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Insulin Resistance Is Associated With Increased Serum Concentration of IGF-Binding Protein–Related Protein 1 (IGFBP-rP1/MAC25)

¹ Diabetes, Endocrinology and Nutrition Unit, Dr. Josep Trueta Hospital, Girona, Spain
² Girona Institute for Biomedical Research, Girona, Spain
³ Diagnostic System Laboratories, Toronto, Canada
⁴ Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon
⁵ Endocrine Laboratory, University Clinical Hospital, Barcelona, Spain
⁶ Lucile Packard Foundation for Children’s Health, Palo Alto, California

Address correspondence and reprint requests to Abel López-Bermejo, MD, Unit of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta Hospital, Av. Francia s/n, 17007 Girona, Spain. E-mail: uden.alopez{at}htrueta.scs.es

Abbreviations: CRP, C-reactive protein; IGFBP, IGF-binding protein; IGFBP-rP, IGFBP-related protein; sTNFR, soluble tumor necrosis factor receptor; TNF, tumor necrosis factor

IGF-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-rP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [S_i] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [K_ITT] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-rP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-rP1 exhibited decreased S_i and adiponectin (both P < 0.01) as well as increased CRP and sTNFR2 (both P < 0.05). Circulating IGFBP-rP1 was also found to be increased in previously undiagnosed type 2 diabetic patients (P = 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-rP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-rP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-rP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S_i, sTNFR2, and age stood as independent predictive variables of IGFBP-rP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-rP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans.

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				A. Lopez-Bermejo, J. Khosravi, W. Ricart, A. Castro, V. Hwa, K. L. Pratt, R. Casamitjana, R. G. Rosenfeld, and J. M. Fernandez-Real Insulin-Like Growth Factor Binding Protein-Related Protein 1 (IGFBP-rP1/MAC25) Is Linked to Endothelial-Dependent Vasodilation in High-Ferritin Type 2 Diabetes Diabetes Care, June 1, 2007; 30(6): 1615 - 1617. [Full Text] [PDF]