IGF binding proteins

Insulin-like growth factors and their binding proteins mediate a number of biological processes that are critical to survival. There is a growing body of evidence that links various components of the insulin-like growth factor system to diabetes and its metabolic complications. The focus of this chapter is the protein insulin-like growth factor binding protein-2 (IGFBP-2) and its associations with diabetes and cardiovascular risk.

The insulin-like growth factor system comprises of the anabolic agents IGF-I and IGF-II, six high affinity IGF binding proteins (IGFBP-1 to IGFBP-6) and cell surface receptors that mediate IGF action.

The peptides IGF-I and IGF-II share significant structural and functional homologies with insulin. The insulin-like growth factor system has been evolutionarily well conserved, with homologous systems described in invertebrates [1]. IGF-I and IGF-II are expressed in most tissues and play vital roles in growth, development, reproduction and neoplasia.

Circulating IGF-I and IGF-II in the human body are bound to six high affinity binding proteins, described in order of their discovery as IGF binding proteins -1 to -6 (IGFBP-1 to IGFBP-6). These binding proteins have a number of structural similarities amongst them, in addition to remarkable homology for individual IGF binding proteins across a range of species. Total circulating IGF-I and IGF-II concentrations are estimated at about 100 nM, which is 1000 times the circulating levels of insulin. IGF-II concentration in serum vastly exceeds that of IGF-I [2]. Nearly all of this is bound within circulating complexes that include IGFBP-3 and the acid labile subunit (ALS), leaving leaving relatively small quantities of ‘free IGF’ that is available to interact with other IGF binding proteins and interact with IGF receptors [3]. It is this free IGF-I and IGF-II that mediate the potent biological roles of these growth factors in disease and health.

IGFBP-1, IGFBP-5 and IGFBP-6 are thought to have greater affinity for IGF-II over IGF-I, while the other three IGF binding proteins have comparable affinity for the two IGF ligands [4]. It is recognized that IGF binding proteins also interact with proteins other than IGF-I and IGF-II, and their biological actions are thought to extend well beyond their roles in IGF transport. Mouse knockout models suggest that loss of a single IGF binding protein could potentially lead to increases in the expression of other IGF binding proteins in an attempt to compensate for functional loss [5].

Individual IGF binding proteins are differentially expressed in various tissues and facilitate many complex biological processes. Despite some recent advances, our understanding of the IGF binding protein function remains inadequate. Most tissues express multiple IGF binding proteins, and their relative concentrations can determine local IGF bioavailability and action [6]. Furthermore, these binding proteins can undergo post-translational modifications in response to specific metabolic circumstances, which in turn can modify the extent of IGF binding and signaling, and in turn affect IGF action. IGF binding proteins may promote, inhibit or act independently of IGF action. Their complex interactions and the ability to regulate IGF bioavailability suggest a vital role for each of these proteins in human biology. While IGF-I and IGF-II share extensive structural and functional similarities with insulin, none of the IGF binding proteins can bind to insulin.

Human IGF binding proteins contain three structural domains- N-terminal and C-teminal domains that are conserved across the IGFBPs and a variable central region [7]. The amino (N) terminal region is the primary site for IGF interaction, while the carbooxy (C) terminal region contains the heparin and glycine-arginine-aspartate (RGD) regions that mediate cell surface binding. The variable central region is the primary site for post-translational modification like glycosylation and proteolysis.

IGFBP-2

IGF binding protein-2 (IGFBP-2) is the second most abundant IGF binding protein in man. It was first identified in 1986 from a rat hepatic cell line and has a molecular weight of 29.5kDa [8]. This protein has a 10-20 fold higher affinity for IGF-II over IGF-I [9]. The human IGFBP2 gene is contiguous to the IGFBP5 gene on chromosome 2 (2q33-34). This is not unique in the IGF system, as the IGF2 and insulin genes are also contiguous, as are the IGFBP1 and IGFBP3 genes.

Like some other IGF binding proteins, IGFBP-2 has IGF dependent as well as independent actions. IGFBP-2 has an arginine-glycine-aspartate (RGD) integrin receptor motif that allows IGF-independent cell membrane association and detachment. IGFBP-2 also contains a heparin-binding domain (HBD) that facilitates cell adhesion. The effects of these domains (a characteristic also seen in IGFBP-1) is that local concentrations of IGF-I and IGF-II may be increased at specific sites.

The precise regulation of this protein remains uncertain, though insulin, IGF-II, glucocorticoids and sex steroids have been variously implicated in this role [10][11][12]. Unlike IGFBP-1, which is acutely and profoundly suppressed by insulin concentration (and therefore affected by meal intake), IGFBP-2 is only elevated following prolonged fasting or protein restriction. Circulating levels increase with age.

The intersection of biological roles for IGFBP-2 and other components of the IGF system in growth and development, ageing, neoplasia, reproduction and metabolism perhaps explains a number of conflicting associations for IGFBP-2 in health and disease.

IGFBP-2 is a marker of insulin sensitivity, and low circulating IGFBP-2 concentration correlates with presence of the metabolic syndrome [13]. In a cohort of middle-aged women, high IGFBP-2 concentration was prospectively associated with lower rates of incident type 2 diabetes [14]. Levels are also elevated in poorly controlled type 1 diabetes, with very gradual normalization in response to insulin treatment [15]. High baseline IGFBP-2 concentration in type 2 diabetes also predicts longitudinal increases in high density lipoprotein (HDL) cholesterol [16].

