IGFBP2 is a biomarker for predicting longitudinal deterioration in renal function in type 2 diabetes

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Abstract

Objective

Insulin-like growth factors are implicated in the development of diabetic nephropathy. IGF-binding protein 2 (IGFBP2) and IGF2 are expressed in the kidney, but their associations with diabetic nephropathy are unclear. We therefore tested the hypothesis that circulating levels of IGF2 and IGFBP2 predict longitudinal renal function in individuals with type 2 diabetes.

Design and methods

IGFBP2 and IGF2 measurements were performed in 436 individuals (263 males) with type 2 diabetes. Linear mixed-effect regression analysis was used to model the relationship between plasma IGFBP2 concentration and longitudinal changes in estimated glomerular filtration rate (eGFR) over an 8-year period. Analyses were also performed for IGF1, IGF2, IGFBP1 and IGFBP3 concentrations as predictors of longitudinal renal outcomes.

Results

High IGFBP2 concentration at baseline was associated with a decreased eGFR over an 8-year period ( β=−0.02, (95% confidence interval −0.03 to −0.01), P<0.001). High IGFBP1, IGFBP2 and IGFBP3 were also associated with low baseline eGFR concentration.

Conclusion

This study demonstrates that IGFBP2 is a predictor of longitudinal deterioration of renal function in type 2 diabetes.

Related collections

Most cited references 27

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Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome.

A Rudenski, Peter G Gibson, Annie S. Anderson … (2006)

IGFs and their binding proteins are increasingly recognised as important in understanding the pathogenesis of cardiovascular disease. Low IGFBP-1, particularly coupled with low IGF-I, is associated with increased cardiovascular risk. In relation to structural and regulatory parallels between IGFBP-1 and - 2 we have now examined the hypothesis that IGFBP-2 may be a marker for cardiovascular risk. Fasting IGFBP-2, IGFBP-1, IGFBP-3, IGF-I, IGF-II, insulin, C-peptide, glucose, lipids, NEFAs, and HbA1c were measured in a cohort of 163 patients with type 2 diabetes. Individuals were categorised according to the presence or absence of the metabolic syndrome. Patients with the metabolic syndrome had a lower IGFBP-2 concentration. Low circulating IGFBP-2 was associated with elevated fasting glucose (rho = - 0.23, p = 0.003). IGFBP-2 correlated negatively with triglycerides (rho = - 0.19, p = 0.01) and LDL-cholesterol (rho = - 0.20, p = 0.01), and positively with insulin sensitivity (HOMA-S) (rho = 0.26, p = 0.02). Multivariate logistic regression demonstrated that low IGFBP-2 was independently associated with an increased risk of the metabolic syndrome (OR 0.31 [95 % CI 0.11 - 0.90]; p = 0.03). IGFBP-3 did not differ according to the presence or absence of metabolic syndrome. Low IGFBP-2 is associated with multiple cardiovascular risk factors similarly to IGFBP-1. Such associations were not apparent for IGFBP-3. Lack of marked prandial regulation of IGFBP-2, in contradistinction to IGFBP-1, may make IGFBP-2 a more robust biomarker for identification of insulin-resistant individuals at high cardiovascular risk in epidemiological studies.

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Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5 and -6).

N Ling, S Shimasaki (1990)

Six different insulin-like growth factor binding proteins (IGFBPs) have been identified by molecular cloning of their cDNAs from rat and human tissues and designated as IGFBP-1, -2, -3, -4, -5 and -6. The total number of amino acid residues for the mature rat BPs ranges from 201 for IGFBP-6 to 270 for IGFBP-2, while the human homologs range from 216 for IGFBP-6 to 289 for IGFBP-2. Except for IGFBP-6, all rat and human IGFBPs contain 18 homologous cysteines; twelve are located at the N-terminal and span approximately one-third of the total amino acid sequence, while the remaining six are distributed at the C-terminal and span the last one-third of the protein sequence. Both rat and human IGFBP-4 possess two extra cysteines at the mid-region of the molecule. By contrast, rat and human IGFBP-6 contain only 14 and 16 cysteines, respectively. Absence of the two and four cysteines in the N-terminal region in the human and rat IGFBP-6 resulted in the deletion of the invariant Gly-Cys-Gly-Cys-Cys sequence which is present in all the other five IGFBPs. Both rat and human IGFBP-3 possess multiple N-linked glycosylation sites at the mid-region of the molecule, which accounts for their apparent molecular size being larger than the calculated molecular weight, based on the amino acid sequence. One potential N-linked glycosylation site is located at the mid-region of rat and human IGFBP-4, whereas only human but not rat IGFBP-6 possesses one N-linked glycosylation site at the extreme C-terminal of the molecule. An RGD sequence is found in the C-terminal of IGFBP-1 and -2. In this short review, updated information on the structural identification and molecular cloning of the six IGFBPs will be presented. In addition, the potential regulation of the BPs at the transcriptional and translational levels will be discussed.

