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Circulating IGF Binding Protein-1 Is Inversely Associated with Leptin In European Journal of Endocrinology (2001) 144 283±290 ISSN 0804-4643 CLINICAL STUDY Circulating IGF binding protein-1 is inversely associated with leptin in non-obese men and obese postmenopausal women Stefan SoÈderberg, Bo AhreÂn1, Mats Eliasson2, Bo Dinesen4, Kerstin Brismar3 and Tommy Olsson Department of Medicine, UmeaÊ University Hospital, 1MalmoÈ University Hospital and 2LuleaÊ Hospital, Sweden, 3Department of Endocrinology and Diabetology, Karolinska University Hospital, Sweden and 4The Steno Diabetes Center, Gentofte, Denmark (Correspondence should be addressed to S SoÈderberg, Department of Medicine, UmeaÊ University Hospital, S-901 85 UmeaÊ, Sweden; Email: [email protected]) Abstract Objective: Hyperleptinaemia and hyperinsulinaemia interrelate to insulin-like growth factor binding protein 1 (IGFBP-1), and disturbances in the growth hormone±IGF-I axis are linked to obesity and cardiovascular diseases. However, whether the association between leptin and the GH±IGF-I axis is altered with increasing obesity is not known. We therefore examined the relationship between leptin, IGF-I, IGFBP-1, insulin and proinsulin in men and women with or without obesity in a population study. Design and subjects: Healthy subjects n 158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) population were studied with a cross-sectional design. Methods: Anthropometric measurements (body mass index (BMI) and waist circumference) and oral glucose tolerance tests were performed. Radioimmunoassays were used for the analyses of leptin, IGF-I and IGFBP-1, and ELISAs for specific insulin and proinsulin. Results: Leptin inversely correlated to IGFBP-1 in non-obese men P , 0:05 and obese postmenopausal women P , 0:05 : In contrast, leptin did not correlate to IGF-I. IGFBP-1 was also significantly associated with proinsulin in non-obese men P , 0:01 and non-obese premenopausal women P , 0:05 : The association between leptin and IGFBP-1 was lost after adjustment for insulin. In multivariate analyses taking measures of adiposity into account, low proinsulin, and IGF-I in combination with old age, but not leptin, predicted high IGFBP-1 levels. Conclusions: Leptin was inversely associated with IGFBP-1 in non-obese men and obese postmenopausal women, and proinsulin was inversely associated with IGFBP-1 in non-obese men and premenopausal women. However, these associations were lost with increasing central obesity in men and premenopausal women and after control for insulin. Therefore, this study suggests (i) that leptin is of minor importance for regulation of IGFBP-1 levels and (ii) that the insulin resistance syndrome is characterised by an altered relationship between leptin, IGFBP-1 and insulin. European Journal of Endocrinology 144 283±290 Introduction (IGFBP-1) production (10). Leptin might also be involved in this regulation, since leptin interacts with The cluster of risk factors named the insulin resistance the growth hormone (GH)±IGF axis in a bi-directional syndrome, which is associated with (central) obesity way. Besides hypothalamic effects (11), it is possible (1, 2), is characterised by hyperinsulinaemia, hyper- that leptin influences GH effects indirectly in the tension, dyslipidaemia and abnormal fibrinolysis (3). periphery through interaction with the IGFBPs (12) Increased leptin levels may mediate several of these and, conversely, levels of leptin decrease after GH manifestations through metabolic and hormonal inter- substitution (13). However, whether the association actions and effects on blood pressure (4±6). In line with between leptin and the GH±IGF-I axis is altered in this, we have reported that leptin is independently insulin resistance is not known. associated with increased risk for cardiovascular In addition, states of insulin resistance are char- disease (7, 8). In addition, the insulin resistance acterised by high circulating levels of proinsulin-like syndrome may include insufficient peripheral effects molecules (14), but the association between the of insulin-like growth factor-I (IGF-I) (9), possibly due GH±IGF-I axis and these molecules has not yet been to insulin-mediated inhibition of IGF binding protein-1 fully elucidated (15). q 2001 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 09/25/2021 11:48:59PM via free access 284 SSoÈderberg and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 144 The aim of this study was to explore the association measured by ELISA without cross-reactivity to human between circulating levels of IGF-I and IGFBP-1 on one proinsulin (21). Split(32±33)- and des(31,32)-proinsu- hand and leptin and proinsulin on the other in healthy lin do not react, whereas split(65±66)- and des(64,65)- men and women representing a wide range of body proinsulin cross-react with an efficiency of 30% and composition and age, and to explore if these associa- 63% respectively, on a molar basis. The detection limit tions differ between men and women in general, and was 5 pmol/l, and the working range was 5± between pre- and postmenopausal women. 