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

  1. Abel López-Bermejo12,
  2. Javad Khosravi3,
  3. José Manuel Fernández-Real12,
  4. Vivian Hwa4,
  5. Katherine L. Pratt4,
  6. Roser Casamitjana5,
  7. Maria M. Garcia-Gil2,
  8. Ron G. Rosenfeld46 and
  9. Wifredo Ricart12
  1. 1Diabetes, Endocrinology and Nutrition Unit, Dr. Josep Trueta Hospital, Girona, Spain
  2. 2Girona Institute for Biomedical Research, Girona, Spain
  3. 3Diagnostic System Laboratories, Toronto, Canada
  4. 4Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon
  5. 5Endocrine Laboratory, University Clinical Hospital, Barcelona, Spain
  6. 6Lucile Packard Foundation for Children’s Health, Palo Alto, California
  1. 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

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 [Si] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [KITT] 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 Si 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, Si, 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted May 2, 2006.
    • Received December 16, 2005.
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  1. doi: 10.2337/db05-1627 Diabetes August 2006 vol. 55 no. 8 2333-2339
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