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Variables controlling the secretion of insulin-like growth factor binding protein-2 in normal human subjects.

Erin Snyder, D Clemmons, Stephen Busby (1991)

Insulin-like growth factor binding protein-2 (IGFBP-2) is one of a family of IGFBPs that are present in extracellular fluids, and binds both IGF-II and IGF-I with high affinity. These studies were conducted to determine the nutritional and hormonal variables that regulate plasma IGFBP-2 concentrations in humans. The mean plasma IGFBP-2 concentration for 38 normal adult subjects was 150 +/- 61 micrograms/L and was 4.7-fold greater than their mean fasting IGFBP-1 value. Mean IGFBP-2 values in cord sera of 26 normal term infants was 3.8-fold greater than the normal adult mean value. Likewise, the mean value for 44 hypopituitary adults was increased 2-fold compared to normal. There was no suppression of IGFBP-2 values in acromegaly. Normal adult subjects showed minimal fluctuations (less than 2-fold changes) in plasma IGFBP-2 concentrations during a 48-h sampling period. These changes were significantly less than the changes that occurred in plasma IGFBP-1 during the same interval. Plasma IGFBP-2 did not change significantly post prandially or after a glucose infusion. Extreme insulin deficiency, after 9 days of fasting, was associated with a 1.7-fold increase in plasma IGFBP-2. Administration of GH, which is known to cause a major decrease in plasma IGFBP-1 and in IGFBP-2 in hypophysectomized animals, did not result in a change in calorically restricted normal adult subjects, suggesting that a normal caloric intake is required for GH to suppress IGFBP-2. In summary, these results show that plasma IGFBP-2 is regulated differently than IGFBP-1. Acute stimulation of insulin secretion does not suppress IGFBP-2, and there is much less daily fluctuation compared to IGFBP-1. These findings suggest that plasma IGFBP-2 levels are more stable than IGFBP-1, and therefore IGFBP-2 may serve as a larger reservior that is available for IGF transport.

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Author and article information

Journal

Journal ID (nlm-ta): Endocr Connect

Journal ID (iso-abbrev): Endocr Connect

Journal ID (publisher-id): EC

Title: Endocrine Connections

Publisher: BioScientifica (Bristol )

ISSN (Electronic): 2049-3614

Publication date (Electronic): 24 October 2012

Publication date Collection: 01 November 2012

Volume: 1

Issue: 2

Pages: 95-102

Affiliations

[1 ]Vascular Research Group The University of Manchester Manchester, M13 9PTUK

[2 ]School of Community Based Medicine, The University of Manchester Manchester, M13 9PTUK

[3 ]Centre for Integrated Genomic Medical Research, The University of Manchester Manchester, M13 9PTUK

[4 ]Cardiovascular Research Group The University of Manchester Manchester, M13 9PTUK

[5 ]Endocrinology and Diabetes, Faculty of Medical, Human and Life Sciences The University of Manchester Manchester, M13 9PTUK

[6 ]Salford R&D, Salford Royal Hospital NHS Foundation Trust Salford, M6 8HDUK

[7 ]Department of Endocrinology and Diabetes Salford Royal Hospital NHS Foundation Trust Salford, M6 8HDUK

Author notes

Correspondence should be addressed to R P Narayanan B-202, Clinical Sciences Building, Salford Royal NHS Foundation Trust, Stott Lane, Salford M6 8HD, UK Email ram.narayanan@ 123456manchester.ac.uk

Article

Publisher ID: EC120053

DOI: 10.1530/EC-12-0053

PMC ID: 3681324

PubMed ID: 23781310

SO-VID: 4fa1c8fa-7e96-4863-a534-aa1c79e329d4

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 21 August 2012

Date accepted : 19 September 2012

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