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.

Insulin-Like Growth Factor Binding Protein–Related Protein 1 (IGFBP-rP1/MAC25) Is Linked to Endothelial-Dependent Vasodilation in High-Ferritin Type 2 Diabetes

“…The novel association between hemoglobin and IGFBP-rP1 was also documented for baseline values in these subjects (r ϭ 0.61, P ϭ 0.002), as well as in a cross-sectional analysis of a sample of nondiabetic men previously reported by us (n ϭ 113; r ϭ 0.28, P ϭ 0.003 [17]). …”

Association between differential gene expression and body mass index among endometrial cancers from The Cancer Genome Atlas Project

“…Unlike IGFBP 1–6, IGFBP7 has a relatively low affinity for IGF-1 while its affinity for insulin is up to 500-fold higher [26]. Elevated serum levels of IGFBP7 are linked to insulin resistance and Type II diabetes [26, 27]. Therefore, the increased expression of IGFBP7 in the mostly obese cohort may be secondary to their increased risk of insulin resistance rather than a direct or indirect effect from their tumor physiology.…”

The role of insulin‐like growth factor‐I and its binding proteins in glucose homeostasis and type 2 diabetes

“…Recent transgenic animal data, for example, demonstrate that overexpression of IGFBP-3 is associated with fasting hyperglycemia and impaired glucose tolerance (IGT) in mice [118,119]. The role of the remaining IGFBPs and IGFBP-rPs in glucose regulation have been little studied, albeit, it was recently reported that circulating IGFBP-rP1 levels are elevated in the presence of insulin resistance [120]. In addition, another study reported a significant correlation (r = 0.4, p < 0.0001) between fasting glucose levels and IGFBP-rP1 levels in cancer tissues [121].…”