600 pmol/l. Interassay coefficients of variation (CV) were 5±6% at 80±350 pmol/l and 11% at 30 pmol/l. Proinsulin immunoreactivity was measured by ELISA Patients and methods with a detection limit of 0.25 pmol/l and a working Study population range of 0.25±100 pmol/l (22). The four major proinsulin conversion intermediates reacted 65±99% The study was performed within the framework of the on a molar basis. C-peptide and insulin did not react. Northern Sweden MONICA Project, which, in turn, is Interassay CVs were 6±7% at 5±30 pmol/l. IGF-I was part of the WHO MONICA (Monitoring of Trends and determined by RIA after separation of IGFs from IGFBPs Determinants in Cardiovascular Disease) Project (16). by acid±ethanol extraction and cryoprecipitation. To In 1994, a population was screened for cardiovascular minimise interference of remaining IGFBPs, des(1±3)- risk factors. A total of 2500 individuals in the 25±74 IGF-I was used as radioligand (23). The intra- and year range were invited by mail from a total population interassay CVs were 4% and 11% respectively. IGFBP-1 of 367 000 in this age range. Within each age group concentrations in plasma were determined according to (25±34, 35±44, 45±54, 55±64 and 65±74 years) the method of PoÂvoa et al. (24). The sensitivity of the 250 men and 250 women were randomly selected RIA was 3 mg/l, and the intra- and interassay CVs were from continuously updated population registers in 3% and 10% respectively. The leptin analysis was Norrbotten and VaÈsterbotten, the two northernmost performed using a double-antibody RIA with rabbit provinces of Sweden. In total 1921 subjects participated anti-human leptin antibodies, 125I-labelled human in the study (76.8%). Subjects were included whose leptin as tracer and human leptin as standard (Linco blood samples were taken between 0700 and 0900 h in Res., St Louis, MO, USA). Interassay CV was 1.9% at order to minimise the influence of diurnal rhythm of low levels (,5 ng/ml) and 3.2% at high levels (10± leptin (17), insulin (18) and IGFBP-1 (19). Subjects who 15 ng/ml). were pregnant, had diabetes or subclinical hypothyroid- ism, or had a history of prior myocardial infarction or stroke, or were using oestrogen replacement therapy, Statistical analysis oral contraceptives, or antihypertensive agents were All the main study variables were positively skewed excluded. Furthermore, women with irregular men- and, therefore, (ln) transformed values were used. struations were excluded. After an overnight fast, a Means (geometric for transformed values) with 95% 75 g oral glucose tolerance test was performed. Three confidence intervals (CI) are presented. Bivariate subjects were found to have previously unknown (Pearson's) and partial correlation coefficients were diabetes and were excluded from further analysis. calculated, adjusted for age and adiposity. One-way After these exclusions, 85 men and 73 women ANOVA analyses with adjustments for covariates were remained and thus formed the basis of this study. used, and significant differences between factor levels Sampling procedures have been described previously were evaluated after Bonferroni correction. Multiple (20). This study was approved by the Research Ethics linear regression analysis was performed with a Committee of UmeaÊ University. stepwise method. Introducing combination terms in the model tested interaction, and dummy variables the Anthropometric and biochemical analyses presence of group effects. The influence of potential outliers was tested by analysis of residuals and by Body mass index (BMI) was calculated as total body excluding subjects. Two-tailed tests were used and a weight in kilograms divided by the square of height in P-value ,0.05 was considered significant. All calcula- meters, and waist hip ratio (WHR) was calculated as tions were made with the statistical program SPSS the ratio of the circumference of the narrowest part of (Chicago, IL, USA) version 6.1 on a Macintosh the waist divided by the broadest part of the hip. All computer. measurements were taken with the subject standing upright and breathing lightly. Blood pressure was measured with the subjects in the sitting position Results after 5 min of rest using the random zero method. Plasma glucose was analysed by the hexokinase Baseline characteristics method (Boehringer Mannheim, Germany) on a Baseline characteristics of the study population are Hitachi 717 analyser (Tokyo, Japan). Insulin was shown in Table 1. Men had higher waist circumference, www.eje.org Downloaded from Bioscientifica.com at 09/25/2021 11:48:59PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2001) 144 Leptin, IGFBP-1, proinsulin and adiposity 285 WHR and fasting glucose levels in combination with lower leptin concentrations versus both pre- and -value P postmenopausal women. Furthermore, men had higher 0.001 ab 0.001 ab 0.001 abc 0.001 ab 0.001 abc , , , , , BMI and higher fasting proinsulin/insulin ratio com- pared with premenopausal women.
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