through changes in circulating total or bioactive IGF-I levels [7, 8]. The associations between IGF-I and indices of body fat such as body mass index (BMI), described in the literature, suggest the existence of a nonlinear relation- ship between them. Prolonged fasting, as observed in patients with anorexia nervosa, and short-term fasting of normal-weight subjects, result in a decrease of IGF-I levels [7, 9, 10]. On the other hand, in anorexic patients there is a stepwise increment in the IGF-I values related to weight gain [10, 11] and short-term overfeeding of normal-weight women also results in an increase of * Address correspondence to: Dr A. Lukanova, Department of Nutrition and Cancer, International Agency for Research on Cancer, 150 Cours Albert Thomas 69372 Lyon, France. Ph.: (33) 4 72 73 86 91; Fax: (33) 4 72 73 83 61; Email: lukanova@iarc.fr Cancer Causes and Control 13: 509–516, 2002. 509 Ó 2002 Kluwer Academic Publishers. Printed in the Netherlands.