Intriguingly, a high baseline circulating IGFBP-2 is also associated with a longitudinal deterioration in renal function in diabetes [17]. It is unclear whether this is merely an association, or whether there is a causative role for IGFBP-2 in renal deterioration. While IGF-II and IGFBP-2 are expressed in the kidney, the actions of these proteins in renal biology remain to be elucidated.

Further suggestions of adverse associations of IGFBP-2 come from studies in elderly community dwelling individuals that suggest that IGFBP-2 may be a marker of decreased bone mineral density and impaired functional ability [18]. Intriguingly, while IGFBP-2 is associated with a favourable metabolic profile, studies in elderly individuals suggest that IGFBP-2 is also a marker of increased mortality [19][20]. The mechanisms of this association remain unclear, but it is possible that this is a consequence of decreased IGF bioavailability as a result of high circulating IGFBP-2 concentration. IGFBP-2 has also been proposed as a marker of tumour progression in cancer but the evidence for this remains somewhat conflicting.

In summary, IGFBP-2 is associated with potentially favourable changes in cardiovascular risk markers, but studies in elderly subjects paradoxically also suggest an association for this protein with increased mortality. Further research into IGFBP-2 and its biological interaction within and outside the IGF system may help explain these findings and their pathophysiological relevance.

References

  1. ^ Chan SJ et al. Evolution of the insulin superfamily: cloning of a hybrid insulin/insulin-like growth factor cDNA from amphioxus. Proceedings of the National Academy of Sciences of the United States of America 1990; 87(23):9319-9323.

  2. ^ Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocrine Reviews 1989; 10(1):68-91.

  3. ^ Baxter RC et al. High molecular weight insulin-like growth factor binding protein complex. Purification and properties of the acid-labile subunit from human serum. Journal of Biological Chemistry 1989; 264(20):11843-11848.

  4. ^ Rajaram S et al. Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocrine Reviews 1997; 18(6):801-831.

  5. ^ Wood TL et al. Selective alterations in organ sizes in mice with a targeted disruption of the insulin-like growth factor binding protein-2 gene. Molecular Endocrinology 2000; 14(9):1472-1482.

  6. ^ Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocrine Reviews 1995; 16(1):3-34.

  7. ^ Hwa V et al. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocrine Reviews 1999; 20(6):761-787.

  8. ^ Mottola C et al. Purification and amino-terminal sequence of an insulin-like growth factor-binding protein secreted by rat liver BRL-3A cells. Journal of Biological Chemistry 1986; 261(24):11180-11188.

  9. ^ Shimasaki S, Ling N. Identification and molecular characterization of insulin-like growth factor binding proteins (IGFBP-1, -2, -3, -4, -5 and -6). Progress in Growth Factor Research 1991; 3(4):243-266.

  10. ^ Nagao K et al. Insulin administration suppresses an increase in insulin-like growth factor binding protein-2 gene expression stimulated by fasting in the chicken. British Poultry Science 2001; 42(4):501-504.

  11. ^ Chesik D, De Keyser J. Progesterone and dexamethasone differentially regulate the IGF-system in glial cells. Neuroscience Letters 2010; 468(3):178-182.

  12. ^ Takeo C et al. Identification of Igf2, Igfbp2 and Enpp2 as estrogen-responsive genes in rat hippocampus. Endocrine Journal 2009; 56(1):113-120.

  13. ^ Heald AH et al. Insulin-like growth factor binding protein-2 (IGFBP-2) is a marker for the metabolic syndrome. Experimental and Clinical Endocrinology and Diabetes 2006; 114(7):371-376.

  14. ^ Rajpathak SN et al. Insulin-like growth factor axis and risk of type 2 diabetes in women. Diabetes 61(9):2248-54, 2012.

  15. ^ Bereket A et al. Insulin-like growth factor-binding protein-2 and insulin: Studies in children with type 1 diabetes mellitus and maturity-onset diabetes of the young. Journal of Clinical Endocrinology and Metabolism 1995; 80(12):3647-3652.

  16. ^ Narayanan RP et al. Insulin-like growth factor-II and insulin-like growth factor binding protein-2 prospectively predict longitudinal elevation of HDL-cholesterol in type 2 diabetes. Annals of Clinical Biochemistry 51 (4) (pp 468-475), 2014;July.

  17. ^ Narayanan RP et al. IGFBP2 is a biomarker for predicting longitudinal deterioration in renal function in type 2 diabetes. Endocrine Connections 2012; 1(2):95-102.

  18. ^ Brugts MP et al. Low circulating insulin-like growth factor I bioactivity in elderly men is associated with increased mortality. Journal of Clinical Endocrinology & Metabolism 2008; 93(7):2515-2522.

  19. ^ Hu D et al. Serum insulin-like growth factor-1 binding proteins 1 and 2 and mortality in older adults: The health, aging, and body composition study: Brief reports. Journal of the American Geriatrics Society 57 (7) (pp 1213-1218), 2009;July.

  20. ^ van den Beld AW et al. High IGFBP2 levels are not only associated with a better metabolic risk profile but also with increased mortality in elderly men. Eur J Endocrinol 2012; 167(1):111-117.

Comments

Nobody has commented on this article

Commenting is only available for registered Diapedia users. Please log in or register first.