title: Insulin resistance is associated with increased serum concentration of IGF-binding protein-related protein 1 (IGFBP-rP1/MAC25).
abstract: 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.
authors.affiliation: Unit of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta Hospital, Av. Francia s/n, 17007 Girona, Spain. uden.alopez@htrueta.scs.es
authors.forename: Abel
authors.initials: A
authors.lastname: López-Bermejo
authors.forename: Javad
authors.initials: J
authors.lastname: Khosravi
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernández-Real
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Pratt
authors.forename: Roser
authors.initials: R
authors.lastname: Casamitjana
authors.forename: Maria M
authors.initials: MM
authors.lastname: Garcia-Gil
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
authors.forename: Wifredo
authors.initials: W
authors.lastname: Ricart
mesh_terms: D052242:Adiponectin / Q000097:blood; D000328:Adult; D000375:Aging; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000032:analysis; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005215:Fasting; D005951:Glucose Tolerance Test; D006801:Humans; D007249:Inflammation / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008297:Male; D008875:Middle Aged; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D012044:Regression Analysis
chemical_list: D052242:Adiponectin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018969:Insulin-Like Growth Factor Binding Proteins; D047889:Receptors, Tumor Necrosis Factor, Type II; C102529:insulin-like growth factor binding protein-related protein 1; D007334:Insulin-Like Growth Factor I; D002097:C-Reactive Protein